CHAPTER XIX

CARDIOMYOPATHIES AND MYOCARDITISCARDIOMYOPATHIES AND MYOCARDITIS

A. CARDIOMYOPATHIESA. CARDIOMYOPATHIES

Definition: Diseases of the myocardium, which may be primary or secondary to disease elsewhere. This excludes diseases of the myocardium due to rheumatic fever, coronary artery disease, systemic hypertension, congenital heart diseases, valvulopathy, cor pulmonale or constrictive pericarditis.

Classifications (Goodwin 1984 – WHO): I. Etiological criteria:A) Primary cardiomyopathy (idiopathic):

1. Dilated cardiomyopathy.2. Hypertrophic cardiomyopathy.3. Restrictive cardiomyopathy

B) Secondary cardiomyopathy (secondary involvement of the myocardium due to a systemic disease)

1. Inflammatory: a) Infective

Viral. Rickettsial. Bacterial. Mycobacterial.

Spirochetal. Fungal. Parasitic.

b) Noninfective Collagen diseases (PAN). Granulomatous (Sarcoidosis).

2. Metabolic disorders: a) Nutritional diseases:

Thiamine avitaminosis (B1).

Pellagra. Kwashiorkor.

Hypervitaminosis D. Obesity. Selenium deficiency.

b) Endocrine diseases: Acromegaly. Thyrotoxicosis. Myxedema. Uremia.

Cushing`s disease. Pheocromocytoma. Diabetes mellitus.

c) Altered metabolism: Gout. Oxalosis. Porphyria.

d) Electrolyte imbalance: Hypophosphatemia. Hypocalcemia.

3. Toxic aggression: A. Alcohol.

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B. Metals: cobalt, lead, antimony compounds, lithium, mercury.C. Insect stings.D. Snake bites.E. Drug therapy (Bleomycin, Adriamycin, Phenothiazines, Tricyclic antidepressants,

Chloroquine, Cyclophosphamide, Paracetamol, Reserpine, Corticosteroids, Cocaine, Methysergide, Doxorubicin).

4. Infiltrative diseases: A. Amyloidosis.B. Hemochromatosis.C. Carcinoid syndrome (neoplastic).D. Mucopolysaccharidosis.

5. Neuromuscular diseases : Myasthenia gravis.6. Hemoglobinopathies (sickle cell anemia, thalassemia).7. Physical agents:

1. Ionizing radiation.2. Hypothermia.

8. Heart transplant rejection

II. Pathological criteria:1. Dilated cardiomyopathy:

Large cavities having thin or normal walls. SYSTOLIC failure.

2. Hypertrophic cardiomyopathy: Obstructive – asymetrical hypertrophy of the interventricular septum. Non-obstructive – small cavities having thick walls. DIASTOLIC failure.

3. Restrictive cardiomyopathy: Fibrosis of the endocardium and myocardium. DIASTOLIC failure.

N.B.! (Braunwald 5th ed.)1. “Most forms of secondary cardiomyopathy are characterized by the dilated cardiomyopathy

pattern.”2. “The distinction between these three functional categories is not absolute, and often there is

overlap; in particular, patients with hypertrophic cardiomyopathy also have increased wall stiffness (as a consequence of the myocardial hypertrophy) and thus present some of the features of a restrictive cardiomyopathy.”

3. “It is difficult to fit a few conditions (such as arrhythmogenic right ventricular dysplasia, early or “latent” cardiomyopathy, and the entity of mildly dilated cardiomyopathy) neatly into the traditional functional classification scheme.”

Diagnosis:1. Clinical, imagistical and electrocardiographical features of myocardial syndrome (heart failure,

rhythm disturbances, gallop, lower limbs edemas, jugular veins distention, pulmonary congestive symptoms, cardiomegaly or cavity pressure disturbances).

2. Exclusion of other cardiovascular diseases (rheumatic fever, coronary artery disease, systemic hypertension, congenital heart diseases, valvulopathy, cor pulmonale or constrictive pericarditis).

3. Endomyocardial biopsy -- interpretation of biopsy specimens is using the Dallas criteria.

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IDIOPATHIC DILATED CARDIOMYOPATHYIDIOPATHIC DILATED CARDIOMYOPATHY

Definition: Dilated cardiomyopathy (DCM) is a syndrome characterized by cardiac enlargement and impaired systolic function (diminution in the contractile function) of one or both ventricles in the absence of external pressure overload, volume overload, or coronary artery disease. The loss of muscle function results in congestive heart failure. Synonym: congestive cardiomyopathy.

Incidence: 5 to 8 cases per 100,000 population per year and appears to be increasing. It occurs almost three times more frequently in blacks and males than in whites and females. Average of age: 20 –40 years.

