Clinical Cardiology: A Disease Specific Approach Achyut Sarkar
INDEX
Page numbers followed by b refer to box, f refer to figure, fc refer to flowchart, and t refer to table.
A
Abdomen, swelling of 330
Absent pulmonary valve 138, 232, 233, 234f
syndrome 232, 232b, 234t
Acidosis 204
Activated partial thromboplastin time 274
Acute rheumatic fever 3, 5, 10, 11, 14t, 15t, 20, 27, 74, 455
diagnosis of 11t
resurgence of 7
Acute vasodilatory test 356
Adventitia 315
Alcohol septal ablation 195, 195t
Alveolar edema 439
Alzheimer's disease 341
Amato's classification 303
American College of Cardiology 175, 193
American College of Rheumatology Criteria 317b
American Heart Association 9, 9b, 10, 12, 22, 23t, 193, 299, 455
guideline 11
revision 9
Amoxycillin 21
Amplatzer duct 366
occluder 366f, 545
Amyl nitrite 101, 102, 192
inhalation 100
Amyloid
fibrils 345
light-chain 341
protein 341, 344
transthyretin 341, 345
Amyloidosis
classification of 341t
hemodialysis-associated 342
prognosis of 342
prognostic staging of 343t
Anacrotic pulse 80
Anemia 10, 272, 274
Aneurysm 141, 149
apical 189, 492f
diameter 152, 366f
formation 156, 172
unruptured 152
Angina 35, 44, 79, 95, 124126
mechanism of 95b
Angiogenesis 72
degradation factors 293f
stimulator level 293f
Angiogram
coronary 65
pulmonary 400
Angiographic classification 564t
Angiography 102, 527
selective 559
Angiotensin-converting enzyme 347
inhibitor 55, 112
Angiotensin-receptor blocker 55, 176
Ankle-brachial index 302
Ankylosing spondylosis 93
Annular dilatation 472
Annular hypoplasia 234
Annuloplasty 68, 69
devices 114
Annulus 49, 63
dilatation 49
nonplanar shape of 114
paradoxus 509, 509f
reversus 509, 510f
Antegrade Inoue technique 41
Anticardiolipin syndrome 47
Anticoagulant
indications of 41b
protocol 41
Antideoxyribonuclease 17, 17t
Anti-M protein antibody 9f
Antiplatelet protocol 384
Antistreptolysin-O 16, 17
antibody test 17
normal range of 17t
Anti-tumor necrosis factor 320
Aorta 242, 243, 280, 282, 532, 556
abdominal 490
diseases of 299
near atresia of 312
overriding of 208
posterior 242f
Aortic allograft 185
Aortic annulus 13, 175, 475f
functional 93
Aortic arch 254, 263, 442f
anomaly 263
interruption 138
right-sided 445
Aortic atresia 138
Aortic click 216
Aortic coarctation 300
Aortic component 81, 82, 362, 372
Aortic cusp, prolapse of 213
Aortic diastolic pressure 534f
Aortic dissection 93, 172, 173, 209
Aortic elastic tissue 149f
Aortic enlargement 102
Aortic flow pattern, abdominal 503f
Aortic isthmus 263
Aortic knob 436, 447
Aortic leaflet
absence of 174
congenital absence of 93
Aortic orifice 477
Aortic pressure
curve 547, 548f
pulse 547
waveform 518
Aortic reflux 123
Aortic regurgitation 13, 32, 36, 38, 48, 73, 92, 95b, 99, 104, 104f, 121, 122, 122t, 123, 124t, 150, 152, 171173, 179, 191, 209, 226, 307, 360, 419, 442, 480482, 494, 518, 533
angiographic classification of 535t
angiography 535
assessment of 123, 133
congenital 93, 94, 174
dominant 132
Doppler features of 457
echocardiographic 122
etiology of 92b
functional classification of 93t, 94f
index 534
mechanism of 173b
murmur 99, 100, 122, 133, 362t
severe 92, 124, 419, 480f, 481f, 533f, 534f
Aortic root 149f, 282f
angiogram 544, 553
angiography 535, 559
dilatation 173
disease 483
treatment 177
Aortic sclerocalcific disease 92
Aortic sclerosis 84
Aortic sinus diameter, Z-score 176
Aortic stenosis 32, 72, 76, 77fc, 80, 82f, 88, 89fc, 93, 121, 124, 125, 125t, 126, 126t, 169b, 172, 173, 196, 196t, 244, 308, 419, 422, 475, 521, 528, 531, 532, 547, 548
assessment of 528
asymptomatic 84b, 87b
congenital 74, 132, 419
continuous wave Doppler jet of 476f
dominant 132
Doppler study 476
etiology of 72b, 475, 478
grading 80t, 176t
leads 78
low-gradient 75, 75f, 76, 76fc, 77, 478
mild 528f
mild-to-moderate 84
pseudo-severe 76
severe 84, 128t, 419, 528f, 529f
severity of 83t, 475
stages of 85t
subvalvular 132, 179, 179b, 180
symptomatic 84b
true severe 76
two-dimensional feature 475
Aortic stenting 312
Aortic surgery 172
Aortic translocation 279
Aortic valve 13, 38, 103, 169, 240, 246, 475, 494
area 76, 77, 86, 476, 477, 529
measurement 86
calcification 86, 86t, 419
cardiac damage 85t
closure 392
disease 42
mixed 132, 133
immobile 476f
isolated 13
orifice 75
repair 103
replacement 72, 87, 87b, 103, 127, 133, 172, 229
indication of 104b
sclerosis 172
stenosis 73
superior 552f
thickening 318
tissue, portion of 552
Aortic valvular click 308
Aortic valvulitis 13, 457
Aortic vascular click 216t
Aortico-left ventricular tunnel 93, 174
Aortitis 92
Aortogram 148f, 448f, 544f, 553, 559, 563f
ductus, descending 559f
Aortopathy 173, 174
Aortopulmonary artery shunt 220
Aortopulmonary collateral artery 259f, 559, 559f
multiple major 442
Aortopulmonary window 146148, 148f, 436, 543, 544
classification of 147f
Apex cardiogram 81f
Apical diastolic flow murmur 141, 144
Apical four-chamber view 484f
Apical hypertrophic cardiomyopathy 189, 492f
criteria of 189b
Apical impulse 141, 214, 257
Aplasia 371
Apoptosis 48
Arch
hypoplasia 306
vessel anatomy 563
Arrhythmia 228, 292, 376
atrial 228, 346, 375
Arrhythmic sudden cardiac death 228, 228b
Arterial bruit 316
Arterial hypertension
hyperkinetic pulmonary 144
severe pulmonary 440
Arterial oxygen saturation 557
Arterial pressure 192
curve 521f
Arterial pulse 244
Arteritis, tubercular 314, 314t
Artery
brachiocephalic 499f
mixed pulmonary 542
nonconfluent pulmonary 255
pressure, femoral 531f, 534f
shunt, subclavian-pulmonary 219
single pulmonary 255
stenosis 389
subclavian 309f
Arthiritis 12
Arthralgia 9
Arthritis 12, 14
poststreptococcal reactive 15, 15t
rheumatic 14
rheumatoid 15, 32
Arthropathies 300
Ascending aorta 74f, 185, 209, 267f, 284f, 447
diameter of 304f, 504
Aspirin 19
Atheroembolism 300
Atherosclerosis 93, 150
Athlete's heart 196, 196t
Atresia 212, 304
Atria, fibrosis of 34
Atrial amyloidosis, isolated 342
Atrial contraction 39, 507f
Atrial diastole 538
Atrial dilation 34
Atrial enlargement 413
Atrial fibrillation 33, 34, 4044, 55, 56, 59, 70, 76, 85, 109111, 122, 127, 189, 195, 385, 461, 524, 537
effect of 39, 117
Atrial natriuretic peptide 330
Atrial pressure 566
Atrial septal defect 37, 38, 42, 138, 170, 209, 288, 306, 354, 368372, 372b, 376f, 379, 381t, 382, 383, 391, 436, 461, 496
anatomical classification 368
balloon sizing 381
classification of 368, 368b
diagnostic evaluation 375
echocardiogram 376
genetic 370
grading 371, 371t
large 383
management 376
margins 379f
multiple 383
natural history 374
physical examination 371
physiology 371
prevalence 368
prognosis 374
surgical closure for 377b
symptom 371
types of 369f
Atrioventricular gradient 526, 536
Atrioventricular septal defect 108, 138, 209, 232, 280, 306, 496
classification of 370t
Atrioventricular valve 245, 556
regurgitation 286
Auscultation 36, 151, 161, 173, 233, 244, 301, 308
dynamic 39, 100, 141, 192
Austin flint murmur 95, 99101, 101t, 122
Autologous pericardial tube 259f
Autosomal dominant familial elastin arteriopathy 182
Azathioprine cyclophosphamide 347
Azithromycin 21
B
Balloon assisted technique 382
Balloon coarctoplasty 311, 312
Balloon mitral
valvoplasty 462, 463, 466
valvotomy 42, 43, 43t, 44
long-term outcome of 42
valvuloplasty 41, 132, 522
Balloon pulmonary valvuloplasty 395
Basement membrane collagen fibers 9f
Becker's sign 97
Behçet's syndrome 300
Benzathine penicillin 21
interval of 22
Berman balloon flotation catheter 559
Beta-blocker 40, 55
evaluation of survival trial 66
Beta-hemolytic streptococci 3, 9
Biatrial enlargement 415
Bicommissural pulmonary valve 278
Bicuspid aortic valve 9294, 150, 170174, 176b, 179, 182, 226, 483
consortium classification 170f
eccentricity index of 175f
echo feature of 174
Bicuspid valve 94, 173, 216
complication 174
types of 171t
Bidirectional cavopulmonary shunt 287
Bidirectional Glenn 159, 287, 288
Bilateral femoral artery technique 531
Bilateral renal artery involvement 564f
Biliary atresia 159
Bioprosthetic valve degeneration 92
Biopsy 344, 347
Biventricular endomyocardial fibrosis 340
Bjork modification 287
Blalock-Taussig shunt 219, 288, 442
advantages of 219b
complications of 219b
Bleeding 79
diastases 272, 272t, 275
gastrointestinal 79
gingival 272
Blood
brain natriuretic peptide 55
pressure 79, 81, 89, 96, 316
diastolic 534
maintain 330
systolic 96, 534
streaked sputum 35
urea nitrogen, higher 113
viscosity 271
Blurred vision 272
Body surface area 56
Bone
Paget's disease of 72
scintigraphy 344
Bonnet's classification 303t
Bottleneck Fontan circuit 286f
Bradyarrhythmia 345
Brain natriuretic peptide 140
Branch pulmonary artery 496, 498, 562
pattern 255t
Breathlessness, exertional 339
Brockenbrough-Braunwald-morrow sign 547
Bronchial situs 430f
Buerger's disease 300
C
Calcific aortic stenosis 72, 73b, 132, 396, 478, 478f
calcium grade in 478t
pathogenesis of 73f
Calcific aortic valve disease, prevalence of 73
Calcification 72
Calcium, absence of 114
Camelback appearance 526
Cannonball pulse 96
Carabello's sign 528, 529f
Carcinoid 108
disease 32
syndrome 119
Cardiac amyloidosis 341, 341b, 343345, 345fc
classification 341
diagnosis 344
investigation 343
management 344
pathobiology 341
prognosis 342
Cardiac border 443
Cardiac catheterization 175, 184, 234, 334, 393, 566, 576
and angiocardiography 393
and angiography 142, 148, 152, 156, 163, 559, 562
Cardiac compression 329
Cardiac computed tomography 258, 278, 334t
Cardiac death, sudden 181, 187, 193, 194, 196, 228
Cardiac dysfunction 344
Cardiac enlargement 102, 376
Cardiac erosion 384
Cardiac implantable electronic device 108, 113, 113fc
Cardiac index and left ventricular function 522
Cardiac involvement 318, 342
Cardiac light-chain amyloidosis 342b
Cardiac magnetic resonance 347
imaging 171, 192, 228, 258, 278, 309, 309f, 347
Cardiac mitral regurgitation 188
Cardiac output 78, 537, 557
Cardiac resynchronization therapy 59, 64
Cardiac sarcoidosis 345, 346, 346f, 347
diagnosis of 347
etiopathogenesis 346
investigation 346
management 347
prevalence 345
prognosis 346
signs of 346
Cardiac silhouette 432, 442, 443, 445, 451
transverse diameter of 430
volume 431
Cardiac size 430, 442, 443
Cardiac Society of Australia and New Zealand 22
Cardiac tamponade 571, 573
Cardiac volume 431f
Cardiomyopathy 188
dilated 62, 155
hypertrophic obstructive 50, 180, 196t, 548
nonobstructive hypertrophic 195
Cardiophrenic angle, acute 435f
Cardiopulmonary exercise testing 55, 56, 227, 228
Cardiothoracic ratio 430, 430f, 450
Cardiovocal syndrome 35
Carditis 7, 912
clinical evidence of 12b
recurrent 12
smoldering 13
subclinical 8, 12, 13, 455
Carey Coombs murmur 13
Carotid artery 301, 499, 499f
diameter of 307
Carotid bodies 203
Carotid pulse 80t, 190, 196
tracing 80
Carotid subclavian artery index 504
Carotid upstroke, delayed 125, 126
Carpentier classification 50, 51f, 108
Carpentier secondary mitral regurgitation 67
Carvallo's sign 112
CATCH 22 syndrome 264
Catheter gradient 390t
Catheter tip 532
Central aortic arterial waveform 518t
Central aortic pressure 518, 533
curve 528, 533f
tracing 518, 518f
Central nervous system involvement 7
Central pulmonary artery 256, 559
complete absence of 258
Cephalization 439
Cephalosporin 21
Cerebral
bleeding, acute 220
embolism 34
Cerebrovascular accident 273
Cervical lymphadenitis, anterior 21
Chamber collapse 571, 572
Char syndrome 140
Chest
computed tomography of 163f
pain 35
trauma 159
X-ray of 40, 55, 85, 102, 112, 117, 123126, 131, 133, 141, 151, 156, 162, 162f, 234, 237, 244, 258, 266, 309, 376f, 393f, 427, 429, 432f, 445, 451f
Chordae 49
Chordal apparatus, muscularization of 48
Chordal lengthening 49
Chordal replacement 68, 69
Chorea 912, 15
Choussat's ten commandments 289b
Chromosomal abnormities 211
Chronic aortic regurgitation
mild-to-moderate 419
Carpentier etiopathological classification of 50
Chronic obstructive pulmonary disease 415, 508
Chylopericardium 293
Chylothorax 310
Circle of Willis, aneurysm of 310
Clarithromycin 21
Cleft
mitral valve 48
tricuspid valve 108
Clindamycin 21, 22
Clockwise depolarization 408
Closed mitral commissurotomy 4143
Coagulation function, abnormal 272
Coandă effect 183
Coarctation of aorta 150, 173, 179, 182, 240, 303, 447, 503, 563
indirect clues 503
measurement 504
stent trial study 311
two-dimensional imaging 503
Coarctoplasty, surgical 312
Cohn theory 18
Collagen vascular disease 47
Collateral circulation, acquired 558
Collins syndrome 371
Color flow imaging 469, 480
Commissural calcium score 463, 464
Common arterial trunk 138, 252, 252f
Complex atrial septal defect 381, 382b
Complex congenital cyanotic heart disease 253, 277, 278
spectrum 277, 277b
Computed tomography
angiography 302
guided bicuspid aortic valve classification 171f
scan 175
Conal septum, Tear-drop appearance of 555f
Conal tissue 245
Concomitant coronary artery disease 77
Conduction tissue 263
Confluent branch pulmonary artery 498f
Confluent hypoplastic pulmonary arteries 258
Confluent pulmonary artery 255, 258, 267f
Congenital anomalies registry
angioplasty of 311
valvuloplasty of 311
Conjunctivitis 21
Connective tissue disease 119
Constrictive pericarditis 327, 327t, 331f, 332, 333, 333f, 450, 450f, 451, 506, 540, 540t, 566, 569, 570, 572
clinical signs 331
effective 329
electrocardiography 334
etiology of 327
hemodynamic 566
investigation 334
management 334
pathophysiology 328
symptoms 330
treatment of 334
types of 329, 329b
Continuous flow pattern 503f
Continuous murmur 135, 216, 249, 251, 257, 265, 308, 445, 542
Continuous wave Doppler 471, 482
Contrast saline study 162
Cor pulmonale 111
Cor triatriatum 32
Cormier score 463, 463t
Coronary arteriovenous fistula 154, 154b, 155, 156
acquired 155
closure of 157f
complications of 156b
Coronary artery 93, 154, 209, 245, 262, 283f, 562, 564
abnormalities 209
anomalies 182
bypass grafting 58, 65, 68, 87, 104, 155, 185
disease 88
involvement 318
origin of 500
single 396
stenosis 184
Coronary sinus 114, 154, 369, 370f
atrial septal defect 369
Coronary syndrome, acute 47
Corrigan's pulse 95, 96
Corrigan's sign 95
Coryza 21
Costocervical trunk 448
Cough 35
Counterclockwise
depolarization 408, 426
loop 413f
C-reactive protein 912
Crista
supraventricularis 551f
terminalis 369
Crochet hook 375
Crochet sign 375f
Cyanose tardive 371
Cyanosis 212, 253, 257, 264, 265, 275, 371, 372b, 391
central 163, 391
chronic 204
Cyanotic burden 202, 257
Cystic fibrosis 159
Cystic medial necrosis 150
D
D'cruz sign 507
Damus operation, original 284f
Damus-Kaye-Stansel technique 280, 283, 284
Dancing carotid 95
Danon disease 188
De Musset's sign 97
Dennison's sign 97
Dental hygiene 176
Descending aorta 303, 304f, 447
post-coarctation dilation of 448f
Dexfenfluramine 120
Dextrocardia 430
Diaphragmatic pericardium 334
Diarrhea 21
Diastasis 533, 534, 534f
Diastolic dysfunction 343, 510, 567
Diastolic filling
period 521, 521f, 531
sound 333
Diastolic pressure 548f
equalization of 540, 572
Dicrotic notch 80f
DiGeorge syndrome 206, 211, 232, 264
Digital subtraction angiography 163
Digoxin 345
Distal pulmonary artery 551
Distal transverse arch 504f
Disuse hypofunction 291
Dizziness 272
Dobutamine stress echocardiography 76
Dopaminergic agonists 120
Doppler
flow 148
gradient 75, 489
information 469, 471
interrogation 504
parameters 505b
spectrum 486, 498f
study 510
Double antiplatelet therapy 384
Double-inlet left ventricle 285
Double-lumen catheter 532
Double-outlet right ventricle 201, 239, 240, 244, 277, 279, 280, 285, 411, 413, 425, 497, 550, 554
classifications of 239
pulmonary stenosis 247
subaortic ventricular septal defect pulmonary stenosis 239, 243
Down syndrome 211
Drug effect 119, 120
Dry ulcer 301
Ductal aneurysm 141
Ductal constriction 140
Ductal occluder 143
Ductal shock 305
Ductal theory 305
Ductus arteriosus 263
Ductus occluder 143f
Ductus, agenesis of 138
Duroziez's murmur 97
Duroziez's sign 95
Dysplasia, fibromuscular 300
Dysplastic disease 300
Dysplastic leaflets 182
Dysplastic myocardium 179
Dysplastic pulmonary valve 395
stenosis 394
Dyspnea 33, 51, 78, 95, 124126 190, 202, 203, 371, 390
class of 33
exertional 44
mechanism of 204b
paroxysmal 33
Dysrhythmias 371
Dyssynchrony 109
E
Ebstein's anomaly 111, 115
Echocardiogram 10, 11, 55, 65, 86, 121, 123126, 132, 133, 147, 152, 156, 162, 192, 234, 244, 266, 278
aortopulmonary window 147f
transesophageal 380, 381
Echocardiographic appearance 180
Echocardiography 40, 70, 102, 112, 118, 142, 143, 174, 180, 184, 188, 227, 228, 258, 309, 453
role of 17, 455b
transesophageal 40, 113, 485
Eddy sound 140
Edema 456
interstitial 439
pulmonary 45
septal 438
Edwards’ classification 303, 355f
Edwards’ syndrome 211
Ehlers–Danlos syndrome 93, 300
Eisenmenger's complex 267, 355
Eisenmenger's syndrome 355, 440
Ejection click 99, 173b, 215, 257, 265, 308, 391, 392
Ejection fraction 104, 345, 458
Ejection sounds 191
Ejection systolic murmur 99, 100, 191, 216, 233, 257
Elastin arteriopathy 182
Elective surgery 310
Electrocardiogram 37, 38, 40, 55, 85, 112, 117, 123126, 131, 133, 141, 147, 151, 156, 162, 181, 188, 192, 234, 237, 257, 266, 309
ambulatory 192
Electrocardiography 84, 244, 309, 403, 405, 412f
age-related variation 405
axis deviation 406
floodgate-surface 405
frontal plane axis 405
northwest axis 407
T wave 406
ventricular dominance 406
Embolism, peripheral 300
Emphysema 412
Endarteritis 156, 310
End-diastolic diameter 66
End-diastolic pressure 568, 576
Endocardial cushion defect 408, 413
Endocardial thrombus 338
Endocarditis 12, 108, 172
Endomyocardial fibrosis 115, 337, 451, 451f, 510, 574
clinical presentation 339
epidemiology 337
etiopathogenesis 338
investigation 340
management 340
natural history 340
pathological anatomy 338
Endothelial cells 9f
Endothelial damage 72
Endothelial dysfunction 286, 305
Endothelial injury 73
Endothelial nitric oxide synthase, reduced 171
Endovascular valve edge-to-edge repair study 68
Entrapment syndrome 300
Enzymatic abnormalities 115
Eosinophilia 339
Epistaxis 16, 272
abdomen anemia 10
Eponymous signs 95
Ergot alkaloids 120
Ergotamine 120
Erythema
anulare 16
marginatum 912, 16
Erythrocyte sedimentation rate 1012
Erythrocytosis 271, 272
adaptive 271
compensated 271
decompensated 271
maladaptive 271
Esophageal displacement 434
Esophagus 434, 435f, 448
Euroheart survey 120, 120fc, 127
European Association of Cardiothoracic Surgery 239
European Society of Cardiology 68, 193, 194
guideline 68
Exercise
isometric 203
treadmill test 85
Extensive mitral annular calcification 32
Extracardiac Fontan
advantages of 290
disadvantages of 290
Eye involvement 319
Eyler sign 433
F
Fabry disease 32, 115, 188, 337
Facial anomalies 213
Faintness 272
Fallot's physiology 199, 558
assessment of 426
Fallot's tetralogy 206, 210, 216
morphology of 206
neonatal 212
nonsyndromic 211
Fatigue 78, 110, 124, 126, 202, 203, 204b, 272, 390
Femoral pressure curve 308f, 534f
Fenestration, closing down of 289
Fenfluramine 120
Fever 912, 16, 21, 33
Fibromuscular ridge 285
Fibrosis 34, 72, 115
pulmonary 439
