Acquired Pediatric Heart Disease Clinic

Kawasaki Disease

Kawasaki disease is an acute self-limited vasculitis of childhood that is characterized by fever, bilateral nonexudative conjunctivitis, erythema of the lips and oral mucosa, changes in the extremities, rash, and cervical lymphadenopathy.

Coronary artery aneurysms or ectasia develop in 15% to 25% of untreated children and may lead to ischemic heart disease or sudden death

Representative scoring systems for evaluating potential IVIG resistance

Kobayashi score8 (≥5 points; 76% sensitivity, 80% specificity) Cut off points
Sodium ≤133 mmol/L
2 Day of illness at initial IVIG
Day 4 or earlier 2 (= KD diagnosed) AST ≥100 IU/L 2
Neutrophil ratio ≥80% 2 CRP ≥10 mg/dL 1
Platelet counts ≤30.0 × 104/mm3 1
Age ≤12 months 1
Egami score9 (≥3 points; 78% sensitivity, 76% specificity)
ALT ≥80 IU/L 2
Day of illness at initial IVIG Day 4 or earlier 1 (= KD diagnosed) CRP ≥8 mg/dL 1
Platelet counts ≤30.0 × 104/mm3 1
Age ≤6 months 1
Sano score10 (≥2 points; 77% sensitivity, 86% specificity)
AST ≥200 IU/L 1
Total bilirubin ≥0.9 mg/dL 1
CRP ≥7 mg/dL 1

Prevention of Thrombosis in patients with Coronary Disease

• Low-dose aspirin for asymptomatic patients with mild and stable disease
• Aspirin with or without dipyridamole or clopidogrel
• Anticoagulant therapy with warfarin or low-molecular-weight heparin
• anticoagulant and antiplatelet therapy (warfarin/Heparin plus aspirin)

Antithrombotic regimen for patients with giant aneurysms

• Low-dose aspirin together with warfarin, maintaining an INR of 2.0 to 2.5

Treatment of Acute Myocardial Infarction

• Streptokinase, urokinase and tissue plasminogen activator (tPA) has been administered with varying success rates.
• Both Intracoronary and intravenous thrombolysis tried
• No randomized, controlled trials in children
• Reduced dose thrombolytic therapy + glycoprotein IIb/IIIa inhibitor - lower rates of reocclusion and reinfarction
• Immediate coronary angioplasty or stent placement used in a small number of children
• Should be based on that which can be administered with the greatest expertise in a timely fashion

Surgical treatment

• Indications
• Reversible ischemia on stress-imaging
• Viable myocardium
• No appreciable lesions present in the artery distal to the planned graft site
• One panel of experts considered the following as indications for surgery
• Severe occlusion of the main trunk of the LMCA
• Severe occlusion of >1 major coronary artery
• Severe occlusion in the proximal segment of the LAD
• Collateral coronary arteries in jeopardy or
• All the above
• Surgery preferred in pts with severe LV dysfunction

Cardiomyopathy

Cardiomyopathy is a somewhat loose term used for group of diseases of the heart muscle that is not secondary to hypertension, valvular or, congenital heart disease or pulmonary vascular disease

Cardiomyopathy is typically divided into several subtypes :

• hypertrophic cardiomyopathy,
• glycogen cardiomyopathy,
• dilated cardiomyopathy,
• restrictive cardiomyopathy, and
• arrhythmogenic right ventricular cardiomyopathy.

Correctable causes of DCM in children

• ALCAPA
• COA/ CRITICAL AS
• TAKAYASU ARTERITIS
• TACHYCARDIOMYOPATHY- EAT,PJRT,C/C ATRIAL FLUTTER
• HYPOCALCEMIA [ IN NEWBORNS]
• INFANTILE BERI BERI
• CARNITINE DEFICIENCY
• HYPOPHOSPHATEMIA
• SELENIUM DEFICIENCY
• CONGENITAL MR

Hypertrophic cardiomyopathy (HCM)

Hypertrophic cardiomyopathy (HCM) is a treatable disease compatible with a normal lifespan.