Etiology: The cause of most cases of dilative cardiomyopathy is unknown. More than 75 specific diseases of heart muscle can produce the clinical manifestations of DCM. It is likely that this condition represents a final common pathway that is the end result of

myocardial damage produced by a variety of cytotoxic, metabolic, immunological, familial, and infectious mechanisms (Fuster 1994).

The following features are mostly linked to IDCM:1. Subclinical viral myocarditis (enteroviruses, coxsakie B, influenza) – 15%.

Specific IgM viral antibodies occur in 1/3 of the patients.2. Genetic predisposition -- 20-25%. Dominant autosomal transmission or X-linked.3. Immunological disorders (HLA class II: DR4 and DQw4; antimyocardial

antibodies to a variety of antigens: the myosin heavy chain, the beta-adrenoreceptor, the muscarinic receptor, laminin, and mitochondria; abnormalities of various T cells, including cytotoxic T cells, suppressor T lymphocytes, and natural killer cells)

The more important causes of secondary DCM include:1. Prolonged ethanol abuse – the most reversible cause of DCM2. Doxorubicin therapy, toxins (Co, Hg, Pb)– irreversible3. Cocaine abuse4. Human immunodeficiency virus, 5. Metabolic abnormalities

Pathology:Macroscopy:

1. Enlargement and dilatation of all four chambers; the ventricles are more dilated than the atria.

2. Ventricular wall is normal or thin.3. Intracavitary thrombi.4. The cardiac valves are intrinsically normal, but the valvular rings are enlarged.5. The coronary arteries usually are normal.

Microscopy:1. Extensive areas of interstitial and perivascular fibrosis, particularly involving the

left ventricular subendocardium.2. Marked variation in myocyte size.3. There is no or little cellular infiltration (in contrast to myocarditis).

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Hemodynamic Considerations:1. Decreased contractility (systolic failure) ventricular failure decreased systolic output.

Compensatory mechanism: mild hypertrophy and increased heart rate. In time, this stage is overpass; dilatation and myocardium quality loss induce decreased cardiac output.

2. Increased residual volume. High end-diastolic ventricular pressure.3. Marked ventricular dilatation enlargement of the atrioventricular rings (mitral and

tricuspid regurgitation).

Clinical Features:Onset:

1. Gradual development of both left and right-sided congestive heart failure symptoms and signs, or

2. Acute onset due to systemic or pulmonary embolism, acute viral infection, or severe arrhythmia.

Symptoms:Left ventricular failure:

1. Dyspnea: exertional dyspnea orthopnea paroxysmal nocturnal dyspnea. The severity of dyspnea is diminishing after the appearance of right ventricular failure.

2. Fatigue and weakness due to diminished cardiac output.3. Exercise intolerance (reduced skeletal muscle perfusion).4. Systemic embolism.5. Reduced cardiac output signs:

Cold, wet skin. Oliguria (functional renal failure). Syncope (reduced cerebral blood flow).

6. Chest pain (angina pectoris - like) occurs in about one-third of patients and may suggest: Concomitant ischemic heart disease (subendocardial ischemia) due to reduction in

the vasodilator reserve of the coronary microvasculature (despite angiographically normal coronary arteries). In the supply equation of the myocardium, there are excessive oxygen demands of the enlarged, thin-walled ventricle(s).

Pulmonary embolism. Congestive hepatomegaly.

Physical examination:1. Apical impulse is usually displaced laterally and powerless.2. Tachycardia (usually sinus) + presystolic gallop sounds (S4) or ventricular gallops (S3)

(summation gallop is heard when there is concomitant tachycardia).3. Low audibility of heart sounds.4. The second heart sound is paradoxical split in the presence of left bundle branch block.5. Systolic murmurs of mitral or, less commonly, tricuspid valvular regurgitation (valvular

annulus dilatation).6. The systolic blood pressure is usually normal or low, and the pulse pressure is narrow,

reflecting a diminished stroke volume (sometimes pulsus alternans).

Right ventricular failure (late occurrence; poor prognosis):1. Lower limbs edema. Ascites.2. Pulsatile hepatomegaly.3. Jugular veins distention (visible a wave means tricuspid regurgitation).

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N.B ! Important anamnestic features for IDCM:A. Previous virus repeated infections – possible repeated myocarditis.B. Unexpected resistance to classical treatment of heart failure.C. Excessive sensibility to digitalic treatment: signs of digitalic intoxication

(suggestive arrhythmias) after low doses of digoxin.

Paraclinical Investigations:

I. Biochemical tests (especially helpful for differential diagnosis): serum phosphorus (hypophosphatemia); serum calcium (hypocalcemia); serum creatinine and urea nitrogen (uremia); thyroid function studies (hypo- and hyperthyroidism); iron studies (hemochromatosis).; test for the human immunodeficiency virus (HIV) (this infection is an important and

often unrecognized cause of congestive heart failure).