Ficolin-2 4
Figure of 3 447, 448f
Figure of E 448, 448f
Fingers, paresthesias of 272
First heart sound 36b, 52, 65, 81, 82, 98, 111, 131, 191, 215, 257, 265, 308, 333, 362, 372, 391, 392
Fistula
bilateral 154
drainage of 154
Flail leaflet prolapse 50
Flow murmur 100t, 112
Flow theory 304
Fluorodeoxyglucose-positron emission tomography 347
Fontaine classification 300t
Fontan anatomy 286
Fontan circuit 285
obstruction 292
Fontan completion 287, 289
desaturation after 292, 292b
Fontan fenestration 290, 292
Fontan original operation 288f
Fontan physiology 285
Fontan procedures 288
Fourth heart sound 52, 82, 99, 191, 216, 308
Framingham study 107
Friederich's ataxia 188
Functional ischemic mitral regurgitation 62, 63, 65
pathophysiology of 63
Functional nonischemic mitral regurgitation 62
pathophysiology of 62
Functional tricuspid regurgitation 107f, 108, 109, 109b, 110, 112t, 113
pathophysiology of 109
surgical management for 113
Fundarò classification 67, 67t
G
Gadolinium enhancement 334
Gallavardin's murmur 83t
Gallavardin's phenomenon 83, 126
Gas pharyngitis scoring 21t
Gasul phenomenon 201, 212, 443
Genetic
mutation 138
pattern 186f
screening 186, 187fc
Genital anomalies 213
Gerbode defect 108
Gerhardt's sign 97
Giant blood cyst 115
Giant cell
arteritis 93, 300
formation of 315
Gianturco-Grifka vascular occlusion device 142
Global longitudinal strain 196, 345, 477
Glomerulonephritis, poststreptococcal 5
Glycogen storage disease 337, 421
Goldenhar's syndrome 214b
Gorlin's famous flow-pressure graph 520f
Gorlin's formula 520, 521, 529, 530
Gradient versus heart rate 521, 530
Grading Pulsation American Heart Association 301t
Graham Steell murmur 122, 362t
absence of 144
Granulomatous infiltration 346
Great artery
congenitally corrected transposition of 48, 201, 211, 277, 410, 413
dextrotransposition of 201
D-transposition of 282f
level 353
relation 245
transposed 280, 280f
transposition of 138, 146, 232, 273, 277
Great vessels 242
Group A streptococci
eradication of 19
isolation of 16
Group A Streptococcus 3
pyogenes 5, 8, 9, 11, 15, 21, 20, 27
Guo classification 152b
H
Hakacove gave 409
Hakacove theory 408
Hakki formula 529
Hangout interval theory 373
Hausdorf sheath 382f
Headache 21, 272, 316
Heart
block 385
complete 419
boot-shaped 442
border 431
defect, congenital 232, 371
disease
carcinoid 115
congenital 93, 137, 154, 211, 230, 249, 269, 271, 363, 407, 408, 412, 445
critical congenital 251
cyanotic congenital 251, 271, 273, 274fc
diabetic 119
rheumatic 1, 3, 5, 9, 10, 18, 20, 23, 27, 47, 92, 108, 115, 119, 121b, 130, 132, 419, 472
valvular 119, 120b
failure 13, 20, 194, 265, 309, 310, 558, 563
congestive 12, 97, 111, 141, 156, 157, 212, 219, 226b
management 365
right-sided 233
sudden 153
rate 530
effect of 521t, 530
small 431, 432f
sound 36, 98, 116, 140, 155, 161, 191, 215, 316, 333
transplantation 293
typical boot-shaped 442f
Heart-hand syndrome 371
Heat-shock protein 314
Hemiplegia 273
Hemitruncus 209, 252
Hemochromatosis 337
Hemodynamic 138, 183, 193, 513
and angiography 246
and cardiac catheterization 86, 258, 267
classification 210, 210f
study 40, 55, 112, 118
Hemoptysis 35, 40, 272
Hemorrhage
intracerebral 306
pulmonary 275
Hemosiderosis 439
Hepatic circulation 293f
Hepatic dysfunction 273
Hepatic pulsation 332
Hepatic vein 154, 508
Doppler, normal 507f
Hepatic venous flow 507, 508, 508f
pattern 507
Hepatojugular reflux 112
Hepatopulmonary syndrome 159
Heterotopic balloon-expandable caval valve implantation 114
Hill sign 9597, 97b
His bundle 114
Hoarseness 35
Hoffman's Fallot's tetralogy 217
Hoffman–Rigler sign 433, 433f
Holter monitoring 227, 228
Holt–Oram syndrome 140, 371
Human leukocyte antigen 4, 315
Hurwitz and Robert's classification 170f
Hydroxyindoleacetic acid 116
Hypercarbia 204
Hypercholesterolemia, familial 72, 74
Hypereosinophilic syndrome, part of 339
Hyperkalemia 412
Hypertension 93, 305
paradoxic rebound 311
systemic 226
Hypertrophic cardiomyopathy 51, 62, 63, 155, 170, 186, 187, 191f, 193, 194, 196, 421, 491, 492b, 546, 547, 548f
end-stage 195
phenocopies of 188t
Hypertrophy 491
asymmetric 491
biventricular 363
eccentric 286
grades of 492
inadequate 77
types of 491
Hyperuricemia 273
Hyperventilation 204
Hyperviscosity syndrome 202, 271, 272b, 274
grading of 272t
Hypocalcemia 264
neonatal 213
Hypoplasia 212, 220, 371, 504
criteria for 304
moderate 303
severe 303
tubular 303, 303t, 304
Hypoplastic annulus 220, 278
Hypoplastic left heart syndrome 285, 305
Hypoxemia 203
Hypoxia 138, 204, 226, 272
and cyanotic burden 210
chronic 203, 273
Hypoxic spell 202, 219
I
Immunoglobulin light-chain 341
Implantable cardioverter defibrillator 109, 189, 195, 345
Indian Academy of Paediatrics 22
Indian Council of Medical Research 5, 27
Indian Takayasu Clinical Activity Score 319
Indolent carditis 13
Infectious Disease Society if America 4
Infective endocarditis 32, 47, 92, 93, 108, 119, 150, 156, 173, 174, 226, 363
large vegetation of 115
Inferior sinus venosus 369
Inferior vena cava 114, 288, 328, 368, 369, 372, 379, 383, 432, 433, 507, 507f, 510, 544, 551
flow 286
Inflammation 72, 456
Inflammatory disease 93
Inflammatory disorders, chronic 341
Infliximab 347
Infundibular obstruction 207
secondary 395
Infundibular pressure 394
Infundibular pulmonary stenosis 213
Infundibular septum 552f, 553
posterior deviation of 285
Infundibulum, hypertrophied 394
Initial carditis, severity of 40
Inlet septum 358
Interatrial septum 368
Interleukin-1 receptor antagonist 4
Internal thoracic artery 448, 449
Internodal fiber 34
Interventricular septum 246, 278
Intra-abdominal pressure 328f
Intracardiac pressures 572
Intracardiac repair 227
Intracardiac shunt 490
Intracavitary and intrathoracic pressures, dissociation of 568
Intrapericardial pulmonary artery 254
Intrathoracic and intracardiac pressures, dissociation of 572
Intrathoracic pressure 328f, 568f, 572
Intraventricular gradient pressure recovery 532
In-utero closure 137
Iron therapy 274
Ishikawa criteria 317b
Isolated pulmonary valve stenosis, prevalence of 389
Isthmus 504f
narrowing, mechanism of 304
J
Jaccoud's arthritis 14
Jaten classification 255t
Joint involvement, frequency of 14t
Jones criteria 9, 9b
modifications of 11
Jugular pressure tracing 110f
Jugular venous pressure 244, 331, 372
Jugular venous pulse 35, 51, 79, 110, 111, 116, 117, 140, 151, 155, 161, 173, 190, 213, 233, 257, 264, 307, 331, 331f, 362, 391, 573
normal 538
K
Kaplan–Meier estimates 367
Katz–Wachtel phenomenon 363, 364, 364f
Kawasaki disease 93
Kawashima procedure 291
Kidney disease, chronic 73, 84, 119
Kirklin's classification 358b
Klippel–Feil syndrome 151
Konno classification 152b
Korotkoff sound, muffling of 96
Kreutzer modification 287
Krichenko angiographic views 543f
Krichenko morphological classification 542b
Kussmaul sign 331, 332, 539, 540, 572
L
Lancefield group A beta-hemolytic streptococci 3
Landolfi's sign 97
Late gadolinium enhancement 192, 194, 229, 344, 345, 347, 348
Lateral tunnel Fontan
advantages of 290
disadvantages of 290
Leaflet 49
abnormality 49, 92b
angle 472
displacement 464, 465
fenestration 93
mobility 459
grades of 459t
thickness 458
grades of 459t
Leflunomide 320
Left atrial
appendage 432, 468
clot 466
compliance 524
enlargement 55, 413f, 414, 415, 417, 434, 434f
index 434, 435f
myxoma 32, 130
oblique diameter 434
pressure 49, 516, 517t, 519, 550
curve 519, 525
tracing 517, 517f, 519f
thrombus 466
classification of 466
presence of 34
Left atrium 67, 68, 150, 154, 156, 282, 283, 328, 369, 432, 456, 466, 469, 472, 524, 568, 573
dimensions 466t
Left axis deviation 364b, 407, 412, 413, 417
mechanism of 408
Left bundle branch block 55, 65, 82, 195, 417, 419
Left coronary artery 154, 185, 504
anomalous origin of 412
Left coronary cusp 171
Left coronary sinus 149
Left heart
border 431, 443
obstruction 243
Left leaf diaphragm 433
Left pulmonary artery 207, 209, 234f, 355, 432, 443, 488, 489, 498, 542, 552
absent 233
anomalous origin of 252
Left subclavian artery 432, 448, 448f, 504, 544
Left ventricle 54, 67, 68, 122, 154, 156, 194, 196, 227, 230, 242, 243, 280283, 328, 432, 433, 471, 477, 482, 495, 501
Left ventricular 32, 36, 38, 63, 66, 85, 432, 472, 481, 540, 553, 576
angiogram 552
apical
aneurysm 189
impulse 144
diastolic
dysfunction 77, 189, 477, 548
function 48, 461, 492
pressure 534f
dissociation 568
dysfunction 34, 49, 77, 87, 99, 191, 228, 561
features of 54b
ejection fraction 56, 58, 59, 59f, 66, 68, 7577, 84, 85, 89, 127, 195, 230, 289, 335, 347, 348, 501
end-diastolic
diameter 104
pressure 56, 226, 228, 286, 289, 516, 526, 533, 534f, 574, 575
endomyocardial fibrosis 339
end-systolic diameter 56, 59, 104
enlargement 141, 433
failure, acute 439
fistula 93, 174
function 228, 500
hypertrophy 77, 84, 173, 181, 186188, 345, 416, 417, 418f, 419, 421, 426, 433
hypoplasia 425
inflow obstruction 138
outflow tract 48, 85, 149, 179, 188, 194, 277, 285, 286, 477, 481, 493, 494f, 546f, 547, 548f, 550, 552
obstruction 138, 188, 278, 278b, 279, 281, 306
pressure 238
tracing 517, 517f
puncture, direct 530
strain 477
systolic
dysfunction 78, 189, 477
function 230, 494
waveform 517t
Leukocyte count 10
Levocardia 430
Light-chain amyloidosis 341
Limbus, superior 368, 369
Lipoprotein 73
low-density 73
Lips, paresthesias of 272
Liver disease, severe 159
Low diastolic pressure 95, 533f
Low glomerular filtration rate 113
Low output syndrome 36, 38, 526f
Low transpulmonary gradient 290
Low-dose dobutamine stress echocardiography 76
Lung 355
fields, nonoligemic 238f
Lutembacher's syndrome 38
Lymphatic dysfunction 292
Lymphoma 337
Lysosome-associated membrane protein-2 188
M
Macrofistula 154
Macrolides 23
Macruz index 414, 415f
Magnetic resonance angiography 302
Main pulmonary artery 146, 234, 255, 256, 488, 489, 497, 499, 544
Major aortopulmonary collateral
arteries 226, 255257, 259, 259f, 498, 558
types of 256f
Major cardiac shadow 430
position of 430
Major hemodynamic determinants 328b
Major histocompatibility complex 315
Mannose-binding protein 4
Marfan syndrome 92, 93, 119, 300
Matrix metalloproteinase 174, 293
Maximal systolic peak 81f
Mayne sign 97
Mayo clinic criteria 509
Mean corpuscular hemoglobin 272
Mean pulmonary artery 432, 552
pressure 289, 526
Mechanical aortic valve repair 103
Mediastinal radiation therapy 119
Mediastinum 448
Membranous septum 358, 368, 369
aneurysm of 213
Memory T cells, effect of 9f
Mendelian inheritance 371
Menorrhagia 272
Mental
growth 213
stress 33
Mesocardia 430
Methotrexate 320, 347
Methylprednisolone 19
Methysergide 120
therapy 32, 115
Mexican Fallot's tetralogy 211
Microdeletion 211
Microfistula 154
Microvascular dysfunction 189
Midcavity obstruction 189
Mid-diastolic murmur 37, 54, 117
Minervini's sign 97
Minimally invasive mitral valve surgery 58
Mitral annular
area 473
calcification 83, 130, 466, 522
dilatation 70
tissue velocity 509
Mitral annuloplasty 68
Mitral atresia 138, 240, 285
Mitral facies 35
Mitral inflow doppler pattern 508
Mitral leaflet 62, 455
anatomy of 458, 468f
anterior 13, 33, 42, 49, 51, 63, 188, 339, 456, 459, 480, 481, 493, 494
nonpliable 44
normal coaptation of 64f
pseudoprolapse of 456f
separation index 460f
septal relation 493
true prolapse of 456f
Mitral regurgitation 32, 3637, 42, 44, 47, 50, 54, 56, 59, 6264, 67, 68, 76, 83t, 85, 110, 119, 121, 123, 124t, 125, 126, 126t, 127b, 128t, 180, 184, 190, 192, 281, 456, 462, 468, 469, 471, 472, 494, 522, 524
acute 47, 526, 526f
anatomy 468
angiographic classification of 527t
asymptomatic severe 58
atrial 62
functional 69
chronic
rheumatic 47
severe 55
degenerative 110
diastolic 100
Doppler features of 456
etiology of 47, 472
functional 47, 62, 66f, 110, 470, 472
hemodynamic phase 524
ischemic 47, 64f, 68, 470, 472, 473
mechanism of 13b, 63, 456b
medical management of 55
mild 41, 132
mild-to-moderate 13
murmur 52, 53, 65, 65f, 83, 339
shapes of 53f
primary 70
progressive 42
residual 49
severe 53, 131
severity 60, 469
grade 469b
Mitral restenosis after balloon mitral valvotomy 42
Mitral scallops 468f
Mitral stenosis 17, 3234, 3638, 44, 45, 76, 101t, 115, 116, 117t, 121, 122, 122t, 124, 125t, 159, 306, 420, 458, 458f, 461, 461t, 466, 519, 521, 526, 530, 531, 537
assessment 132
congenital 32
Doppler assessment of 460
juvenile 44
severity 458
supravalvular 179
Mitral valve 13, 36, 38, 49, 131, 132, 175, 188, 240, 465f, 468
abnormalities 57
arcade 48
area 33t, 34, 4144, 459, 460f, 465, 520, 520f
calcification 131
closure 48
premature 534
competent 265, 289
deformation 66
disease, mixed 130
dysplasia 48
Ebstein's-like anomaly of 48
hypoplasia 48
involvement 12
premature closing position of 98f
prolapse 52, 54, 170, 190
repair 56, 57t, 110, 127
advantages 57t
disadvantages 57t
replacement 41, 43, 57
straddling 48
Mitral valvulitis 12, 455, 456, 456b
Mitralign and Tricinch devices 114
Mixed single valve disease 130
M-mode
echo 181f
mitral valve 493f
Moguls of heart 432
Monarc annuloplasty ring 69f
Monoarthralgia 1012
Monoarthritis 10, 12, 14
aseptic 11
Mononuclear cells 315
Morgan classification 239b
Morris index 414, 415f
Muller's sign 97
Multidetector computed tomography 65, 122, 309, 309f
angiography 309
Multifunctional occluder 366f
Multisystem disorder 271
Multivalvular heart disease 119, 128
etiology of 119b
management of 127
pathophysiology of 121
Multivalvular lesions 121, 121fc
Murmur 83, 99, 111, 116, 133, 140, 155, 156, 161, 191, 192, 196, 216, 251, 308, 334, 374, 392
appearance of 361
classical 140
diastolic 131, 191, 216, 257, 265, 267, 308, 362
early diastolic 265
length of 99
peaks 230f
quality of 99
systolic 131, 191, 265, 308
decrescendo 362
Muscle weakness 272
Muscular arterioles, pulmonary 355
Mutant transthyretin amyloidosis 342
Myalgia 272
Mycobacterium tuberculosis 314
Myeloma 8f
proteins 9f
Myocardial biopsy 14, 344
Myocardial disarray 189
Myocardial fibrosis 229
Myocardial infarction 66, 156
acute 155
thrombolysis in 65
Myocardial involvement 14b, 318
Myocardial ischemia 152
chronic 562
Myocardial oxygen consumption 557
Myocarditis 13
smoldering 33
Myocardium, restrictive 570
Myocytes 189
Myxomatous degeneration 47, 92
N
Nakamura classification 170f
Narrow pulmonary artery 561
National Heart Foundation 22
Necrotizing enterocolitis 220
Neoportal system 285
Neutral septum 492f
New York Heart Association 24, 43, 57
Nikaidoh procedure 282284
Nitric oxide 159
Nodule, subcutaneous 912, 16
Noncardiac anomaly 306
severe associated 220
Noncoronary sinus 149, 150
Nondihydropyridine calcium channel blocker 40
Nonrheumatic mitral stenosis, etiology of 32b
Nonsteroidal anti-inflammatory drugs 14
Noonan syndrome 93, 151, 371, 389
Norfenfluramines 120
Normal abdominal aortic flow pattern 503f
Northwest axis, causes of 412b
N-terminal pro-brain natriuretic peptide 227
Nuclear perfusion imaging 156
O
Obsessive-compulsive disorder 15
Obstruction
dynamic 493
features of 192b
intrapulmonary 558
pulmonary 243
resection of 185
Obstructive hypertrophic cardiomyopathy 194
Obstructive lesions, left-sided 563
Occult constrictive pericarditis 329
Ochronosis 72, 119
Oculo-auriculo-vertebral dysplasia 214b
Oligemia, pulmonary 438, 438f
Open mitral commissurotomy 41, 43
Open valvotomy 118
Opening snap 36, 37, 52, 131
presence of 131
Operability vascular resistance 356
Oral penicillin 23
Organic aortic stenosis 100t
Orthodeoxia test 162
Orthopnea 33, 78
Ortner's syndrome 35
Osteogenesis imperfecta 93
Ostial pulmonary stenosis 561
Ostium primum 369
atrial septal defect 370, 370f
Ostium secundum 369
atrial septal defect 369, 381
Oximetry 562
data 551
Oxygen 156
carrying capacity 210
delivery 210
P
P congenitale 414f
P mitrale 414f
P pulmonale 414, 414f
P wave 425
Pacemaker implantation 281
Packed cell volume 272, 274
Padial mitral stenosis score 462, 463t
Paget's disease 72
Pain 21
abdomen 10, 16, 21
Palatal anomalies 213
Palfrey's sign 97
Palliative surgery 258
Pallor time 301t
Palpation 36, 51, 81, 97, 111, 116, 124, 132, 140, 151, 155, 161, 173, 190, 214, 233, 244, 264, 301, 308, 332, 362, 372, 391
Papillary muscle 64, 64f, 458
dysfunction 49
hypertrophy 493
normal position of 48
Paradoxical low-flow 76
Parasternal impulse 52, 124
Parasternal pulsation 214
Paroxysmal atrial
fibrillation 190
tachycardia 203
Paroxysmal nocturnal dyspnea 33, 34, 78, 117, 122, 125, 190
Patau syndrome 211
Patent ductus arteriosus 37, 137, 138, 141, 142, 144, 146, 151, 156, 170, 173, 179, 209, 214, 232, 255, 260, 263, 288, 303, 353, 488, 489, 503, 542
anatomical
classification of 139f
information 488
classification of 139f, 141t
dependent dual circulation 138
dependent pulmonary circulation 138
dependent systemic circulation 138
detrimental circulation 138
diameter 489
hemodynamic information 488
physiological closure of 137
presence of 563
related circulation 138
staging 143, 143t
Patent foramen ovale 140, 162, 305, 354, 371
Pectus excavatum 431
Penicillin 21
allergy 23
G benzathine 22
Percutaneous transluminal coronary angioplasty 155
Pergolide 120
Pericardial calcification 450f
Pericardial knock 333
Pericardial patch 283f
Pericardial pressure, normal 571
Pericardial rub 374
Pericardial tamponade 572
Pericardiectomy, mortality of 335
Pericarditis 13, 19, 329
annular constrictive 329
tuberculous 451
Pericardium 328
absent 431
respiratory 567
Perimembranous ventricular septal defect, angiographic classification of 365b
Peripheral arterial waveform 518, 518t
Peripheral artery disease 299, 302
etiology of 299, 300b
Peripheral artery pressure 528
tracing 518f
Peripheral artery stenosis 400f
Peripheral pulmonary artery stenosis 184, 216
saw-tooth appearance of 498f
Peripheral signs 97
Perloff's hemodynamic classification 361t
Pharyngitis, streptococcal 15, 16
Phenocopies 187
Phenoxymethyl penicillin 21
Phlebogram 538
Phlebotomy protocol 274
Phrenic nerve injury 310
Plasma
cell dyscrasias 341
oncotic pressure 39
Plateau pulse 80
Platelet derived growth factor 315
Platelet function, abnormal 272
Pleural effusion 439
Plexogenic arteriopathy 440f
Poland's syndrome 214b
Polyarteritis nodosa 300
Polyarthralgia 1012, 15
Polyarthritis 912
Polycythemia 271
Polysplenia syndrome 159
Pompe's disease 188
Popliteal artery entrapment 300
Postaortic balloon valvuloplasty 93
Postaortic valve replacement 93
Postballoon mitral valvoplasty 461
Postchemotherapy 337
Postcoarctectomy syndrome 310, 311
Posterior atrioventricular septum 552f
Posterior mitral leaflet 13, 33, 51, 52, 63, 188, 458, 468, 494
Posterior rib 429
Postinfarction papillary muscle 64f
Postleft heart valve surgery 110
Poststenotic dilatation 238f
Post-tricuspid shunt 355
Potts shunt 220
Pre-Fontan palliation 285
Pressure
curve 235f
gradient, transpulmonary 49
half-time 123, 461, 482, 487
tracing 400f, 522f
wire 531
Presystolic murmur 54, 116
Pretricuspid shunt 354, 355
Primary tricuspid regurgitation 108
pathophysiology of 108
Prophylaxis failure 24
Prosthetic valve dysfunction 47, 49
Proteasome inhibitors 345
Proximal coronary artery 500