Risk Factor	Imaging modality
Maximum wall thickness ≥ 3 cm	Echocardiography, CMR, Cardiac CT
End-stage HCM ( EF < 50%)	Echocardiography, radionuclide angiography, CMR, cardiac CT
Apical aneurysms	Contrast echocardiography, CMR, and Cardiac CT
LVOT gradient ≥ 30 mm Hg	Doppler echocardiography
Perfusion defects	SPECT (though no association in some studies)
Reduced coronary flow reserve	PET (observations limited to very few patients)
LGE (presence and extent)	CMR (evidence not conclusive)

It is the most common inherited cardiac disease with an incidence of 1in 500

• More than 1400 mutations account for approximately 50% of identifiable patients with HCM.
• The most common cause of sudden cardiac death among young adults

Hypertrophic cardiomyopathy (HCM) is a relatively common disorder with a prevalence of about 1:500. It is recognized clinically by the presence of cardiac hypertrophy in the absence of an increased external load. Echocardiographically, it is associated with preserved systolic, but impaired diastolic, function. Hypertrophy is asymmetric in about two thirds of cases, with the septum being the predominant site of involvement. Significant left ventricular outflow tract obstruction is observed in approximately one-quarter of cases.

HCM is usually inherited as an autosomal dominant trait. The first gene linked to HCM was reported in 1990. This was the gene encoding cardiac b-myosin heavy chain (MYH7), a component of the sarcomere, the contractile unit within the cardiomyocyte. The sarcomere is an immense protein complex that is organized into thick and thin filaments that, in the presence of calcium and ATP, slide past each other, thereby generating contractile force.After the discovery of mutations in MYH7, mutations in another 10 sarcomeric genes were linked to HCM, leading to the proposition that HCM was a disease of the sarcomere. Most commonly affected are the MYH7 and the MYBPC3 genes, with the other genes accounting for far fewer cases. Mutations in sarcomeric genes account for about 60% of cases of HCM.

Dilated cardiomyopathy (DCM)

Dilated cardiomyopathy (DCM) is characterized by left ventricular chamber enlargement and systolic dysfunction, with normal or a modest increase in ventricular wall thickness. It has an estimated prevalence of 1 : 2500. Affected individuals gradually develop heart failure, often in association with lifethreatening atrial or ventricular arrhythmias. The disease is familial in about 35% of cases, pointing to an important role of genetics in disease pathogenesis [10]. In such cases, inheritance is most commonly autosomal dominant, but autosomal recessive, X-linked, or matrilinear (mitochondrial) inheritances also occur. DCM has been linked to 25 different chromosomal loci and genes. Known mutations affect proteins with a wide range of unrelated functions. Mutations have been identified in several components of the myocyte cytoskeleton, which, through a complex network of proteins, links the sarcomere to the sarcolemma and extracellular matrix and functions to transmit force generated during contraction. Cytoskeletal components found to be associated with DCM include cardiac muscle LIM protein (MLP), cypher/ZASP (LBD3), d-sarcoglycan (SGCD), desmoplakin (DSP), desmin (DES), dystrophin (DMD), telethonin (TCAP), and vinculin (VCL). A myriad of phenotypes, besides DCM, are associated with lamin A/C mutation, including Emery–Dreifuss muscular dystrophy type B1 and Charcot–Marie–Tooth disease. Several genes encoding sarcomeric proteins linked to HCM, including TTN, ACTC, TPM1, MYH7 and TNNT2, may also cause DCM. Other genes linked to DCM include genes encoding ion channel subunits. One of these is SCN5A, which encodes the pore-forming subunit of the cardiac sodium channel. Conduction disease and atrial fibrillation are a common finding in patients with DCM harbouring mutations in SCN5A. Another ion channel gene subunit linked to DCM is the sulfonylurea receptor 2A (SUR2A), which is the regulatory subunit of KATP channels in the heart. DCM is also caused by mutation in phospholamban (PLN), which has an essential role in calcium metabolism by modulating calcium