II. Chest roentgenogram: generalized cardiomegaly (cardio-thoracic index > 0.60); pulmonary interstitial and alveolar edema; the azygos vein and superior vena cava are dilated.

III. Electrocardiography (+ Holter): Sinus tachycardia. Microvoltage or left ventricle hypertrophy aspect. Atrial fibrillation (15-20%). LBBB (30%). RBBB. ST and T wave abnormalities (ST depression and negative T). Q waves or QS in V1-V4 or in V5-V6 (5-10%) due to fibrosis.

IV. Echocardiography (always necessary; assessing the heart function and excluding concomitant valvular or pericardial disease):

Dilated cavities (especially the ventricles). Normal or thin ventricular walls and interventricular septum. Cardiac thrombi. Wall-motion abnormalities (usually global). Increased end-diastolic ventricular volume. Reduced ejection fractions < 30% (N = 50%) Doppler studies are useful in assessing the severity of mitral (and tricuspid)

regurgitation. *Combining echocardiography with dobutamine infusion may identify patients with left ventricular dysfunction due to coronary artery disease by demonstrating provocable regional differences in wall motion and thus distinguish them from patients with idiopathic DCM.(Braunwald)

V. Cardiac catheterization and coronarography (usually are not necessary for positive diagnosis, but important in differentiation from ischemic heart disease or aortic stenosis):

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left ventricular end-diastolic, left atrial, and pulmonary artery wedge pressures are usually elevated;

elevation of the right ventricular end-diastolic, right atrial, and central venous pressures;

normal aspect of coronary arteries (useful especially in the presence of Q waves);

VI. Thallium 201 scanning (helpful in distinguishing left ventricular enlargement caused by DCM from that caused by coronary artery disease): Normal image of left ventricle during rest.

VII. Endomyocardial biopsy (searching a secondary myocardial involvement).

Positive diagnosis:”per exclusionem:

1. Congestive heart failure having severe cardiomegaly, without an obvious cause.2. Persistent ECG changes.3. Effort gallop, usually released by rest.

Prognosis: Poor long-term prognosis: 50% of hospitalized patients die in less than 3 years.

Differential diagnosis:1. Ischemic cardiopathy (ischemic heart disease) – history, coronarography, +/- ECG.2. Hypertensive cardiopathy – history, retinal examination, renal function evaluation.3. Congenital cardiopathy – age, echocardiography.4. Valvulopathy – possible history of rheumatic fever, characteristics of murmurs,

echocardiography, chest X-ray.5. Acute or chronic pericarditis – character of pain, chest X-ray, echocardiography +/- ECG.6. Other cardiomyopathies (including alcoholic) – suggestive or specific laboratory tests.

ALCOHOLIC CARDIOMYOPATHYALCOHOLIC CARDIOMYOPATHY

The consumption of alcohol may result in myocardial damage by three basic mechanisms (Braunwald):

(1) a presumed direct toxic effect of alcohol or its metabolites; (2) nutritional effects, most commonly in association with thiamine deficiency that leads to

beriberi heart disease;(3) rarely, toxic effects due to additives in the alcoholic drinks (e.g.: cobalt in beer).

Diagnosis of Alcoholic Cardiomyopathy needs some criteria, divided by Prof. C.I. Negoiţă into:

A) MAJOR CRITERIA:1. Chronic (> 5 years) and excessive (80 g/day pure alcohol) abuse (80 g pure alcohol = 2

liters of beer = 1 liter wine = 200 ml whisky).2. Congestive cardiopathy (heart failure). Diagnosis:

Clinical features: cardiomegaly, effort dyspnea, pulmonary stasis, lower limbs edema, jugular distension, various arrhythmias, etc.

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Hemodynamic features: ventricular end-diastolic volumes are increased; reduced ejection fraction.

3. Clinical and paraclinical exclusion of other causes of heart failure and arrhythmias.4. Total stop of alcohol consumption leads to improvements in clinical and hemodynamical

features of the patient (N.B.!)5. Laboratory features suggestive for chronic alcohol abuse: MCV > 93 3, GGT > 40 U.I.,

de Rittis index > 2. These tests are non-specific (increased also in cholestatic syndromes, liver carcinoma, megaloblastic anemia), but suggestive.

B) MINOR CRITERIA:1. Chronic alcoholism “marks”: psychical disorders, trembling of distal extremities,

characteristic face.2. Other organic diseases, induced by alcohol consumption: liver cirrhosis, acute/chronic

pancreatitis, polinevritis, delirium tremens, Korsakov psychosis.3. Age < 50 years.4. Increased level of Ig A.5. Normal coronary arteries. No cardiac pain.6. Electrocardiographic abnormalities (ST, T) -- atrial fibrillation, atrial flutter, or ventricular

premature contractions, particularly during the year-end holiday season (the “holiday heart syndrome”).