Proximal isovelocity surface area 123, 132, 461, 469471, 482, 486
Proximal right ventricular outflow tract 281f
Pseudocoarctation 304
Pseudoejection click 192
Pseudoejection sound 191
Pseudotruncus arteriosus 252, 254
P-terminal force, calculation of 415f
Pullback pressure 184
tracing 546f
Pulmonary annulus 283f, 498
hypoplasia of 220
Pulmonary arterial hypertension 36, 38, 54, 56, 59, 141, 147, 354, 383, 439, 446, 489, 503, 524, 554, 561
assessment of 542
grading 440, 440t
Pulmonary arterial pressure 226
Pulmonary arteriolar resistance 289
Pulmonary arteriovenous fistula 159, 160, 160f, 162f, 163, 163f, 164, 251, 292
acquired 159
Anabtawi classification of 160f
mechanism of 293f
Pulmonary arteriovenous malformation 293
Pulmonary artery 154, 156, 206, 208, 209, 216, 220, 234, 235f, 240242, 242f, 243, 243f, 263, 266f, 279, 280f, 282, 282f, 283, 283f, 284f, 355, 398, 412, 432, 436, 437, 437f, 488, 498, 516, 543, 553, 554, 556, 558, 562
absent 255
aneurysm 396
branching abnormality of 232
capillary wedge pressure tracing 516
diastolic pressure 233
distortion, absence of 289
end-to-side anastomosis of 284f
extrapericardial 255
flow 210
idiopathic dilatation of 233
involvement 318
management of 400
murmur of 399
natural history of 400
origin 437f
ostial stenosis 263
pressure 44, 56, 110, 234, 516, 550, 563
tracing 516
proximal 394
stenosis 397, 398f, 401, 498
systolic pressure 41, 49, 365, 567
waveform, camelback appearance of 526f
wedge pressure 551
Pulmonary atresia 138, 209, 251, 252, 254, 255, 257, 260, 285, 445, 445f, 499, 558
Pulmonary autograft 185
Pulmonary blood flow 557
additional source of 499
classification of 256t
Pulmonary capillary wedge pressure 41, 65, 439, 517f, 517t, 520, 522f, 525, 526, 534, 570, 575, 576
curve 522f
Pulmonary circulation 285, 354, 558
Pulmonary click, absence of 144
Pulmonary component 82, 362, 372, 392
presence of 215
Pulmonary congestion 438
manifestation of 438
Pulmonary flow, unobstructed 561
Pulmonary hypertension 34, 44, 49, 77, 108, 109, 112, 113, 117, 148, 219, 220, 355, 365, 383, 472, 522, 526
assessment of 545
Pulmonary in situ thrombosis 273
Pulmonary infundibular stenosis 395, 396
features of 392b
Pulmonary orifice 281
Pulmonary stenosis 201, 237, 238f, 239, 240, 243, 277279, 280f, 282f, 393f, 425, 554, 556, 557
Brock anatomical classification of 389b
murmur
duration of 392f
shape of 392f
severity of 390, 392t
types of 390t
Pulmonary trunk 254, 281, 400
Pulmonary valve 13, 207, 235f, 285, 389
leaflet 237
replacement 227, 229, 501
indications for 501
stenosis 389
tissue 232
Pulmonary valvular stenosis, mild 394
Pulmonary vascular click 216t, 374
Pulmonary vascular obstructive disease 49, 141, 355, 356, 375, 558, 561
Edwards’ classification of 355b
Pulmonary vascular resistance 34, 49, 138, 201, 289, 354, 356, 356t, 365, 383, 556558, 562
indication of 230t
Pulmonary vascularity 286, 364, 436, 443, 446
Pulmonary vein 328, 379, 436, 470, 568, 572
Pulmonary veno-occlusive disease, development of 363
Pulmonary venous Doppler 493f
Pulmonary venous hypertension 33, 35, 49, 130, 437439, 450, 524, 556, 561
staging of 438
Pulmonary venous pressure 524, 569
Pulmonary venous wedge
angiography 560
pressure 517
Pulsatile flow, lack of 286
Pulsatile Fontan 291
Pulse 35, 51, 79, 95, 132, 155, 161, 173, 190, 214, 257, 264, 265, 307, 316, 362, 372, 391
pressure 547
wave
Doppler 471, 482
Lobster claw appearance of 495f
Pulsus alternans 80
Pulsus bisferiens 96, 141, 192
Pulsus celer 96
Pulsus paradoxus 332, 572, 573
incidence of 332
mechanism of 332
Pulsus parvus et tardus 79
Q
Quadricuspid aortic valve
Hurwitz and Robert's classification of 170f
Nakamura classification of 170f
Quadricuspid valve 93, 170, 174
Quincke's sign 97
Q-wave, ischemic 55
R
Radiation 83
arteritis 300
associated cardiac disease 119
exposure 429
Rapid antigen detection test 17
Rapid filling wave 333, 540, 540f, 568
Rastelli operation 280, 284
Recurrent laryngeal nerve injury 310
Red blood cell 271
Red cell distribution width 272
Regurgitant jet area 469
Regurgitant orifice, effective 48, 65, 470, 486
Regurgitation
acute aortic 93b, 534
atrioventricular 293
mild-to-moderate 122
pulmonary 226, 229, 500, 501
severe pulmonary 232
Reid score 464t
Reiter's syndrome 93
Renal dysfunction, mechanism of 274fc
Renal failure, chronic 72
Renal function 273
Renin–angiotensin system 87, 113, 305
Respiration, effect of 117, 537
Respiratory hemodynamic 568, 569b, 575
Restrictive cardiomyopathy 62, 337, 337b, 348, 510, 574
causes of 337
etiology 337
Restrictive physiology 576t
Restrictive pulmonary flow 561
Retinopathy
hypertensive 319
ischemic 319, 319t
Retrograde pullback method 530
Revisited echo score 463, 465b
Rheumatic aortic
regurgitation 93
stenosis 73, 478, 478f, 478t
Rheumatic carditis 1214, 20, 47, 49, 73
prognosis of 17
Rheumatic disease 57
Rheumatic fever 3, 6, 9, 17, 18, 21, 23, 32, 44
management of 19
pathogenesis of 7
Rheumatic mitral regurgitation 55, 473
pathological anatomy of 49
surgical management of 56
Rheumatic mitral valve disease 115
Rheumatic tricuspid valve disease 115
Rib notching 448
Richardon's classification 146
Right anterior oblique 189, 551
Right aortic arch 209
Right atrial
appendage 432
dissociation 568
enlargement 413, 413f, 435, 436f
pressure 328f, 537, 550, 566, 567, 570, 571, 574
curve 536, 538
pulse 567b
tracing 515, 515f
tumor 115
volume, normal 289
wave pattern 574f
Right atrium 150, 154, 156, 282, 283, 328, 369, 431, 456, 544, 573
Right axis deviation 416
Right bundle branch block 195, 227, 309, 375, 407, 423, 426
Right coronary artery 114, 154, 149, 150
fistula, large 157f
Right coronary cusp 171
anterior 475
Right coronary sinus 150
Right heart border 431
enlargement of 435
Right heart catheterization 184, 526
Right heart chambers 567
Right hilar vascular complex 433
Right hilum 432
Right pulmonary artery 146, 234, 287f, 288, 489, 498, 499f, 542, 552
distal origin of 252
proximal origin of 252
Right upper
abdominal pain 330
lobe bronchus 432
pulmonary vein 369, 382
Right ventricle 109f, 113, 122, 125, 154, 156, 227, 230, 234, 240244, 280283, 328, 501
outflow tract 356
Right ventricular 540, 544, 552
angiocardiogram 393f
angiogram 551, 551f
compliance 226
diastolic pressure 235, 540f
dilatation 226, 442
dysfunction 109
ejection fraction 230, 348, 501
end-diastolic
pressure 574
volume 227, 501
endomyocardial fibrosis 339
end-systolic volume 501
enlargement 435
function 229
hypertrophy 36, 38, 226, 228, 415, 416, 423, 425, 435, 442
features of 393f
infundibulum 202
morphology 114
outflow 401
obstruction 245, 279, 387
stenosis 184
outflow tract 108, 150, 152, 206, 210, 227, 230, 233, 234, 255, 260, 279, 282f, 283f, 488, 497, 500, 501, 552
dilated 234f
normal 206f
obstruction 208t, 213b, 225, 360, 389
stenosis 244f
outlet obstruction 207
pressure 237, 423, 516, 537, 550
tracing 516, 516f
remodeling 109
systolic pressure 567
normal 516
volume overload 233
waveform 517t
Right-noncoronary cusp fusion 170f
Rim deficiency, incidence of 381t
Romhilt–Estes point score system 417, 417t
Root abnormality 93b
Rosenbach's sign 97
Ross procedure 103
Rubella syndrome, congenital 138, 140
Rupture sinus of Valsalva 149, 152, 153f, 170, 174, 545
aneurysm 544
angiographic classification of 153b, 544b
Rutherford classification 301t
S
Saint Vitus dance 15
Sakakibara classification 152b, 157b
Salicylates 19
Sarcoidosis, prevalence of 345
Scarlatiniform rash 21
Scarlet fever 9
Schistomiasis 159
Scleroderma 47, 337
Seagull appearance 559f
Seagull sign 559f
Second heart sound 36, 52, 81, 82, 98, 111, 131, 191, 215, 257, 265, 308, 333, 362, 363, 372, 373, 391, 392
aortic component of 98, 184
Secondary attack rate 18t
Secondary mitral regurgitation 62, 67t, 70
functional classification of 67
Secondary tricuspid regurgitation 108
Seizures 273
Selzar and Cohn theory 33
Semilunar-atrioventricular valve continuity 553
Sepsis 220
Septal aneurysm 360, 366f, 383
Septal defect, aortopulmonary 146
Septal hypertrophy 285
grades of 492b
Septal margins, atrial 379f
Septal motion 506
Septal myectomy, surgical 194, 195, 195t
Septal reduction therapy 194
Septal shudder 506b
Septal tricuspid leaflet 107
Septomarginalis 262f
Septum
aortopulmonary 562
beak-shaped deflection of 506f
Severe mitral stenosis 34, 35
features of 33
Severe tricuspid regurgitation 486, 539f, 540, 540f
Doppler imaging of 486f
Severe tricuspid stenosis, giant P wave of 420f
Sharma modified criteria 317b
Shock syndrome 310
Shunt 371
grading 489
pathophysiology 353
post-tricuspid 353
surgery 219
ventricular level 353
Sigmoid septum 491f
Significant aortic regurgitation, presence of 34
Silent patent ductus arteriosus 141b
Simon grading 438
Single arterial trunk 252, 252f
Single gene mutation 140, 211
Single valve surgery 127
Single ventricular physiology 159
Sinoatrial node 34
Sinotubular junction 93, 475f
Sinus aneurysm, acquired 150
Sinus arrhythmia, respiratory 376
Sinus of Valsalva 149f, 152, 170, 174, 360
acquired aneurysm of 150
aneurysm of 93, 149151, 173
level, midpoint of 475f
Sinus reconstruction, multiple 185
Sinus rhythm 289, 419
presence of 519
Sinus venosus 369
atrial septal defect 369f
Situs 430
Skeletal abnormality 430
Skeletal anomalies 213
Skin 7
lesion 316
Society of Thoracic Surgeons 239
Sokolow–Lyon criteria 416
Sore throat, sudden onset of 21
Soto's classification 359b
Sound 374
Spell management 219fc
Spherical remodeling 286
Spike-and-dome pulse 190f
Spinal artery, anterior 448, 449
Spinal cord ischemia 311
Spironolactone 340
Split outflow right ventricle 213
Spontaneous echo contrast 44, 464, 466
Sporadic elastin arteriopathy 182
Standard Tessellation language 246
Steal phenomenon 156
Stenosis 499
mild-to-moderate 390
pseudo-severe 75
recurrent 401
severe 400f, 422
severe pulmonary 390
valve 394
severe valvular pulmonary 237
subaortic 179, 277
subvalvular 173
supravalvular 173
Stenotic lesion 132
Steroid 19, 345
sparing agents 320
Streptococcal antibody 9
detection of 17
Streptococcal antigen, detection of 17
Streptococcus pyogenes 3
Stress
mechanical 72
testing 85
Stroke 273, 316
Subaortic membrane 93, 180f, 181f
Subaortic obstruction 182
management of 283
Subaortic stenosis, idiopathic hypertrophic 191
Subclinical left ventricular dysfunction 58
Subpulmonary conus 278
Subvalvular apparatus 459, 464
Subvalvular disease 464
Subvalvular fusion, severe 44
Subvalvular membrane 278
Sulfonamide 23
Superior sinus venosus atrial septal defect 369
Superior vena cava 154, 156, 282, 283, 286, 287f, 288, 328, 368, 369, 379, 431, 432, 507
bilateral 557
left 557
persistent left 179
Suprasternal ductal view 489
Suprasystemic right ventricular pressure 424f
Supravalvular aortic stenosis 93, 132, 182
angiographic view of 184f
types of 183f
Surgery, single-stage 259
Surgical aortic valve replacement 88, 88fc, 89, 127b, 128
Swelling, abdominal 339
Sydenham's chorea 15
Syncope 79, 125, 126, 316
Syndromic Fallot's tetralogy 211
Systemic elastin arteriopathy 182
Systemic lupus erythematosus 16, 32, 47
Systemic oxygen saturation 554
Systemic vascular resistance 139, 192, 210, 225, 353, 365, 426, 556
Systemic venous
blood 556
return, normal 289
Systolic anterior motion 50, 51, 188, 196, 493
grades of 493t
mechanism of 493
Systolic area index 569, 575
Systolic ejection
period 521, 530f, 531
time 80f
Tachypnea 361
Takayasu's arteritis 93, 314t, 565
childhood 318b
Takayasu's conference 563
Takayasu's disease 300, 314, 315, 317319, 319t, 321, 449, 563
angiography 318
autoimmune etiology 314
biochemical parameters 318
clinical presentation 316
diagnostic criteria 317
disease activity 319, 320b
epidemiology 315
etiology 314
genetic etiology 315
infective etiology 314
management 320
medical treatment 320
natural history 319
pathology 315
percutaneous intervention 320
prognosis 319
surgical intervention 320
vascular phase feature 316
X-ray chest 318
Takayasu's retinopathy 319
Tamponade 571
Taussig–Bing heart 243
Taussig–Bing malformation 280
T-cell deficiency 213
Telangiectasia
hereditary hemorrhagic 159
pulmonary 159
Tension apparatus, abnormal 285
Tetralogy of Fallot 37, 138, 146, 201, 202, 206, 209t, 215b, 215t, 218f, 225, 225f, 227, 230, 232, 235f, 237, 240, 251, 254, 257, 260, 263, 273, 407, 412, 423, 424f, 442, 445, 445f, 496, 550552, 558
angiography 551
classical 234t
clinical types of 212t
fatigue in 204b
grading 217t
hemodynamic 550
physiology 554
pink 424f
postcorrection 425
postneonatal 212
postoperative 443
postrepair 226, 226b, 500
typical 424f
Tetralogy physiology 201, 204, 210, 243, 423
presentation of 202b
Third heart sound 53, 99, 111, 131, 191, 216, 265, 308, 362, 363
Thoracic aorta, magnetic resonance angiography of 309
Thoracic outlet syndrome 300
Thoracic radiation therapy 119
Three-dimensional
echocardiogram 122, 278, 473
transesophageal echocardiography 56
Throat culture 16
Thromboangiitis obliterans 300
Thromboembolic event 79, 292, 384
Thrombosis in situ 300
Thrombotic diastases 274
Thrombotic diathesis 272, 273
Thrombotic milieu 464
Thymus 211
Thyrocervical trunk 448
Thyroxine 342
Tinnitus 272
Tissue
Doppler
imaging 188
velocity 59
tags 285
T-lymphocyte protein 4
Tocilizumab 320
Toes, paresthesias of 272
Tofler's series 215t
Tonsillopharyngeal patchy exudative involvement 21
Total anomalous pulmonary venous connection 251, 372
Total cavopulmonary connection 159, 285
Total pulmonary outflow resistance 201
Total stroke volume 524
Trabecula septomarginalis 262
Trabecular bands obstructing right ventricular outflow 213
Trabecular septum 358
Trabeculo-septomarginalis 206208, 240, 241, 244
Trabeculo-septoparietalis 208
Tracheal bifurcation 434
Transannular patch 221, 228
Transcatheter aortic valve replacement 88fc, 89, 120, 127b, 128, 177, 419, 479, 532
Transcatheter closure 142, 377, 379
Transcatheter intervention 128
Transcatheter mitral
regurgitation intervention 68b
valve replacement 68, 69
Transcatheter therapy 113
Transcathether aortic valve implantation 72
Transeptal puncture 530
Transesophageal echocardiography, perioperative 65
Transient arterial occlusion 101
Translocated aortogenic patch closure 283, 283f
Transmitral gradient 521, 522b
Transmitral pandiastolic gradient 522f
Transthoracic echocardiogram 109, 379, 380, 381, 490
Transthyretin 342
amyloidosis, wild type 341, 342
hereditary 341
tetramer 342
Transvalvular gradient 79, 420, 530
techniques of measurement of 531b
Transvalvular pressure gradient 531b
Transverse arch 304f, 504
proximal 504f
Transverse cardiac diameter 430, 430f
Transverse thoracic diameter 430f
Traub's sign 97
Trauma 47, 93, 150
Tricuspid annular
dilatation 109
plane systolic excursion 85, 501
Tricuspid annulus 107, 107f, 110, 485
large 114
Tricuspid aortic valve 94, 169
Tricuspid atresia 138, 201, 277, 285, 409
Tricuspid leaflet
anterior 107
posterior 107
Tricuspid murmur 537
Tricuspid opening snap 117t
Tricuspid pulmonary annulus distance 246, 278
Tricuspid regurgitation 76, 107109, 110f, 111, 112, 114, 116, 128t, 150, 176, 226, 229, 230, 233, 281, 360f, 485, 486, 500, 538, 540, 540t
congenital 108
management 113, 113fc
mechanism of 485
mild-to-moderate 538f
moderate 127, 486f
murmur 111
noncongenital organic 108t
organic 112t
physiological 485
prevalence of 107
severity, newer grading of 486t
Tricuspid stenosis 115, 116f, 117, 118, 420, 487, 536, 536f, 537
effect of 537
etiology of 115b
frequency of 115
severity, grading of 487t
Tricuspid valve 13, 107, 109, 113, 368, 537, 540f
anatomy 107
annulus 551f
bioprosthetic 115
echocardiographic 108
flow pattern 508
involvement, primary 108
lesion 484
normal 484
prolapse 108
Triple apical impulse 192, 196
Trisomy 13 211
Trisomy 18 140, 211
Trisomy 21 140
Truncal anomalies 252, 252b
Truncal regurgitation 264, 265, 265t
Truncal valve 262
regurgitation 265, 561
stenosis 561
Truncus arteriosus 211, 251, 252, 262, 445, 446f, 561, 562f
angiography 562
Collett and Edwards classification of 263f
hemodynamic 561
T-sign 147
Tumor necrosis factor 4, 9, 73
Turner's syndrome 93, 173, 306, 312, 371
T-wave 416, 425
giant inverted 422f
Two-dimensional echocardiogram 458, 510
U
Uhl's anomaly 108
Unequivocal roentgenographic sign 447
Unicommissural valve 278
Unicuspid aortic valve 169, 169f
Unicuspid unicommissural valve 93
Univentricular connection 201, 277
Upper lobe pulmonary venous redistribution 438
Uric acid metabolism 273
V
Valve
area 487
calcification 44
dysplasia 169
involvement 13t, 120, 338
lesion 385
surgery 127
Valvular aortic stenosis 180, 183
congenital 169
Valvular endothelial cell 9f
Valvular obstruction 207
Valvulitis 12, 456
murmur 457
rheumatoid 11, 49
severity of 17
Valvulo-vascular impedance 75
van Praagh classification 264f, 359b
Vascular cell adhesion molecule 8
Vascular endothelial growth factor 293, 315
Vasculitis 300
Vector direction 411f, 412f
Velocardiofacial syndrome 213b
Vena contracta 469, 470, 481, 481f
Venogram, superior 331f
Ventricular assist device 59
Ventricular diastole 516, 536
Ventricular diastolic pressure 567
Ventricular dysfunction 290, 293
management of 292
Ventricular dyssynchrony 64
Ventricular fibrillation 193
Ventricular function 271
Ventricular interdependence 539, 569, 569f, 572
Ventricular outflow tract 277
Ventricular papillary muscle dysfunction 67
Ventricular premature beat 190
Ventricular pressure 550
tracing 567
Ventricular septal aneurysm 360
Ventricular septal defect 37, 93, 138, 146, 147, 170, 173, 174, 180, 201, 208f, 226, 229, 232, 237, 238f, 239241, 241f, 242, 245, 260, 262, 277, 279, 280f283f, 303, 353, 356, 358, 359, 359b, 363b, 364, 365, 366f, 367, 370, 396, 410, 413, 426, 496, 497, 550, 558
additional 496
anatomical classification 358, 359b
aortogenic closure of 279
association 360
closure 247
indication of 365f
different type of 359f
grading 360, 361t
Kirklin's classification of 358b
large 237
location 208f
management 364
moderate to large defect 361
murmur 362
natural history 363
noncommitted 241, 241f, 278280
patch 500
physical findings 362
physiology 361, 554
prevalence 358
prognosis 363
residual 281
restrictive 138
small 364
defect 361
subaortic 240, 241f
subpulmonic 241, 241f, 280
syndrome 360
Ventricular septal
rupture 525
segments 358f, 358b
Ventricular septum crest-aortic valve distance 246, 278
Ventricular systole 400
Ventricular tachycardia 189, 193, 195, 227, 228, 346, 348, 347, 412
nonsustained 194, 228
Ventriculoaortic junction 93
Ventriculo-arterial alignment 245
Ventriculoinfundibular fold 207, 240
Ventriculotomy incision 228
Venturi effect 96, 149
Vertigo 316
Vestibular defect 369
Viral pharyngitis 21t
Vitamin D 338
Voltage criteria 416
Von Willebrand factor 79
W
Water hammer pulse 96
Waterston shunt 220
Watson's water hammer pulse 96
Well's index 37
Werner forssmann 518f
Whipple disease 32, 115
Wide pulse pressure 124, 141, 533f
Wilkins score 462, 463, 463t
Williams syndrome 182, 185
Winter bronchitis 35
Wolff–Parkinson–White syndrome 188, 413, 421
World Health Organization 6, 9, 10, 10b, 22, 23
World Heart Federation 5
×
Chapter Notes