• Viral Myocarditis clinically overlaps with DCM.
• Symptoms and functional consequences are related to the severity of ventricular dysfunction.
• Clinical diagnosis of myocarditis is based on short history, clinical features of cardiac failure and echo evidence of ventricular dysfunction.
• Histologic evidence of inflammation on biopsy/necropsy.
• Viral serology may be helpful in some cases

Differentiation between these two has major impact on management and prognosis- Viral myocarditis needs aggressive management

Etiology

• Acute and chronic viral myocarditis- coxsackievirus, adenovirus, HIV
• Hereditary Cardiomyopathies- autosomal dominant, autosomal recessive, X-linked, mitochondrial
• Drugs-Antimitotic (Adriamycin, Doxorubicin), sympathomimetics,
• End-stage hypertrophic cardiomyopathy
• Endocrine- GH deficiency, hyper/hypothyroidism, hypocalcemia, Dibete Mellitus , pheochromocytoma
• Inborn errors of metabolism-
• Collagen vascular disease
• Muscular dystrophies
• Nutritional deficiency- selenium, carnitine, thiamine
• Toxins- cobalt, lead
• The variety of causes that can eventually result in DCM suggest that the disorder is the final common pathway for a number of mechanisms that produce myocardial damage, including cytotoxic, metabolic, immunologic, and infectious mechanisms

Familial DCM

• In 9% to 20% of cases of DCM, asymptomatic relatives have left ventricular dilatation. This serves as a marker for later progression to DCM
• Familial DCM most commonly inherited as autosomal dominant trait, conferring 50% risk
• Less commonly X-linked asymptomatic males have been reported
• Autosomal Recessive and maternally inherited forms are rare and they are usually associated with neuromuscular disease or metabolic disease.

Pathogenesis---Pathology---Clinical

Clinical Features

• Older Child :
  – Exercise intolerance – Dyspnea on exertion – Tacycardia – Palpitations – Chest pain – Syncope or near syncope – Occasionally cardiovascular collapse/sudden death
• Infants
  • Respiratory distress
  • Preceding history viral respiratory or GIT infection
  • Abdominal distension
  • Poor feeding
  • Subacute presentation as failure to thrive
• Short History suggests viral myocarditis

Investigations

• Biochemical Investigations :
  • Complete Hemogram including ESR
  • Electrolytes, Calcium, Magnesium
  • C- Reactive Protein
• ECG
• X- Ray Chest
• ECHO
• MRI- Gives accurate estimation of LV/RV volumes, masses, and ejection fraction.
• Cath- primarily performed for endocardial biopsy
• Rarely hemodynamic assessment if there discrepancy in findings on echo
• Important if cardiac transplantation is considered to measure PA pressures and vascular resistance

Management

• The aim must be to offer definitive treatment at the earliest.
• All correctable causes with CHF require surgery/intervention at the earliest.
• Conditions like tachy-cardiomyopathy and ALCAPA easily mistaken for dilated cardiomyopathy.

Medical treatment is for a few days/weeks when you are planning surgery or for those few conditions not amenable to surgery

Acute Phase

• Acutely Sick patient in cardiac failure
  • Intubation may be required
  • Inotropes- Dopamine, Dobutamine
  • IV diuretics
• Role of IVIg
  • May reduce progression to DCM if given within 14 days of onset in viral myocarditis
  • 2gm/kg i.v. single dose

ACE inhibitors

• ACE inhibitors lower aortic pressure and SVR, do not affect PVR significantly, and lower LA and RA pressures in pediatric patients with heart failure.
• In infants with shunt lesions and pulmonary hypertension, ACE inhibitors decrease left-to-right shunt in those infants with elevated SVR.
• ACE inhibitors induce a small increase in LVEF, LV fractional shortening, and systemic blood flow in children with LV dysfunction, MR and AR.