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1Rheumatic Heart Disease2

Acute Rheumatic FeverCHAPTER 1

“The chain that binds the heart to the throat…”
— Wannamaker LW
(Circulation. 1973;48:9)
 
INTRODUCTION
Acute rheumatic fever (ARF) is a systemic inflammatory autoimmune disease that follows throat infection with Lancefield group A beta-hemolytic streptococci [GABHS (GAS: Group A Streptococcus pyogenes)]. ARF is believed to involve the triad of a genetically susceptible individual, infection with a rheumatogenic strain of GAS, and a host immune response.
 
AGENT
Beta-hemolytic streptococci, according to its cell-wall polysaccharide antigen, can be divided in number of serological groups, such as Group A, B, C, G, and F. GAS, most commonly, have been related to human infection. Group C and G can cause infection and evoke an antigenic response including streptolysin-O. However, pharyngitis caused only by GAS has been linked with ARF and rheumatic heart disease (RHD). GAS can be subdivided in 130-myeloma (M) types.
Group A Streptococcus is the most common pathogen to cause bacterial pharyngitis with its peak incidence in children 5–15 years of age.1 At this age, in any episode of pharyngitis, GAS is responsible in 15–20% cases and viral pathogens in 80% cases.2 Its incidence is uncommon in children below 3 years of life and in adult population. About of 10% of sore throats in adults are due to GAS infections. GAS is droplet spread with a cross-infection rate of 19–50% within a household.
Over years, incidence of GAS pharyngitis has remained at a steady rate. Interestingly, though incidence of ARF has come down remarkably in developed country, incidence of GAS pharyngitis has not declined.3 What happened over 20 years in GAS is the emergence of more virulent type of strains and non-M types.
Usually, GAS pharyngitis may lead to rheumatic fever (RF). Occasionally GAS skin infection can lead to RF in certain population such as Aboriginal communities of central and northern Australia.4
 
HOST
Acute rheumatic fever is equally common in male and female population. However, RHD is more common in female, with a relative risk of 1.6–2 in comparison to male. Not all GAS pharyngitis episodes are associated with RF. Other than agent factor, host factor plays an important role. This is evidenced from the facts that certain ethnic races and individual with certain genetic marker are more susceptible to RF.4
 
Hereditary Susceptibility
As only 0.3–3% of individuals affected by streptococcal pharyngitis may develop ARF, host factor including a genetic factor may be the determinable factor. The genetic rule does not follow Mendelian inheritance but follows the rule of polymorphism, which occurs in genes coding for immune-related protein. The proteins include:
  • Mannose-binding protein C2
  • Ficolin-2
  • Toll-like receptor 2
  • Tumor necrosis factor
  • Interleukin-1 receptor antagonist
  • Transforming growth factor β1
  • T-lymphocyte protein 4
A new technology, genome-wide association studies (GWAS) by which millions of variants can be tested for any association in thousands of individuals. Early reports are very hopeful and implicate not only human leukocyte antigens (HLA), but also the immunoglobulin heavy chain locus, including IGHV4-61 gene segment, on chromosome 14.
Most studies5 have shown an association of HLA with ARF. DR7 and HLA*B5 are the most common allele. In Indian context, important association is among HLA-A33, DR2, DR3, and ARF. HLA-DR4 and DR7 are important associations in Pakistan, Brazil, and Turkey. Among B-cell alloantigen, D8/17 is an important association to ARF.
There are other evidences in favor of genetic role. First, children raised separately from their parents who had RHD are more prone to ARF with a relative risk of 2.93.6 The largest meta-analysis of 175 monozygotic and 260 dizygotic twin pair, the largest meta-analysis showed that the risk of ARF in a monozygotic twin with a history of ARF in the co-twin is increased by more than six times in comparison to dizygotic twins. Thus, the estimated heritability was 60%, implicating genetic factor as playing a significant role in RF.7
 
Ethnic Susceptibility
Prevalence of RHD is highest in Samoa in Hawaii and reported8 to be 77.7 per 1,000 Aboriginal population, Maori in New Zealand, south central Asia, and sub-Saharan Africa have also a high prevalence rate. Crowding, hygiene practice, carrier of rheumatogenic strains, and genetic predispositions are the presumption of this ethnic susceptibility. All of these population have high rate of pyoderma, which may be another causative factor.9
 
Environment
Poverty and economic disadvantage are the two most important responsible factors, deciding the environmental background. Household overcrowding is the most important environmental risk factor. Rural area is more susceptible, as overcrowding is more common in poor rural community, along with poor medical service. War leading to social disruption, displacement, overcrowding, and unhygienic living condition is an important environmental factor.
Is RF abating globally: Genetic and environmental perspective factor?
 
CARRIER2
Isolation of GAS in upper respiratory tract indicates either true infection or a carrier state. True infection is associated with rising antibody titer, whereas carrier state is not. Thus, beta-hemolytic streptococci carrier is defined as isolation of GAS without rising titer of antistreptococcal antibodies. Its rate is 10–50% in asymptomatic schoolchildren. In temperate countries, 50–60% of carriers harbor GAS, whereas in tropical countries, 60–70% harbor group C and G streptococci. Though carriers harbor organisms, they do not develop ARF or spread infection.10 About of 25% of patients with GAS pharyngitis remain culture-positive even after optimum antibiotic therapy. They are GAS carriers. The Infectious Disease Society of America (IDSA) does not recommend routine eradication of GAS carrier because of low risk of spreading infection.11 However, in area where RHD is of highly prevalent, routine eradication of GAS carrier has been advised.12 In certain situations, committee on infectious disease13 recommends eradication of GAS carrier (Box 1).
There are several treatment options including clindamycin, amoxicillin, and intramuscular penicillin plus 4 days of rifampicin. Therapy of choice is a 10-day course of clindamycin.135
 
EPIDEMIOLOGY
 
India14
India contributes to 25–50% of the global burden of newly diagnosed case, deaths, and hospitalization from RHD.15,16 Historically, one of the early reports of ARF and RHD in India was from Kolkata. Basu reported, in 1925, the incidence of rheumatic carditis 8.5% in his series of 446 patients of acquired heart disease.17
Incidence and prevalence of ARF and RHD in India can be assessed from hospital admission data (Table 1), population-based studies and school survey. In 1941, Kutumbiah from Chennai reported 39% of hospital admission as RHD.18 In 1965, it was reported as 44.6% from Bengal.19
Population-based surveys (Table 2) are a very few one. In earlier survey, prevalence range of RHD was 1.23/1,00020 to 2.2/1,00021 in rural and urban area of India. In a recent Indian Council of Medical Research (ICMR) survey, prevalence of ARF has been found as low as 0.0007–0.2/1,000 and that of RHD as 0.2–1.1/1,000.22
School survey (Table 3) in Gujarat,23 in 1986, showed prevalence of RHD 2.03/1,000, whereas, in 2006, in Rajasthan24 it was 0.67/1,000. The largest serial school survey was done by ICMR between 1972 and 1975, 1984 and 1987, and 2007 and 2010. Prevalence of RHD in-between 1972 and 1975 in 133,000 was 5.3/1,000, in-between 1984 and 1987 in 53,786 children was 2.9/1,000, and in-between 2007 and 2010 in 176,904 was 0.9/1,000.22 Thus, the prevalence of RHD in school children came down from 5.3/1,000 to 0.9/1,000 from 1970 to 2010.
Many of the school survey done in the first decade on this century included echocardiography to confirm the clinically suspected RHD. Then came up the studies, which surveyed to detect RHD by echocardiography. In consequence, prevalence was shot up. In one of the latest echo Doppler study25 by Nair et al. in 5–15 years-old 2016 schoolchildren in Kerala, using the World Heart Federation (WHF) criteria for RHD, the prevalence of RHD was found as 5.83/1,000.
TABLE 1   Hospital survey.
Study
Year
Admission (%)
Kutumbiah (Chennai)
1941
39.5
Padmawati (Delhi)
1958
39.1
Mathur (Agra)
1960
35.1
Banerjee (Kolkata)
1965
44.6
TABLE 2   Population survey.
Study
Year
Prevalence/1,000
Berry JN (Northern India)
1972
1.23–2.07
SB Roy (Ballabhgarh)
1968–1969
2.2
ICMR
2000–2010
0.2–1.1 (RHD)
0.0007–0.2 (ARF)
(ARF: acute rheumatic fever; ICMR: Indian Council of Medical Research; RHD: rheumatic heart disease)
In the latest rheumatic study by Saxena et al.,26 school survey was done in Ballabhgarh, South Gujarat, Manipur, and Goa. The same WHF echocardiographic criteria were followed in 16,294 school-going children between 5 and 15 years of age. They found “clinical” RHD with a prevalence of 0.36/1,000, whereas “echocardiographic” RHD with a prevalence of 7.7/1,000.
 
Acute Rheumatic Fever and Rheumatic Heart Disease: Really Declining in India?
All the above data indicate a downward trend of both incidence as well as prevalence of ARF and RHD in India. How certain scientifically is this conclusion?
A survey from Orissa showed that hospital admission of ARF/RHD remained same over a 20-years period, 45% of total cardiac cases even during 1991–2000.27 From an institution in Mumbai, autopsy data showed similar incidence of ARF/RHD as on 2002 and 25 years back.28 In a paper from the premier institution such as All India Institute of Medical Sciences (AIIMS), in 2009, the most common cause of heart failure admission was due to RHD.29 With a median incidence of 0.5/1,000, 131,000 children are affected by ARF every year. In consequence, around 44,000 children with RHD are added every year to RHD burden. Considering the lowest and highest prevalence rate of RHD, total cases suffering from RHD in India could be between 0.44 and 3.37 million.306
Table 3   School survey.
Region
Year
Age
Sample size
Prevalence
ICMR
1972–1975
133,000
0.8–11/1,000
ICMR
1984–1994
5–10
40,000
3.9/1,000
Gujarat
1986
8–18
11,346
2.03/1,000
Shimla
1992–1993
5–16
10,805
2.98/1,000
Vellore
2003
6–18
229,829
0.68/1,000
Bikaner
2006
5–14
3,292
0.67/1,000
Gorakhpur
2007
4–18
118,212
0.5/1,000
ICMR
2010
176,904
0.9/1,000
Shimla
2013
5–15
15,145
0.59/1,000
(ICMR: Indian Council of Medical Research
This has nicely been narrated in a review article by Kumar RK et al.,31—“Statistics from one region would most certainly not apply to the country as a whole. Sharp differences are likely to result from extreme variations in geography, living standards, economy, human-development indices, urbanization, and health infrastructure. Given the undeniable relationship between incidence of RF and living standard, it is particularly difficult to make generalizations for ARF and RHD using data collected from various parts of India scattered over the last five decades”.
 
Global Data
Global incidence and prevalence of ARF and RHD is variable. In industrialized country, it started showing lowering trend since early 60. Incidence of RF is now below 0.1/10,000, 0.7/1,000 in French Polynesia, 1/1,000 in Sudan, 1.5/1,000 in China.32 Prevalence of RHD is 0.2/1,000. Excluding industrialized countries, global burden of RHD is 0.8–5.7/10,000 in schoolchildren.33
 
Burden
From 1994 World Health Organization (WHO) data, global burden of RHD and ARF was 12 million individuals worldwide; 3 million had heart failure requiring hospitalization. Annual deaths from RHD in year 2000 were 332,000 worldwide.34 Disability-adjusted life years lost to RHD was 6.6 million worldwide. In another series from 1982 through 2002, 15.6 million people had RHD worldwide with 2,282,000 new cases each year and 233,000 resultant deaths each year.35 In a recent observation, there are around 33 million people with RHD globally with nearly 275,000 deaths every year.36
 
Epidemiological Trend: Is Rheumatic Fever Abating Globally?
Overall trend shows a downward trend of incidence and prevalence of ARF/RHD in developing countries, even after considering the higher detection of silent carditis/RHD by including echocardiogram in diagnostic tool. This trend mostly has been explained as socio-economic changes. However, Kaplan37 was a strong proponent of changing profile of virulence of GAS strain responsible for the variable trend.
The GAS strain, responsible for outbreak of ARF in early to mid-part of last century, was virulent mucoid strain, rich in M protein—same strain was found in the rheumatic outbreak in the United States as discussed below. Those strains are different from the strain now found in tropical country. Penicillin treatment and prophylaxis may have induced a genetic change of GAS strains over decades. There has been also a change in the host genome. Those who were susceptible to ARF epidemic in industrial countries in mid-part of last century have either died or were physically unable to bear offspring. Consequently, genetically most susceptible population may have been 7extinguished. Thus, the factors responsible for abatement of global ARF are:
  • Loss of GAS strain virulence
  • Change in host's genome
  • Less exposure to GAS due to improved environmental factor.
 
Resurgence of Acute Rheumatic Fever in the United States of America (Fig. 1)
As mentioned earlier, from 1985 to 1992, 250 new cases of ARF were reported in Utah and another 15 cases were seen at Primary Children's Hospital in Salt Lake City between January and November, 1992. This was not an epidemic artifact. During the same period, number of ARF was 5–12 times more than expected in 24 cities in the United States of America.38 The outbreak that occurred in middle-class family with easy access to medical care could not be explained only by socio-economic factors. What found interesting was a more mucoid GAS strain with M-18 type protein associated with ARF and M-1 type associated with toxic-shock syndrome and sepsis. Those two virulent strains were not common in prior decades.
 
Ethnic Burden
As mentioned earlier, in specific ethnic groups, the disease burden for ARF/RHD is enormous, even rising. In New Zealand, the rate of ARF was almost doubled between 2005 and 2010.39 From 0.19/10,000, it became 0.38/10,000. Mostly, they are occurring in the northern and central North Island. Rate is actually decreasing in New Zealand Europeans, whereas it is 23 times more likely in Maori and 50 times more likely in Pacific peoples than in other ethnic groups.
zoom view
Fig. 1: Insurgent of mucoid strain during 1985–1990 in the United State of America (USA).
Prevalence of RHD was mentioned earlier in Samoa as 77.7/1,000, which was based on a school survey on auscultation of murmur by Steer. In subsequent study,40 heart murmur prevalence was 18/1,000 and confirmed RHD on echocardiogram was 3/1,000. Annual incidence of RHD as per registry is 0.66/1,000 and as per echo registry, prevalence is 3/1,000.
 
PATHOGENESIS OF RHEUMATIC FEVER
Why only a few with GAS pharyngitis will develop ARF? Is it an interaction between rheumatogenicity of the strain, genetic factor of the host, and conductive environment? Pathogenesis lies in the answers. May be the answer is not so simple.
What is a rheumatogenic strain? It must be an M serotype of GAS, which is heavily encapsulated, rich in M protein and is capable of forming large mucoid colonies. Those properties help the specific strains to adhere to host tissue and to fight destruction by host defense system. In most of the RF outbreak, limited number of M proteins was isolated, namely M-5, M-6, and M-18. May be those specific M proteins only have the antigenic mimicry to human tissue protein and, thus, the strains bearing those proteins are the rheumatogenic strains.
However, due to lack of animal model and nearly 130 types of M proteins, no specific rheumatogenic factor, so far, has been identified incontrovertibly. Antigenic mimicry has been questioned on the issue of predominant mitral valve involvement in rheumatic carditis, though all the four valves originate from the same embryonic cell rest. EL Kaplan raised another issue in an editorial,15 “conceptually it has never been explained how five individual humans infected with the same—possibly pathogenetic—strain of group A streptococci respond differently to the antigenic challenge, unless unique host factors are also considered? One of the five might have valvar involvement (carditis), another only arthritis (joints), a third chorea (central nervous system involvement), a fourth erythema marginatum (skin), and the fifth individual does not develop any sequelae? What other interpretation is logical?”8
Looking back in 1924, Home F Swift described the pathological findings in rheumatic carditis,41It is a moot point whether the destruction of the endothelium is primary or subsequent to an injury to the underlying tissue. Of this, however, we are certain that characteristic lesions occur in the mural subendocardial region without primary injury to the endothelium and, also, are found in the base of the valve leaflets. It is not difficult to conceive, therefore, of the primary injury of the valves occurring in their substance rather than on their surface; and if this is true it would be better to consider rheumatic disease of these structures as a valvulitis rather than a simple endocarditis”.
In a simple way, M protein of rheumatogenic GAS strain has mimicry to human tissue including valve and myocardium (Fig. 2). Molecular mimicry is defined as sharing of epitopes between antigen of the host and streptococcal strain. Autoreactive antibodies, which initiate the autoimmune process, are formed against streptococcal as well as host tissue. Then, a two-staged reaction42 occurs.
In the first stage (Fig. 3), in a genetically predisposed host, endothelium of valve leaflets is inflamed and damaged by that autoantibody of the rheumatogenic strains, which can identify epitopes in laminin of the valvular endothelium as well as myosin. This process leads to upregulation of vascular cell adhesion molecule-I (VCAM-I), which promotes the second stage, CD4+ and CD8+ T-cell infiltration and adhesion. Those M protein specific T cells produce inflammatory cytokines [γ-interferon (IFN)], which lead to destruction, scarring, and neovascularization of the valve tissue.
A new concept43 has been given over the time old concept of autoimmune therapy (Fig. 4). Streptoccal M protein N-terminus domain uses to bind to the CB3 region in the collagen type IV of the subendothelial and perivascular connective tissue matrix. This binding initiates antibody response to collagen, resulting in inflammation. All the organs containing collagen matrix and endothelial cells enveloping them are affected during RF. The characteristic of heart valve is its two layers of endothelial tissue with minimal tissues in between. In consequence heart valves heal with scarring, whereas other organs heal without any residual damage. Thus, this is not a reaction due to failure of immune system and there is no molecular mimicry in the pathogenesis.
 
CLINICAL CRITERIA
One should not overdiagnose ARF. But, more importantly, not a single patient of RF should be missed. Thus, beyond all the criteria, one should apply his clinical judgment. This is for two reasons. Firstly in 31–78% of cases, depending on economic status, there is no history suggestive of ARF and secondly, in around 16.8% (pooled prevalence) cases, there may be subclinical carditis.
zoom view
Fig. 2: Myeloma (M) protein liberated from Streptococcus is presented to CD4+ lymphocytes. The B lymphocyte liberates antigen against M protein and CD4+ lymphocytes become memory cells.
9
zoom view
Fig. 3: Effect of memory T cells and anti-M protein antibody on valvular endothelial cell.
zoom view
Fig. 4: Myeloma (M) proteins bind to basement membrane collagen fibers and degrade them. In consequence, endothelial cells are also damaged. They heal by scarring.
 
Jones Original Criteria
T Ducket Jones, in 1948, proposed the criteria to diagnose ARF,44 in a very unceremonious way in the journal of American Medical Association only with 11 references! And those criteria became the most quoted criteria in cardiac science. Over next six decades, several modifications by American Heart Association (AHA) and WHO have been done (Box 2 and Table 4). None of those modifications were evidence-based, rather than consensus-based. In his original criteria, Jones kept erythema marginatum in minor criteria, whereas pre-existing ARF/RHD was a major criterion. He did not include evidence of recent streptococcal infection as criteria.
 
American Heart Association Revision
American Heart Association made the first revision of Jones criteria in 1956, followed by 1965 and 1992.
 