Some studies have demonstrated survival benefit in patients with severe LV dysfunction from DCM in pediatric patients

• Hypotension and renal failure, if they occur, usually occur within 5 days. In most cases, recovery is seen after reduction or cessation of the drug.
• Smaller doses are administered initially to prevent excessive hypotension, and doses are increased gradually to the target dose.
• Captopril is administered orally, usually every 8 hours in a dose of 0.3 to 1.5 mg/kg/day in children.
• Enalapril is administered orally, once or twice a day (0.1 to 0.5 mg/kg).

Carvedilol

• Prevents and reverses adrenergically mediated intrinsic myocardial dysfunction and remodeling.
• Other beneficial effects include decreased stimulation of other neurohormonal systems, anti-arrhythmic effects, coronary vasodilation, negative chronotropic effects, and antioxidant effects.
• Useful adjunct to standard therapy for heart failure.
• Many studies (small number) showed significant improvement in symptoms, positive effects on ventricular remodeling and significant reductions in end-diastolic and end-systolic diameters, with an increase in LVEF. Increased survival and reduced need for transplantation in some studies.
• The results of a multicenter, randomized, double-blind, placebo-controlled study of 161 children and adolescents with symptomatic systolic heart failure from 26 US centers (Shaddy et al 2006) suggested that carvedilol did not significantly improve clinical heart failure outcomes. The finding was largely due to unexpected (55%) improvement in Placebo arm.
• Treatment is initiated with a dose of 0.01 mg/kg/day and titrated to 0.2 mg/kg/day.
• Frequent dose adjustments may be necessary and although side effects are common they are well tolerated.

Follow Up

• Regular out patient f/u with hospitalisation for episodic worsening.
• Attention to feeding, weight gain, side effects of drugs

Prognosis In DCM

• DCM in children may recover completely in as many as 50%.
• Patients whose EF has improved over the first 1 to 6 months have better prognosis.
• Young age at presentation has been considered with better outcome by some groups.
• Familial CM and persistent CHF have poor prognosis.
• Marked elevation of LVEDP, presence of ventricular arrhythmias, tissue diagnosis of Endocardial fibroelastosis have poor outcome
• Tissue biopsy diagnosis of myocarditis has been shown with better prognosis.
• Coexistence of RV dysfunction is associated with poor outcome

Restrictive Cardiomyopathy

Restrictive cardiomyopathy is a rare disorder characterized by a normal or decreased volume of both ventricles, associated with bi-atrial enlargement, impaired ventricular filling with restrictive physiology, normal myocardial wall thickness, and normal or near-normal systolic function. A mutation has been described in cardiac troponin I (TNNTI3) in a family in which carriers exhibited restrictive or hypertrophic cardiomyopathy. Additional TNNTI3 mutations were also found in unrelated patients with restrictive cardiomyopathy

DIAGNOSIS OF RHEUMATIC FEVER

Clinical and laboratory Criteria

Major criteria (more specific)
– Carditis
– Polyarthritis
– Chorea
– Subcutaneous nodule
– Erythema marginatuma

Minor criteria (less specific)
– Fever
– Polyarthralgia
– ESR, CRP, polymorphonuclear leukocytosis (follow standard laboratory values)
– *ECG: Prolonged PR interval

Supportive evidence of preceding streptococcal infection (essential except for diagnosis of Chorea)

Anti streptolysin O ASO titer :
>333 unit for children and > 250 for adults.