World Health Organization Revision
Last modification (Box 3) in 2003 by WHO46 did not change much from its preceding AHA update excepting that it included pre-existing ARF/RHD as special consideration instead of minor criteria and scarlet fever as evidence of previous streptococcal infection.
According to these criteria, new onset of ARF may be diagnosed by presence of two major or one major and two minor manifestations along with evidence of preceding streptococcal infection. Recurrent attack of RF in person without preceding ARF/RHD may be diagnosed by presence of similar criteria as above, whereas in presence of past ARF/RHD, recurrence may be established by the presence of two minor manifestations along with evidence of preceding streptococcal infection. Rheumatic chorea or insidious onset carditis does not require any other major manifestation or evidence of preceding streptococcal infection to diagnose ARF.10
TABLE 4   Jones criteria with its various modifications.
1944
1956
1965
1988
1992
2003
2015
Jones
AHA
AHA
WHO
AHA
WHO
AHA
Carditis
M
M
M
M
M
M
M
Polyarthritis
M
M
M
M
M
M
Monoarthritis
M
Polyarthralgia
M
m
m
m
m
m
M
Monoarthralgia
m
SCN
M
M
M
M
M
M
M
EM
m
M
M
M
M
M
M
Chorea
M
M
M
M
M
M
M
Prior ARF/RHD
M
m
m
m
m
S
  • Epistaxis abdomen Anemia
  • Pain abdomen
  • Anemia
m
Lab finding
Prolonged PR interval
m
m
m
m
m
m
Acute phase reactants
m
m
m
m
m
m
m
  • Evidence
  • Recent Streptococcal infection
m
E
S
S
S
E
Echo
M
(AHA: American Heart Association; ARF: acute rheumatic fever; E: essential criteria; EM: erythema marginatum; M; major criteria; m: minor criteria; RHD: rheumatic heart disease; S: special consideration; SCN: subcutaneous nodule; WHO: World Health Organization)
 
2012 Australian Guidelines
Subsequently came Australian (Table 5) and New Zealand guidelines, which made some important inclusions. Subclinical carditis, monoarthritis, and polyarthralgia have been included as major criteria. Fever has been defined as temperature >38°C. Increased erythrocyte sedimentation rate (ESR) has been defined as ESR >30–50 mm/h, whereas increased C-reactive protein (CRP) has been defined as CRP >30 mg/L.
High risk: High-risk groups are those living in communities with high rates of ARF (incidence >30/100,000 per year in 5–14 years old) or RHD (all-age prevalence >2/1,000). Aboriginal people and Torres Strait Islanders living in rural or remote settings are known to be at high-risk.11
Table 5   2012 Australian guidelines for diagnosis of acute rheumatic fever (ARF).
Definite initial episode of ARF
2 major or 1 major and 2 minor manifestations plus evidence of a preceding GAS infection
Definite recurrent episode of ARF in a patient with known past ARF or RHD
2 major or 1 major and 1 minor or 3 minor manifestations plus evidence of a preceding GAS infection
Probable ARF (first episode or recurrence)
A clinical presentation that falls short by either 1 major and 1 minor manifestation, or the absence of streptococcal serology results, but one in which ARF is considered the most likely diagnosis. Such case should be further categorized according the level of confidence with which the diagnosis is made:
  • Highly suspected ARF
  • Uncertain ARF
High-risk group
All other group
Major manifestations
  • Carditis (including subclinical evidence of rheumatic valvulitis on echocardiogram)
  • Polyarthritis or aseptic monoarthritis or polyarthralgia
  • Chorea
  • Erythema marginatum
  • Subcutaneous nodules
  • Carditis (including subclinical evidence of rheumatic valvulitis on echocardiogram)
  • Polyarthritis
  • Chorea
  • Erythema marginatum
  • Subcutaneous nodules
Minor manifestations
  • Monoarthralgia
  • Fever
  • ESR ≥30 mm/h or CRP ≥30 mm/L
  • Prolonged P-R interval on ECG
  • Fever
  • Polyarthralgia or aseptic monoarthritis
  • ESR ≥30 mm/h or CRP ≥30 mm/L
[(ARF: acute rheumatic fever; CRP: C-reactive protein; ESR: erythrocyte sedimentation rate; GAS: Group A Streptococcus pyogenes) High-risk: High-risk groups are those living in communities with high rates of ARF (incidence >30/100,000 per year in 5–14-year-old) or RHD (all-age prevalence >2/1,000). Aboriginal people and Torres Strait Islanders living in rural or remote settings are known to be at high-risk]
 
Latest Revision: 2015 American Heart Association Guideline
Last revision by AHA (Box 4) came out in 2015. There are four major revisions:
  1. The proposed criteria are determined by pretest probability and background disease prevalence in the population to avoid overdiagnosis of ARF in low-risk population and underdiagnosis in high-risk population.
  2. This was first time, when echocardiographic carditis was included in major criteria.
  3. Preceding GAS infection is considered as essential criteria.
  4. “Possible” RF has been introduced. Jones criteria may not be fulfilled in those areas where RF is common, but laboratory facility is not available. A diagnosis of “possible” RF is made and patient is put on secondary prophylaxis. Patient is re-evaluated at 1 year by history, clinical examination, and echocardiography.
To diagnose ARF, there must be two major criteria and one minor criterion or one major and two minor criteria, in the presence of preceding GAS infection.
To diagnose recurrent RF, there must be two major criteria and one minor criterion or one major and two minor criteria or three minor criteria in the presence of preceding GAS infection.
Why so many modifications of Jones criteria?
All the modifications were made to increase the sensitivity and specificity to diagnose ARF.
First modification, in 1956, was to make objective arthritis as major criteria and arthralgia as minor criteria. History of previous ARF/RHD was changed to minor criteria. Thus, in recurrence, documentation of major criteria was made essential. Erythema marginatum was considered as major criteria. Documentation of preceding GAS infection was included in minor criteria.12
In 1965, next revision, evidence of preceding GAS infection was included as essential criteria.
What happened on those modifications? Specificity increased at the cost of sensitivity. At least 25% of ARF diagnosed on 1956 criteria could not be diagnosed on 1965 revision.
In 1984 modification, antecedent GAS infection criteria were no more essential to diagnose RF with late manifestations. Further modification included diagnosis of recurrence, which included findings of pericarditis or obvious change in cardiac findings.
However, pericardial involvement being not common and new changes in cardiac findings being difficult to assess, in 1992 update, past history of ARF/RHD was excluded from criteria. The implication was that Jones criteria would be applicable only for new onset of ARF and not for the diagnosis of recurrence of ARF, as intended by original Jones criteria.
In 2003, in WHO criteria, two minor criteria with evidence of antecedent GAS infection were included as diagnostic criteria for recurrent RF in patients with past history of RHD.
Polyarthralgia and echocardiogram48 have been included as major criteria in high-risk population in preceding and latest 2012 Australian guidelines. In the latest 2015 AHA revision, echocardiography and polyarthralgia were included in major criteria in low-risk population.
 
RHEUMATIC CARDITIS
Rheumatic carditis is essentially a pancarditis, involving endocardium, myocardium, and pericardium. But to diagnose carditis (Box 5), endocardial involvement, i.e., murmur is essential.
Carditis occurs within 2 weeks of onset of RF in 80% cases. Rule of thumb is severe with the arthritis, lesser the carditis and vice versa. The most common major manifestation during the first episode of ARF is carditis.
Recurrent carditis in presence of pre-existing RHD is difficult to establish. New onset/changing murmur and pericardial rub may be found occasionally. Cardiomegaly may be due to pre-existing cardiac lesion and congestive heart failure (CHF) may be due to progressive deterioration of the pre-existing lesions.
 
Mitral Valvulitis
Endocarditis or valvulitis is the most important prognostic determinant in rheumatic carditis and murmur is its hallmark. Mitral valve involvement is the most common in rheumatic carditis. There is no known explanation to this fact.
13
Leaflets, annulus, and chordate are all involved in the process. Mild-to-moderate mitral regurgitation (MR) is common rather than severe MR. If recurrence can be prevented, mild and occasionally moderate MR may be resolved49 over time. Severe MR is responsible for heart failure, progressive, and commonly due to flail leaflet. There may be macroscopic verrucous vegetation on valve apparatus appearing as nodules. Otherwise, leaflets remain remarkably normal in rheumatic valvulitis. Posterior annulus involvement is the most contributory factor to MR. It leads to (posterior) annular dysfunction, lesser movement of posterior mitral leaflet (PML) and anterior mitral leaflet (AML) (pseudo) prolapse. In one series, AML prolapse was found in 90% cases, with average posterior annulus diameter as 37 mm compared with matched control diameter as 23 mm.16 As prolapse is the major mechanism (Box 6), MR murmur in rheumatic carditis may be mid or late systolic, rather than pansystolic.50
Carey Coombs murmur: In the acute stage of acute rheumatic mitral valvulitis there may be a transient and short mid-diastolic murmur. It is presumably due to edema of the leaflets or a functional murmur in presence of severe MR. Dr Carey Coombs, in 1924, described this murmur.
Aortic valvulitis: Aortic annulus is involved by rheumatic process, leading to annular dilatation, dysfunction, and leaflet malcoaptation leading to mild-to-moderate aortic regurgitation (AR). Occasionally, aortic valve may show gross prolapse with severe AR.
Frequency of different valve involvement is different in different series (Table 6).
Pal Wood52 provided a pathophysiological postulation for this order of frequency of valve involvement. Mitral valve is subject to the highest pressure, a systolic pressure of around 120 mm Hg. Aortic valve withstands aortic diastolic pressure, which is around 80 mm Hg. Tricuspid valve is exposed to right ventricular systolic pressure, which is around 15–20 mm Hg, whereas pulmonary valve is subject to pulmonary diastolic pressure of around 8–10 mm Hg. This explains rheumatic aortic valve involvement without mitral valve involvement is uncommon, whereas isolated tricuspid valve involvement without mitral or aortic valve involvement is not reported.
Table 6   Valve involvement.47
Mitral valve
70–75%
Mitral and aortic valve
20–25%
Isolated aortic valve
5–8%
Tricuspid valve51
(pathological)
Clinically rare in 1st attack
15–30%
Pulmonary valve
Almost never recognized clinically
Incidence of clinical cardiac involvement in ARF has been reported in 50–70% in various studies.53 In prospective studies, incidence has been reported as high as 50%.54 In the resurgence of ARF in the United States in ’80s, the Utah series showed clinical carditis in 72% of children, whereas echocardiographic carditis was found in 91% of cases.55
  • Subclinical carditis: When clinical examination is normal but echocardiogram is abnormal.
  • Indolent carditis: It is a common entity in developing country. Patient presents with persistent features of heart failure, murmur, and cardiomegaly. There is no other manifestation of ARF.
  • Smoldering carditis: Chronic subclinical rheumatic activity which may be responsible for very early stenotic lesions in developing country.
  • Heart failure in first attack: 5–10% cases.
 
Myocarditis
Incidence of myocarditis is difficult to decide in ARF. Time-old concept that myocardial involvement (Box 7) being responsible for heart failure and significant cardiomegaly has not been established. Rather, it has been shown in several studies5658 that myocardial involvement is unlikely to cause heart failure.
 
Pericarditis
Pericarditis in rheumatic carditis may be detected clinically in 6–25% cases. It never happens without valvulitis. Its association indicates severe carditis. It may be transient and missed easily. Pericardial fluid may be hemorrhagic. Spontaneous remission is the norms. Tamponade or constriction is rare.14
 
RHEUMATIC ARTHRITIS
Rheumatic arthritis (Table 7) occurs in around 35–66% of patients with first episode of ARF. This is the most common, earliest, and sometimes the only major manifestation of RF. More the age, more common and severe is the arthritis, whereas lesser the age, more common is carditis.
Classically, arthritis is migratory, involving most commonly knee and ankle joints, whereas axial joints are rarely affected. Involved joints show all the features of inflammation such as redness, swelling, and tenderness. Excruciating tenderness is essentially the hallmark of rheumatic arthritis. Another characteristic feature is arthritis being exquisitely responsive to nonsteroidal anti-inflammatory drugs (NSAIDs), more specifically to aspirin. Inflammation of an affected joint is usually resolved within 2 weeks and arthritis as a major manifestation is resolved without any residual by 1 month, even without treatment.
TABLE 7   Frequency of joint involvement in acute rheumatic fever (ARF).54
Joint
Incidence (%)
Single large joint
25
One or both knee
76
One or both ankles
50
Elbow, wrist, hips, and small joint of feet
12–15
Shoulder, small joints hand
7–8
Lumbosacral joints
2
Cervical joint
1
Temporomandibular joint
0.5
Small joints of hand/feet alone
1
 
Jaccoud's Arthritis
Jaccoud,60 in 1869, first described residual deformities following rheumatic arthritis. Subsequently, Bywaters61 described the following criteria for Jaccoud's arthritis.
  • History of severe RF with repeated and prolonged attack.
  • Recovery delayed and associated with stiffness in metacarpophalangeal joints, which later results in the appearance of joint deformity.
  • Deformity appears to be due to periarticular fascial and tendon fibrosis rather than to synovitis.
  • The deformity consists of flexon at the metacarpophalangeal joints with some associated periarticular soft tissue swelling and ulnar deviation most marked in the fifth finger.
  • Associated hyperextension at the proximal interphalangeal joints.
  • Joint disease is usually inactive with little or no symptoms and good functional capacity.
  • Radiologically, the earliest bone changes are erosion of the metacarpal head on the palmar and radial part of their circumference in an anteroposterior projection producing a hoof-like erosion.
 
Monoarthritis
Monoarthritis is not very uncommon in high-risk group. Septic arthritis must be excluded in this sort of presentation. In an Australian national study, monoarthritis was found in 19% of high-risk children and account for 24% of all joint manifestation 15with ARF in 2 years prospective study. Monoarthritis has been included in major criteria in high-risk children in Australian guideline62 and in moderate-to-high-risk population in 2015 AHA guideline. Its incidence is more frequent when NSAID has been started earlier in the disease process.
 
Polyarthralgia
Polyarthralgia more specifically migratory polyarthralgia is not uncommonly seen as the major joint manifestation in ARF, particularly in developing country. Thus, it has been included in major criteria in high-risk patient in Australian, New Zealand, and latest AHA guideline. Polyarthralgia is more common in ARF recurrence.
There is an inverse relation between severity of arthritis and carditis. In one study, severe carditis was found in 10% cases with classical arthritis, 33% cases with arthralgia, and 50% without any joint involvement.63
 
Poststreptococcal Reactive Arthritis
Arthritis may be a reactive phenomenon following streptococcal pharyngitis, called “poststreptococcal reactive arthritis (PSRA)”. Potential relationship of PSRA to ARF remains unresolved (Table 8). Features of PSRA include the development of arthritis 3–14 days after streptococcal pharyngitis; fever and a scarlatiniform rash are often present during the acute phase of pharyngitis but are absent by the time arthritis appears. Typically, these patients have prolonged symptoms and protracted arthritis, without any other major manifestation for ARF. Extra-articular manifestations such as tenosynovitis and renal abnormalities are more common.
TABLE 8   Poststreptococcal reactive arthritis (PSRA) versus acute rheumatic fever (ARF).
Arthritis
PSRA
ARF
Onset of arthritis after GAS
10 days
14–21 days
Aspirin
Slow response
Dramatic response
Joint involvement
Cumulative
Migratory
Course
Persistent
Transient
Joints
Large, small, and axial
Large
(GAS: Group A Streptococcus pyogenes)
Some of these patients fulfill the Jones criteria and should be diagnosed as having ARF. For those who do not fulfill the Jones criteria, the diagnosis of PSRA should be made only after other rheumatologic diagnoses [e.g., Lyme arthritis and rheumatoid arthritis (RA)] have been carefully excluded.
Close follow up, because some of those patients may develop RHD.64 Penicillin prophylaxis is recommended by AHA for 1 year and then discontinued, if found no carditis. If found any carditis, prophylaxis should be continued as ARF with carditis.65
 
CHOREA (CHOREA MINOR OR SAINT VITUS’ DANCE)
Chorea, popularly called Sydenham's chorea, is a late neurological manifestation of ARF. It is an uncommon major manifestation, more common in female and rare beyond the age of 21 years, reported in a wider range from 5 to 36% cases.66 Manifestation is in the form of sudden, pseudopurposive, repetitive involuntary movements along with muscular weakness, and emotional disturbances. Latent period between GAS infection and chorea is around 1–7 months. Thus, it is not associated with concomitant arthritis. Associated carditis or its sequel may be the only evidence in favor of RF.
Median duration of its natural course is around 4 months, ranging from 1 week to 2 years. Convulsive disorders, behavioral problems, learning disorders, and psychotic problems are the long-term sequel of rheumatic chorea. Recurrence, even on penicillin prophylaxis, has been reported.
Chorea is often preceded and followed by behavioral abnormalities, simulating obsessive-compulsive disorder (OCD). Recently, a strong association between D8/17B cell marker, preceding streptococcal infection and children suffering from OCD has been found.67 The theory has been proposed that GAS induces antibrain antibody, which functionally disrupts the basal ganglia pathways, leads to chorea and abnormal behavioral disorder.16
 
SUBCUTANEOUS NODULE
Reported incidence is variable (0–10%); may be up to 20% cases.55 They are painless, firm, and freely mobile, 0.5–1.5 cm. Site of occurrence is over bony prominence and extensor tendon, such as elbow (the most common), wrist, ankles, Achilles tendon, occiput, and spinal process of vertebrae. They appear in corpses, average 2–3 in number, and persist average for 2 weeks. They are usually associated with severe carditis and appear when carditis has already set in. Similar nodules also appear in RA and systemic lupus erythematosus (SLE). However, in ARF, nodules are smaller and shorter-lived than in RA. In both situations, they appear on elbow, but in ARF they are on olecranon, whereas in RA, they are 3–4 cm distal to it.
 
ERYTHEMA MARGINATUM (ERYTHEMA ANULARE)
Erythema marginatum is the uncommon major manifestation of ARF, particularly in dark-skinned persons. Incidence may be 4–15% in various series. As the rash may appear in early part of the disease and is evanescent in nature, it may be missed. A hot bath or shower may make them prominent. They appear on trunk and proximal limbs, uncommon on distal limbs, and never on face. Lesions are pink or red, nonpruritic, not raised from skin, and blanching in nature. They extend centrifugally with central clearing. Lesions may appear late in the disease process, during convalescence, even months after remission. They are usually associated with carditis.
 
MINOR MANIFESTATIONS
 
Fever
Fever is the most consistent minor manifestation of ARF. Australian and New Zealand guideline, fever has been defined at or >38°C. In 2015 AHA guideline, fever should be ≥38°C in moderate—and high-risk population and ≥38.5°C in low-risk population. Temperature uses to persist 1–2 weeks and not more than a month.
 
Epistaxis
Epistaxis is reported less and less in number. In and old series, its incidence was reported as high as 48%.55 Epistaxis was thought to be related to severe carditis. It may be a simple effect of high-dose aspirin.
 
Abdominal Pain
Abdominal pain may be the presenting feature in some children. As it may happen before other manifestation of ARF, pain abdomen may mimic mesenteric vasculitis or acute appendicitis.
 
Acute Phase Reactants
Acute phase reactants, including ESR (≥60 mm in the 1st hour) and CRP (≥30 mg/L), are the two most important markers to assess disease activity. They decide how long patient should be on rest and anti-inflammatory treatment should be continued.
 
EVIDENCE OF RECENT STREPTOCOCCAL PHARYNGITIS
In initial guidelines, evidence of recent streptococcal infection was an essential criterion. Subsequently, it is considered as supporting evidence, because ARF may have a late presentation with chorea or smoldering carditis, which can be diagnosed as ARF without evidence of recent streptococcal infection. In 2015 AHA guideline, it was again fixed as essential criteria.
As per AHA 2015 guideline preceding GAS infection is evidenced by any one of the following:
  • Throat swab culture, positive only in 11% of patients at diagnosis of ARF.
  • Rising titer of antistreptococcal antibody, either antistreptolysin O (ASO) or antideoxyribonuclease B (anti-DNase B).
  • Positive rapid group A streptococcal carbohydrate antigen test
 
Isolation of Group A Streptococci: Throat Culture
  • Throat culture should be done in all suspected patients of ARF before starting antibiotics.
  • Swab should be taken vigorously from tonsillar and pharyngeal area and culture should be looked at least for 48 hours.
  • When properly done, a single culture on a blood agar plate has a 90–95% sensitivity to detect GAS pharyngitis.68
  • A positive culture does not always indicate an infection and may be a carrier state.17
 
Detection of Streptococcal Antigen
  • Rapid antigen detection test (RADT) kit can be used to detect carbohydrate cell-wall antigen to GAS from throat swab materials.
  • A positive test bears a high specificity, nearing 85–100%, but a low sensitivity, nearing 31–95%.
  • Thus, a positive test ensures the presence of GAS, but a negative test needs a confirmation by doing a throat culture, specifically in children. In adult, a negative RADT can exclude the presence of GAS.
  • However, a positive RADT does not differentiate carrier state from infection.
 
Detection of Streptococcal Antibody69
Antistreptolysin-O antibody test and anti-DNase B test are commonly recommended. Antihyarulonidase test is no more done. Streptozyme test, a slide agglutination test for the detection of antibodies to several streptococcal antigens, is not standardized and is not recommended.
Upper limit of normal value (Table 9) defined as level not >20% of the population is variable, depending upon age and population in a region. In endemic area, ASO level may be up to 250 Todd units and in nonendemic area, level can be even 50 Todd units.
A single increased level of their titer indicates antecedent streptococcal infection. However, a rising titer at 3–4 weeks is more convincing. ASO begins to rise 1 week and peaks 3–6 weeks, remains detectable at a plateau level up to 3–6 months after infection, becomes undetectable in the next 6–12 months, whereas anti-DNAse begins to rise at 1–2 weeks and peak 6–8 weeks after GAS infection. This antibody titer remains high for 2–3 months and start declining up to 5–6 months. Anti-DNase level is not affected by liver disease or bacterial contamination, unlikely of ASO titer. It is falsely elevated in hemorrhagic pancreatitis. Some detectable ASO titer may be found in healthy population from previous minor GABHS infection.
TABLE 9   Normal range of ASO and anti-DNase titer.
Age (years)
ASO
Anti-DNase
2–4
120–160
60–240
5–9
160–240
320–360
10–12
240–320
480–640
(ASO: antistreptolysin-O; anti-DNase: antideoxyribonuclease)
Antibiotics or steroids may affect this level.70 Most patient with chorea and 20% patients with 1st episode of ARF may have low titer of anti-streptococcal antibody. ASO level is determined first and, if found normal, anti-DNase level is tested. When combined, specificity is raised to 90%69 and sensitivity is near 100%.
 
Other Evidences
During active stage, patients with ARF express abnormal level of D8/17+ B cells, almost in all cases. This monoclonal antibody test can be used for diagnosis of ARF in doubtful case.71
 
ROLE OF ECHOCARDIOGRAPHY IN RHEUMATIC FEVER
 
NATURAL HISTORY AND PROGNOSIS OF RHEUMATIC CARDITIS
 
First Episode
Active rheumatic process uses to persist around 6–8 weeks. The activity is decided by the symptoms of manifestations and acute phase reactants. No more mentioned, still useful is the pulse rate of the patient. There is a disproportionate tachycardia during disease activity. Few manifestations may manifest, even after cessation of rheumatic activity. They are rheumatic chorea and erythema marginatum and obviously carditis, indolent, or smoldering.
Severity of valvulitis on first episode determines the prognosis of that single episode. Mild-to-moderate MR can be resolved over time. Moderate-to-severe MR progressively deteriorates. Aortic valve lesion on presentation is usually mild-to-moderate. What cannot be predicted on first attack is the stenotic lesion. As a late squeal, its development appears inevitable in susceptible population. Mitral stenosis (MS) to develop after the initial episode takes 1–2 years to two decades. In developing country, MS develops quickly. There are several theories. One is subclinical recurrence. Another is smoldering carditis.18
But the most reasonable is Selzar and Cohn theory,72 in which they stated: “Considering an alternate explanation for progression of MS beyond its early stages, the most attractive hypothesis is to abandon the postulate of continuing rheumatic activity and to accept a theory that the initial rheumatic valvulitis and its early scarring consequences produce changes upon the valve that are capable later of perpetuating themselves in a nonspecific manner. ...One should thus visualize the rheumatic process as one responsible for the early changes upon the leaflets leading eventually to their fusion. Such fusion, producing the commissural type of MS, may cause only minimal trauma or none at all, because the normal atrioventricular filing pathway may not be affected. In such cases, mild MS may persist for life. Slight alteration of flow pattern producing minimal trauma to the valve may be analogous to a bicuspid aortic valve, i.e., produce progressive valve changes over a period of many decades. More severe involvement of the commissures and the involvement of the cusps and chordae by the early rheumatic process would alter flow patterns through the mitral orifice to a degree that progressive valvular deformity would ensue earlier in life”.
 
Recurrence
Recurrence is probably most important prognostic factor. It increases cardiovascular mortality and residual heart disease. Recurrence is the responsible factor for the aggressive nature of the disease in tropics. RF recurrence rate can be divided in two components: The rate of GAS infection per patient-year and the rate of rheumatic recurrence per streptococcal infection, the primary and secondary attack rate respectively. In a sporadic GAS pharyngitis, primary attack rate is 0.3%, whereas in epidemic GAS pharyngitis, primary attack rate is 3%. In patients with recent history of ARF, GAS pharyngitis may cause secondary attack rate as high as 65%.73 Secondary attack rate (Table 10) uses to come down from 23 to 11% between 1st and 5th year after the last attack.74
Among all patients with GAS infection with a previous history of ARF, recurrence rate is 16.5%.75
Chance of recurrence is high in the 1st year of the first attack and then decreases over years. This is explained by the fact that as children grow older, they are less prone to GAS infection. Another reason is that there is a reducing tendency of GAS infection to elicit ARF. In the 1st year, the secondary attack rate is 50%, whereas after 5 years of first attack, attack rate is only 10%. The risk becomes minimum after the age of 35–40 years of age.
TABLE 10   Secondary attack rate.75
Secondary attack rate
Interval since onset of last RF
<2 years
28%
2–5 years
15%
>5 years
10%
Number of previous attack of RF
≥2
27%
1
14%
RHD
Present
26%
Absent
13%
(RF: rheumatic fever; RHD: rheumatic heart disease)
To enumerate factors responsible for recurrence of RF:75
  • Symptomatic GAS infection
  • Young age
  • Short interval since preceding rheumatic attack
  • Number of previous attacks
  • Existing RHD
  • Prophylaxis by oral penicillin only
In contrast to popular belief, following factors are not responsible for recurrence:75
  • High ASO titer
  • Overcrowding, family welfare status
  • Rheumatic fever in sibling
  • Ethnic group
As mentioned earlier, recurrence can be diagnosed by WHO criteria: Two minor criteria with evidence of antecedent GAS infection with a history of RHD. As per AHA 2015 guideline, recurrent ARF requires two major, one major and two minor or three minor criteria, along with evidence of preceding GAS infection. Recurrent carditis upon existing RHD may be difficult to diagnose. In a known patient of RHD, new onset heart failure, appearance of new or changing murmur or pericardial rub are suggestive.
 
Related Terminology
Recurrence: A new episode of ARF following another GABHS infection; occurring after 8 weeks following stopping treatment.19
Rebound: Manifestations of ARF occurring within 4–6 weeks of stopping treatment or while tapering drugs.
Relapse: Worsening of ARF while under treatment and often with carditis.
 
UK/US Cooperative Trial70
This very old trial is excellent for information on follow-up and prognosis. This was a 10-year follow-up study of ARF. In the study, 94% of patients who had not any carditis at presentation did not show cardiac disease at 10 years of follow-up. Those who had grade 1 apical systolic murmur at presentation, only 30% showed significant valvular lesions at the end of 10 years, whereas those who presented with grade 2–3 apical systolic murmur, only 36% showed valvular lesions. In cases with pre-existing heart disease, the prognosis was poor. 60% of those initially without CHF and 89% of those with CHF were with significant valvular lesions at 10 years.
 
Disadvantaged Population
Prognosis is poor in certain population, who are very susceptible to ARF, as mentioned earlier. In a 13 years follow-up study in the indigenous Australian and Northern Territory, after the first RF diagnosis, 61% developed RHD within 10 years. After RHD diagnosis, 27% developed heart failure within 5 years. The relative survival rate was 88.4% with standardized mortality ratio 1.56.76
 
MANAGEMENT OF RHEUMATIC FEVER
 
Hospital Admission
All patients with RF preferably should be admitted in the hospital for diagnosis, management, and counseling for secondary prophylaxis plan.
 
Rest
Duration of ARF is around 10–12 weeks. Bed-chair rest is advised in the initial phase. Patient without carditis may be allowed to be ambulatory,2 once symptoms of arthritis get subsided and acute phase reactants are returning to normal. For patients with carditis, minimum 4-week rest77 is advised. For patients with heart failure, rest is advised for a longer period. Duration of rest and ambulation should be decided by physician as individual case basis.
 
Eradication of Group A Streptococci (Vide Primary Prevention)
Before starting antibiotic therapy, two throat swab cultures should be sent. But full course of therapy has to be given to everyone, once diagnosis of ARF is done irrespective of culture report. Antibiotic treatment reduces the infectivity and chance of relapse. However, it does not alter the disease course.
 
Anti-inflammatory
Aspirin (salicylates) is the first line of therapy. It is given in the dose of 100 mg/kg/day in 3–4 divided doses and can be increased to 125 mg/kg in children or 6–8 g/day in adult.78 Blood level of salicylate may be determined for a safer therapeutic window. Optimum level is 20–30 mg/dL. After 2 weeks, doses may be reduced to 60–70 mg/kg and be continued for 3–6 weeks.77
Nonsteroidal anti-inflammatory drug is not evidence-based. However, in aspirin-intolerant patient, naproxen in the dose of 10–20 mg/kg/day can be used.79
Steroid can be used when patient is unresponsive to aspirin or deteriorating on aspirin or is developing heart failure.2 Steroid may help to reduce pericarditis and toxic state faster. Apical systolic murmur may disappear earlier. Steroids neither have any mortality benefit nor any effect on course of the disease, but it may be life-saving in carditis with heart failure.80 Meta-analysis of several small studies, however, did not show any difference in the risk of cardiac disease at the end of 1 year.81 There had been no study in postecho era with modern corticosteroids.82 Prednisolone is used in the dose of 1–2 mg/kg/day. Dose tapering is started after 2 weeks, 20–25% each week and continued another 2 weeks.6577 In the last week, aspirin is started in its full therapeutic dose to prevent rebound.2
Methylprednisolone has been used as pulse therapy in severe rheumatic carditis in the dose of 1 g/day, three consecutive days in the 1st and 2nd weeks, 2 days in the 3rd week and 1 day in the 4th week.83 However, pulse therapy did not show any better result than prednisolone therapy.8420
Duration of therapy is not well-defined. To prevent rebound, prolonged anti-inflammatory has been suggested even up to 3 months.14 Duration should be guided by disappearance of symptoms and signs and acute phase reactants, rather than any fixed duration. Acute phase reactants may be checked in every week.14 In occasional cases, rheumatic activity may linger for a longer time, even 6 months. In those cases, anti-inflammatory drugs will have to be continued for longer time.
Rebound78 is not uncommon when therapy is stopped prematurely. Rebound may occur 2–3 weeks after completion of therapy. Remission occurs without further treatment, excepting occasional cases, which needs reinstitution of therapy.
 
How to Monitor Disease Activity?
Acute phase reactants can be used for monitoring disease activity and duration of therapy. Leukocytosis and prolonged PR interval have lesser role. ESR and CRP are the main determinants. ESR may be falsely low and high in heart failure and anemia respectively. Both ESR and CRP may be found normal, even if disease is active, such as in chorea and smoldering carditis.
Induction of subcutaneous nodule by injecting autologous blood or concentrated leukocytes on olecranon process of the patient along with frictional pressure upon it has been described without much validation.
 
Surgical Management85,86
Rheumatic carditis with heart failure not responding to medical management should be treated surgically. Hospital mortality in various study varied from 3.2 to 2.6%. 5-year mortality was around 15%. When valve repair was done in relatively early part of carditis, reoperation was very high and was in 27% cases. Thus, event-free survival at 5 years was 73%. Surgeon should check the valve during operation. If macroscopic inflammation can be seen, valve replacement, rather repair is a better choice to prevent continuation of rheumatic activity and reoperation.
 
PREVENTION
Prevention (Fig. 5) should play the most important role in RF.
zoom view
Fig. 5: Various modes of preventive measures.
 
Primordial Prevention
Primordial prevention targets to prevent GAS infection in population, thus, related to the socio-economic and health vision of the society and of the country. It involves creating an environment that will prevent the occurrence of GAS infection. This is difficult to achieve in the developing country. Other measures include:
  • Mass chemoprophylaxis that involves huge economic burden, wastage, and relative ineffectiveness.
  • To identify susceptible host and to treat them by chemoprophylaxis.
  • Vaccine
 
Primary Prevention
Primary prevention targets treating GAS infection in a susceptible host to prevent occurrence of ARF.
 
To identify Group A Streptococci Pharyngitis
Around 15 million acute pharyngitis per year in the United States of America, 20–30% in children, and 5–15% in adult of sore throat visits are from GAS pharyngitis.87 Mostly, etiology is viral (Table 11). There are scoring systems for diagnosing GAS etiology. But bacterial confirmation is always needful.21
TABLE 11   GAS versus viral pharyngitis.
GAS
Viral
Age 5–15 years
Sudden onset of sore throat
Conjunctivitis
Fever, headache, pain on swallowing
Coryza/cough
Abdominal pain
Diarrhea
Tonsillopharyngeal patchy exudative involvement
Hoarseness
Anterior cervical lymphadenitis
Winter and early spring
Scarlatiniform rash
Typical viral rash
(GAS: Group A Streptococcus pyogenes)
TABLE 12   GAS pharyngitis scoring.88
Age (years)
Score
<3
1
3–6
2
>6
3
+ Number of signs
Bacterial signs
Tender cervical node
1
Headache
1
Petechiae on palate
1
Abdominal pain
1
Sudden onset
1
− Number of signs
Viral signs
Conjunctivitis
1
Coryza
1
Diarrhea
1
Total score
(GAS: Group A Streptococcus pyogenes)
When score is ≤2, only symptomatic treatment is given and when score is ≥3, antibiotic treatment is given.
Guideline does not follow scoring system (Table 12) for decision to treat. Rather, scoring is done to decide pretest probability of GAS etiology. If it is low, further test is not done and antibiotic treatment is withheld. If the probability is high, throat culture is done. As mentioned earlier, RADT can be done. In children, a negative RADT must be cross-checked by throat culture. In adult, however, a negative RADT is enough documentation against GAS etiology. GAS antibody test is not recommended to establish the bacteriological etiology.
 
Treatment65
Rheumatic fever may be prevented (Table 13), even when treatment is delayed for 9 days89 from onset of symptoms. Thus, treatment can be started after culture report being available. RADT can help starting treatment and to make patient ambulant earlier. Patient becomes noncontagious within 24 hours of antibiotic treatment.90
Penicillin is the drug of choice because it is cheap, easily available and resistance to GAS has never been reported. Oral penicillin V (phenoxymethyl penicillin) or G can be used. Penicillin V is preferred because it is more resistant to gastric acid,65 thus absorption is better. It is given in the dose of 40 mg/kg/day (maximum up to 750 mg in <27 kg child) in three divided doses. Average dose is 250 mg two times a day.91 Therapy should be continued for 10 days. Both of them are available in:
Table 13   Primary prevention.65
Drug
Dose
Duration
Penicillin
Penicillin V/G
  • 250 mg 2–3 times/day ≤27 kg
  • 500 mg 2–3 times/day ≥27 kg
10 days
Or,
Amoxycillin
50 mg/kg/day (maximum 1 g)
10 days
Or,
Benzathin penicillin
  • 600,000 IU ≤27 kg
  • 1,200,000 IN ≥27 kg
Single I/M
Those allergic to penicillin
Cephalosporin
Variable
10 days
Clindamycin
20 mg/kg/day in 3 doses
(maximum 1.8 g/day)
10 days
Azithromycin
12 mg/kg once daily
(maximum 500 mg/day)
5 days
Clarithromycin
15 mg/kg/day in 2 doses
(maximum 500 mg/day)
10 days
22
  • Tablet 250 mg (400,000 units)
  • Tablet 500 mg (800,000 units)
Alternately, oral amoxicillin can be used (in the dose of 50 mg/kg, maximum to 1,000 mg) for 10 days.
When noncompliance is an issue or patient is in high-risk to develop RHD, single intramuscular benzathine penicillin can be used.
In patients allergic to penicillin, narrow spectrum cephalosporin can be used for 10 days. Clindamycin (GAS resistance around 1%) and macrolides (including erythromycin, clarithromycin, and azithromycin; GAS resistance around 5–8%) are reasonable alternates.
Routine post-therapy throat culture is not needful. Only when patient remains symptomatic, or recurrence of symptom or patient is of high risk for RHD, it may be done. In those patients, if culture is positive, re-treatment is indicated. Narrow spectrum cephalosporin, clindamycin, or penicillin plus rifampicin can be used in penicillin failure cases.65
 
SECONDARY PREVENTION (TABLE 14)
Recurrence of ARF is the most important prognostic factor and its prevention is the best way to prevent RHD burden.
Table 14   Secondary recommendation: Different guidelines.
Body
Interval
Dose
WHO15
3–4weeks
  • ≥30 kg: 1.2 million
  • <30 kg: 0. 6 million
AHA76
3–4 weeks
  • ≥27 kg:1.2 million
  • <27 kg: 0.6 million
*NHF/CSANZ
4 weeks
  • ≥20 kg: 1.2 million
  • <20 kg: 0.6 million
IAP
  • 3 weeks
  • 2 weeks
  • >27 kg: 1.2 million
  • <27 kg: 0.6 million
*New Zealand guideline94/Australia and New Zealand guideline95 (AHA: American Heart Association; CSANZ: Cardiac Society of Australia and New Zealand; IAP: Indian Academy of Pediatrics;96 NHF: National Heart Foundation; WHO: World Health Organization)
 
Drug of Choice
Intramuscular long-acting penicillin is the drug of choice. Preferred molecule is the benzathine salt of penicillin G (benzylpenicillin), combined with procaine salt of penicillin G to reduce pain at injection site. Penicillin G benzathine is prepared by combination of dibenzylethylenediamine with two molecules of penicillin G. Penicillin G procaine is an equimolar salt of procaine and penicillin G. Procaine is a local anesthetic agent, thus reducing pain. Penicillin G benzathine and penicillin G procaine have a low solubility and they are slowly released from intramuscular sites. They are then hydrolyzed to penicillin G. Both hydrolysis and slow absorption result in blood serum level much lower but more prolonged.
 