Anti-deoxyribonuclease B (normal values Anti DNase B titer 1:60 unit in preschool, 1:480 units in school children & 1:340 in adults)

History of (within previous 45 days)
– streptococcal sore throat
– scarlet fever
– positive throat culture
– positive rapid streptococcal antigen detection test

* Normal upper range; – PR Interval:3-12 yrs:0.16sec; 12-14 y: 0.18 sec; >17y:0.20 sec)

First episode : Two major or one major and two minor criteria plus supportive evidence of previous streptococcal throat infection

Recurrence in a patient without established heart disease :
Two major or one major and two minor criteria + supportive evidence of previous streptococcal throat infection.

Recurrence in a patient with established heart disease :
Two minor criteria and supportive evidence of previous streptococcal throat infection.

Rheumatic chorea and insidious onset rheumatic carditis :
No requirement of other major manifestations or supportive evidence of streptococcal sore throat infection

Indicators of recurrence of rheumatic fever in established heart disease :

• new murmur / change in pre-existing murmur;
• pericardial rub (and other evidence of pericarditis); and
• unexplained congestive heart failure (CHF), including cardiomegaly.

Terminology

Recurrence : A new episode of rheumatic fever following another GABHS infection; occurring after 8 week following stopping treatment.

Rebound : Manifestations of rheumatic fever occurring within 4-6 wk of stopping treatment or while tapering drugs.

Relapse : Worsening of rheumatic fever while under treatment and often with carditis.

Sub clinical carditis : When clinical examination is normal but echocardiogram is abnormal. Around 30 percent of patients having chorea present as sub clinical carditis.

Indolent carditis : It is a common entity in our country. Patient presents with persistent features of CHF, murmur and cardiomegaly. There are no or very few features of carditis.

Drugs For Control Of Inflammation In Acute Rheumatic Fever

Inflammation	Doses
Arthritis ± mild carditis Aspirin*	Regime I Starting doses: children 100 mg/kg/day for 2-3 weeks adult 6-8g/day - divide in 4-5 doses Tapering doses :once symptoms resolved, taper to 60-70 mg/ kg/day. For older children 50 mg/kg/day (Level of evidence : Class I) Regime II 50 to 60 mg//kg /day for total 12 weeks (Level of evidence-Class Ib)
Naproxen*(If aspirin intolerance detected) No response to aspirin in four days	10-20 mg/kg/day Switch over to steroid. Rule out other conditions like chronic inflammatory/ myelo-proliferative disorders before switching over to steroids.
Moderate to severe carditis Steroids*	Regime I Prednisolone: 2mg/kg/d, maximum 80mg/day till ESR normalizes -usually 2 weeks. Taper over 2-4 weeks, reduce dose by 2.5-5mg every 3rd day. start aspirin 50-75mg/kg/d simultaneously, to complete total 12 weeks. (Level of evidence : Class I) Regime II Prednisolone same doses × 3-4 weeks. taper slowly to cover total period of 10-12 weeks (Level of evidence-Class IIb)
Non responders Methyl Prednisolone (Intravenous)	If no response to oral steroid therapy then start IV methyl prednisolone 30mg/kg/day for 3 days

Management Of Atrial Fibrillation

Usually associated with chronic valvular heart disease.

Clinical presentation: irregularly irregular pulse.

ECG : Fibrillatory wave.

Rate control	(hemodynamically stable, untreated patients of rheumatic heart disease having chronic AF with fast AV conduction ) Digoxin*, Ca++ channel blocker*, beta blockers (Evidence level: Class I)
Rhythm control	(hemodynamically unstable patients of chronic RHD having AF of recent onset), Cardioversion** (level of evidence: Class I ), Amiodarone infusion (Level of evidence: IIa)
Anticoagulant	Warfarin to achieve INR of 2-3 ( level of evidence: Class I) Avoid vitamin K containing food like green leafy vegetables

Duration of secondary prophylaxis

• No carditis: 5 years/18yrs of age, whichever is longer.
• Mild to moderate carditis and healed carditis: 10 yrs/25 yrs of age, whichever is longer.
• Severe disease or post intervention patients: Life long.

One may opt for secondary prophylaxis up to the age of 40 years