Interval
Interval of benzathine penicillin, 2 weeks versus 3 weeks versus 4 weeks, is debated. A nicely methodological review, known as Cochrane review92 explored nine studies, mostly methodologically poor and suggested a 2-weekly or 3-weekly penicillin regime. They argued that a 2- or 3-weekly regimen maintains blood penicillin level above minimum inhibitory concentration (0.02 mcg/mL) better than a 4-weekly regime. Others favor a 4-weekly regime. They93 showed a better adherence with 4-weekly regime, thus the same recurrence rate between this regime and 2- or 3-weekly regimes. Guidelines, including AHA,65 Australian95 and New Zealand94 guidelines suggest a 3-weekly regime for high-risk group (moderate or severe carditis or history of valve surgery or a breakthrough on 4-week regime), otherwise a 4-weekly regime. Indian Pediatric guideline suggests a 2-weekly and 3-weekly regime.96
 
Doses
All guidelines suggest 1.2 million-unit doses of benzathine penicillin for adult patient. For children, opinion differs as mentioned on the Table 14. One pharmacokinetic study97 suggested that 0.6-million-unit dose in <27 kg was insufficient to maintain optimum blood level of penicillin.23
 
Duration
There are consensus guidelines regarding the duration of prophylaxis. But physician should consider several factors in an indexed case. Those who have higher risk of recurrence (Box 8 and Table 15) should be considered for a longer prophylaxis.
Rheumatic fever is uncommon between 25–40 years of age and rare after 40 years of age. In high-risk Northern Territory Aboriginal patients, ARF beyond 40 years of age was 1%.98 Chance of recurrence becomes uncommon after 5 years from last episode. All those factors should be considered before deciding the duration of secondary prophylaxis.
World Health Organization ARF and RHD technical report46 suggests: Duration should be 5 years after last attack or until 18 years of age (whichever is longer) in patients without carditis; duration should be 10 years after last attack, if carditis is present or at least 25 years of age (whichever is longer). It should be lifelong, if severe valvular disease or after valve surgery.
New Zealand guideline94 suggests: Minimum 10 years after the last episode of ARF with no or mild carditis; duration should be minimum of 10 years after last attack or until the age of 30 years whichever is longer, if moderate carditis is present. If severe carditis is present, prophylaxis as above and then specialist review for consideration of lifelong prophylaxis.
Table 15   American Heart Association (AHA) 2009 duration of secondary prevention.65
RF without carditis
5 years or 21 years of age (whichever is longer)
RF with carditis
No residual heart disease
10 years or 21 years of age (whichever is longer)
RF with carditis and residual heart disease
10 years or 40 years of age (whichever is longer) or lifelong
(RF: rheumatic fever)
Australian guideline95 suggests: Minimum 10 years after the episode of ARF or 21 years, whichever is longer. Same duration is applicable, if there is a mild regurgitant lesion without any cardiomegaly on echocardiogram. In moderate carditis, prophylaxis should be continued till 35 years of age. In severe carditis, it should be continued till 40 years of age or lifelong.
 
Penicillin Allergy
In view of benefit far outweighing risk, penicillin should be continued in most of the patients. Allergic reaction, anaphylaxis and fatality are uncommon, in the tune of 3.2% and 0.2% and 0.05%, respectively.99 Skin test does not always ensure safety (Box 9).
 
Oral Penicillin
Adherence is the most important problem. Chance of recurrence is also high. Molecules and dosage have been described in primary prevention.
 
Sulfonamide100
Sulfadiazine and other sulfonamides can be used in penicillin allergic patients. It is not effective in eradicating GAS, but can prevent recurrence. It is given in the dose of 1 g (>27 kg) and 500 mg (below 27 kg) daily.
 
Macrolides
Macrolides can be used in penicillin and sulfadiazine allergic patient.
24
 
Prophylaxis in Pregnancy
Penicillin prophylaxis must be continued in pregnancy. It has no documented ill effects on pregnancy. In penicillin allergic patients, erythromycin can be used.95 However, no controlled trial has been done.
 
Prophylaxis after Valve Replacement
Remaining native valve tissue of the replaced prosthetic valve and other native valve may be affected by recurrent carditis. Intramuscular bleeding in anticoagulated patients on intramuscular penicillin is not common.95 Thus, penicillin prophylaxis should be continued after valve replacement surgery.101
 
Prophylaxis Failure
In the above-mentioned Cochrane review,92 in four studies, 561 received intramuscular penicillin and 537 received oral penicillin. There were seven recurrences of ARF in the former group and 89 recurrences of ARF in the later group.
In Irvington House study,102,103 recurrence of RF on intramuscular penicillin, oral penicillin, and sulfadiazine had been shown as 0.4, 5.5, and 2.8 per 100 patient-years, respectively. In that way, sulfonamides offer better prophylaxis than oral penicillin.104
 
CONCLUSION
May be, incidence and prevalence of ARF/RHD are declining in developing country too. It may resurge again with the appearance of more virulent strain. Jones criteria are still useful. So far, secondary prevention with benzathine penicillin is the best way among the preventive measures. However, best ways to prevent ARF/RHD in future are primordial prevention and rheumatic vaccine. Over last five decade, trials so far have been failed to isolated M protein based vaccine.
In the latest WHO statement in 71st World Health Assembly, published in April 2018, epidemiological data has been updated. As per this data, some 30 million people are currently thought to be affected by RHD globally. About of 305,000 deaths and 11.5 million disability-adjusted life years loss due to RHD happened in 2015. The most important statement made by WHO 2018 was:
Also came out the REMEDY study,105 in which between 2010 and 2012, 3,343 patients from 25 centers in 14 low- and middle-income countries were studied for 2 years to assess mortality, CHF, stroke, recurrent ARF, and infective endocarditis. Mortality rate was 116.3/1,000 patients-years in the 1st year and 65.4/1,000 patients-years in the 2nd year. Median age at death was 28.7 years. Predictors of death were severe valve disease, CHF, New York Heart Association (NYHA) III/IV, atrial fibrillation, and older age.
Ramakrishnan S et al. can be quoted from their elegant review,28—“RHD is not gone, but forgotten. The decline in the incidence of RF/RHD in the developed world has unfortunately resulted in a parallel decline in the research interest in the disease. The developed world has forgotten RHD with a waning of the disease burden among <20% of the world's population living in the high-income countries. Similarly, a reduction in the RHD burden among the 20% privileged population in India should not make us lose focus from this enigmatic illness”.
Statistical data in relation to ARF/RHD are summarised in the Table 16.
When did ARF occur first on this earth? Was it present at the time of Hippocrates? Described106 in Hippocratic Corpus (*) as,—“An ulcerated throat with fever is serious; but if some other symptom also supervene that has been already classed as bad, forecast that the patient is in danger. Angina is very serious and rapidly fatal, when no lesion is to be seen in either throat or neck and moreover it causes very great pain and orthopnea……”. The enigma is unending.25
TABLE 16   Statistical data related to ARF/RHD.
Data
Reference
ARF incidence rates have been reported to be as high as 155/100,000 children aged 5 to 14 years in indigenous populations in North Queensland, Australia
Gray C, Brown A, and Thomson N. (2012). Review of cardiovascular health among Indigenous Australians. Retrieved February 6, 2017, from Australian Indigenous HealthInfoNet: http://www.healthinfonet.ecu.edu.au/chronic-conditions/cvd/reviews/heart_review
Prevalence of RHD is highest in Samoa in Hawaii and reported to be 77.7/1,000.
In Saoma, in subsequent study, heart murmur prevalence was 18/1,000 and confirmed RHD on echocardiogram was 3/1,000. Annual incidence of RHD as per registry is 0.66/1,000 and as per echo registry, prevalence is 3/1,000
Adams J, Carlin J, Nolan T, Shann F. Rheumatic heart disease in school children in Samoa. Arch Dis Child. 1999;81(4):372
Viali S. Rheumatic fever and Rheumatic heart disease in Samoa. Pacific public health 2006;13(2):31-38
Between 1993 and 2009, the average incidence rates for ARF based on hospitalization data for children 5–14 years were 81.2/100,000 for Pasifika children, as compared with 40.2/100,000 for
children and 2.1/100,000 for non-
, non-Pasifika children
Milne RJ, Lennon DR, Stewart JM, Vander Hoorn S, Scuffham PA. Incidence of acute rheumatic fever in New Zealand children and youth. Journal of Paediatrics and Child Health. 2012a;48(8):685-91
Global disease estimates in 2005 reported 471,000 ARF cases annually, which largely occurred in children and teens aged 5–15 years, with the prevalence of RHD cases ranging between 15.6–19.6 million
The number of new cases of RHD diagnosed was estimated at 282,000 per year, with approximately 233,000 deaths annually
Carapetis JR, Steer AC, Mulholland EK, Weber M. The global burden of group A streptococcal diseases. The Lancet Infectious Diseases. 2005;5(11):685-94
In 2015, an estimated 33.4 million people worldwide had RHD, resulting in 319,400 deaths and 10.5 million disability-adjusted life-years lost per annum
Watkins DA, Johnson CO, Colquhoun SM, et al. Global, regional, and national burden of rheumatic heart disease, 1990e2015. N Engl J Med. 2017;377:713e722
A meta-analysis of twin studies found that the pooled proband wise concordance risk was 44% and 12% in monozygotic and dizygotic twins respectively, and the association between zygosity and concordance was strong, with an odds ratio of 6.4 (95% CI 3.4 to 12.1)
Engel ME, Stander R, Vogel J, Adeyemo AA, Mayosi BM. Genetic susceptibility to acute rheumatic fever: a systematic review and meta-analysis of twin studies. PLoS One. 2011;6(9):e25326
The Global Rheumatic Heart Disease Registry study (REMEDY) showed that the proportion of patients with RHD who had a previous history of ARF is 22.3% in low-income countries, 44.3% in lower-middle-income countries, and 59% of upper-middle-income countries
Zuhlke L, Engel ME, Karthikeyan G, et al. Characteristics, complications, and gaps in evidence-based interventions in rheumatic heart disease: The global rheumatic heart disease registry (the REMEDY study). Eur Heart J. 2015;36:1115e1122
GAS is the commonest pathogen to cause bacterial pharyngitis, with its peak incidence in children 5–15 years of age. At this age, in any episode of pharyngitis, GAS is responsible in 15–20% cases and viral pathogens in 80% cases. About 10% of sore throats in adults are due to GAS infections. GAS is droplet spread with a cross-infection rate of 19–50% within a household
Rheumatic fever and rheumatic heart disease. Report of a WHO Study Group. Geneva, World Health Organization, 1988 (Technical Report Series, No. 764)26
As only 0.3–3% of individuals affected by streptococcal pharyngitis may develop ARF
The chorea of ARF, also referred to as Sydenham's chorea or St. Vitus's dance, occurs 10–30% of patients with ARF
The skin manifestations of ARF occur in <10% of patients (subcutaneous nodule: 0–10%; erythema marginatum: <6%)
Gewitz. MH. Baltimore. RS, Tani Y, et al. Revision of the Jones criteria fro the diagnosis of acute rheumatic fever in the era of Doppler echocardiography: A scientific statement from the American heart association. Circulation 2015;131:1806-1827
In low-risk populations, defined as an “ARF incidence <2/100,000 school-aged children per year or an all-age prevalence of RHD of ≤1/1,000 population per year”
In the pre-penicillin, pre-echocardiography era, 24% of patients at 10 years and 44% of patients at 20 years who had no clinical carditis at ARF presentation had auscultatory findings of chronic RHD, despite only one-third having documented ARF reoccurrences
Bland EF, Duckett Jones T. Rheumatic fever and rheumatic heart disease; a twenty year report on 1000 patients followed since childhood. Circulation. 1951;4(6):836-43
Pure aortic valve disease is uncommon, occurring in only 4.5% of individuals <18 and 2.8% of those >18 in a large series of patients from India
Chockalingam A, Gnanavelu G, Elangovan S, Chockalingam V. Clinical spectrum of chronic rheumatic heart disease in India. The Journal of Heart Valve Disease. 2003;12(5):577-81
Aortic stenosis is a less common rheumatic valvular pathology that is found in only 9% of study subjects in a recent large prospective data collection across Africa
Zühlke L, Mayosi BM, Echocardiographic screening for subclinical rheumatic heart disease remains a research tool pending studies of impact on prognosis. Current Cardiology Reports. 2013;15(3):343
Rheumatic tricuspid involvement is more common than pulmonary involvement, with clinically apparent disease in 3–5% of patients
Carpentier A, Deloche A, Hanania G, Forman J, Sellier P, Piwnica A, et al. Surgical management of acquired tricuspid valve disease. The Journal of Thoracic and Cardiovascular Surgery. 1974;67(1):53-65
A systematic review of echocardiographic screening studies to date calculated a pooled prevalence of RHD of 2.9/1,000 people by auscultation, as compared to 12.9/1,000 people by echocardiography
Rothenbühler M, O'Sullivan CJ, Stortecky S, Stefanini GG, Spitzer E, Estill J, et al. Active surveillance for rheumatic heart disease in endemic regions: a systematic review and meta-analysis of prevalence among children and adolescents. The Lancet Global Health. 2014;2(12):e717-26
Carditis occurs within 2 weeks of onset of rheumatic fever in 80% cases. Incidence of clinical cardiac involvement in first episode of ARF has been reported 50–70%
In prospective studies, incidence has been reported as high as 50%
Gewitz MH, Baltimore RS, Tani Y, et al. Revision of the Jones criteria fro the diagnosis of acute rheumatic fever in the era of Doppler echocardiography: A scientific statement from the American heart association. Circulation 2015;131:1806-18
Kothari SS, Chandrashekhar Y, Tandon RK. Rheumatic carditis. In: Narula J, Virmani R, Reddy KS, Tandon R, eds. Rheumatic Fever. Washington, DC: American Registry of Pathology Publication; 1999:257-70
The prevalence of subclinical carditis ranges from 0% to 53% in 23 articles with a pooled prevalence of 16.8% (95% confidence interval 11.9–21.6%) increased slightly to 18.1% when the analysis was limited to the 10 studies that used the full World Health Organization
Tubridy-Clark M, Carapetis JR. Subclinical carditis in rheumatic fever: a systematic review. Int J Cardiol. 2007;119:54-8. doi: 10.1016/j. ijcard.2006.07.046
Gewitz MH, Baltimore RS, Tani Y, et al. Revision of the Jones criteria fro the diagnosis of acute rheumatic fever in the era of Doppler echocardiography: A scientific statement from the American heart association. Circulation 2015;131:1806-18
Mitral valve 70–75%
Mitral and aortic valve 20–25%
Isolated aortic valve 5–8%
Tricuspid valve: Clinical 5–6%
Pathological 15–30%
Narula J, Chandrasekhar Y, Rahimtoola S. Diagnosis of Active Rheumatic carditis The Echos of changes. Circulation. 1999;100:1576-81
Rheumatic arthritis occurs around 35–66% of patients with first episode of rheumatic fever
Monoarthritis was found in 19% of high-risk children and account for 24% of all joint manifestation
Gewitz MH, Baltimore RS, Tani Y, et al. Revision of the Jones criteria fro the diagnosis of acute rheumatic fever in the era of Doppler echocardiography: A scientific statement from the American heart association. Circulation. 2015;131:1806-18
Pericarditis in rheumatic carditis may be detected clinically in 6–25% cases
INDIAN data
Around 13.17 million cases of RHD in the year 2015
Watkins DA, Johnson CO, Colquhoun SM, Karthikeyan G, Beaton A, Bukhman G, et al. Global, regional, and national burden of rheumatic heart disease, 1990-2015. N Engl J Med. 2017;377:713-22
In a recent ICMR survey, prevalence of ARF has been found as low as 0.0007 to 0.2/1,000 and that of RHD as 0.2 to 1.1/1,000
Shah B, Sharma M, Kumar R, Brahmadathan KN, Abraham VJ, Tandon R. Rheumatic heart disease: Progress and challenge in India. Indian J pediatr. 2013; 80 (suppl 1): 77-86
Prevalence of RHD in school children came down from 5.3/1,000 to 0.9/1,000 from 1970 to 2010
Shah B, Sharma M, Kumar R, Brahmadathan KN, Abraham VJ, Tandon R. Rheumatic heart disease: Progress and challenge in India. Indian J pediatr. 2013; 80 (suppl 1): 77-86
Around 16,294 school-going children between 5-15 years of age. They found “clinical” RHD with a prevalence of 0.36/1,000, whereas “echocardiographic” RHD with a prevalence of 7.7/1,000
Saxena A, Desai A, Narvencar AD, et al. Echocardiographic prevalence of rheumatic heart disease in Indian school children using World Heart Fedaration criteria-a multisite extension of Rheumatic study (e-RHEUMATIC study). Int J Cardiol. 2017; http://doi.org/10.1016/j.ijcard.2017.09.184
Total cases suffering from RHD in India could be between 0.44 to 3.37 million
Ramkrishnan S, Kothari SS, Juneja R, et al. Prevalence of rheumatic heart disease: has it declined in India? The national medical J of India. 2009;22:72-74
A study from territory care center in Orissa showed no change in admission rate over a decade and the admission rate of 50% in 2013
Mishra TK, Routry SN, Bohora M, Patanaik UK, Sapathy C. Has the prevalence of rheumatic fever/rheumatic heart disease really changed? A hospital based study. Indian Heart J. 2003;55:152e157
Early ‘90s to early 2000s reported prevalence ranging from 1.3/1,000 to 6.4/1,000
From available data from RHD studies, the estimated average prevalence is reduced to 0.5/1,000 children in age group of 5–15 years
There are expected to be >3.6 million patients of RHD estimated from 2011 census. Almost 44,000 patients are added every year, and expected mortality is 1.5%–3.3% per year
Negi PC, Sondhi S, Asotra S, et al. Current status of rheumatic heart disease in India. Ind Heart J. 2019;71:85-90
(ARF: acute rheumatic fever; GAS: Group A Streptococcus pyogenes; ICMR: Indian Council of Medical Research; RHD: rheumatic heart disease)28
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