ARRHYTHMOGENIC RIGHT VENTRICULAR DYSPLASIAARRHYTHMOGENIC RIGHT VENTRICULAR DYSPLASIA

Definition: Partial or total replacement of right ventricular muscle by adipose and fibrous tissue, leading to reentrant ventricular tachyarrhythmias of right ventricular origin (left bundle branch block configuration of the QRS complex). Synonym: right ventricular cardiomyopathy

Etiology: unclear; in 1/3 of the patients there is autosomal dominant inheritance of the disease

Clinical features Male predominance Normal physical examination Inverted T waves in the right precordial electrocardiographic leads Symptoms of palpitations and syncope

Echocardiography: dilated, poorly contractile right ventricle, usually with a quite normal left ventricle function. Magnetic resonance imaging

fat in the right ventricular free wall regional contractile abnormality

Endomyocardial biopsy: fatty or fibrous tissue in the right ventricle myocardium.

Diagnosis: The diagnosis of arrhythmogenic right ventricular myocardial is based on meeting two major, one major plus two minor, or four minor criteria as outlined in the table XIX-1. These criteria are based on the known structural and functional abnormalities of the right ventricle, family history, and repolarization/depolarization and electrical conduction disturbances.

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Category Major criteria Minor criteria

Global and/or regional dysfunction and structural alterations.

Severe dilatation and reduction of RV ejection. Localized RV aneurysms (akinetic or dyskinetic areas with diastolic bulging).Severe segmental dilatation of the RV.

Mild global dilatation and/or EF reduction with normal LV.Mild segmental dilatation of the RV.Regional RV hypokinesia.

Tissue characterization of walls. Fibrofatty replacement of myocardium on endomyocardial biopsy.

Repolarization abnormalities.

Inverted T-waves in right precordial leads (V2 and V3)*

Depolarization/conduction abnormalities.

Epsilon waves or localized prolongation (>110 ms) of.the QRS complex in right precordial leads (V1–V3).

Late potentials on signal averaged ECG.

Arrhythmias.

LBBB type ventricular tachycardia (sustained and non-sustained).Frequent ventricular extrasystoles (more than 1000/24h).

Family history.

Familial disease confirmed at autopsy or surgery.

Family history of premature sudden death (<35) due to.suspected RV dysplasia.Family history (clinical diagnosis based on present criteria).

Table XIX-1: Criteria for the diagnosis of arrhythmogenic right ventricular cardiomyopathy. (Reproduced from McKenna WJ, Thiene G, Nava A, et al. Diagnosis of arrhythmogenic right ventricular dysplasia/cardiomyopathy. Br Heart J 1994; 71:215–218.)

Note: RV, right ventricle; EF, ejection fraction; h, hours; LBBB, left bundle branch block. * Patient must be greater than twelve years old; in the absence of right bundle branch block.

HYPERTROPHIC CARDIOMYOPATHYHYPERTROPHIC CARDIOMYOPATHY

Definition: Massive hypertrophy of the ventricle walls and of the interventricular septum, associated with reduction in ventricular cavities dimensions, in the absence of a cardiac or systemic cause. Hypertrophic cardiomyopathy (HCM) is a genetically transmitted disease and an important cause of morbidity and sudden cardiac death in young people, including competitive athletes (Maron 1995).

Historical and General Considerations1. Unexplained myocardial hypertrophy have been observed and reported for more than 100 years

ago, but the first documented descriptions of the asymmetrical myocardial hypertrophy and the subsequent dynamic obstruction of the left ventricle were published in the late 50`s (Sir Russel Brock 1957, Donald Teare 1958).

2. The diagnosis criteria have changed in the last 40 years, in direct relationship with the technology available to the cardiologists: First, the left ventricular outflow tract obstruction was considered to be the diagnostic

hallmark of HCM. In the early stage of echocardiography (M-mode) the asymmetric nature of left ventricular

hypertrophy and established asymmetric septal hypertrophy (ASH) was considered the “sine qua non” of the disease. That implies in fact a synonymy between the terms “hypertrophic cardiomyopathy”(HCM) and “obstructive hypertrophic cardiomyopathy”(OHCM).

The medical technological advent of imaging techniques, especially of 2-D echocardiography, and the comprehensive studies of Maron and other researchers have demonstrated that the spectrum of ventricular involvement is much more diverse, with virtually any pattern of unexplained myocardial hypertrophy.

In the 80`s, the identification of several disease-related genes that affect cardiac sarcomeric proteins has shown that HCM is genetically as well as clinically heterogeneous. At the same time, the concept of the disease has evolved from one defined purely by the presence of ASH and an outflow gradient, to a much broader phenotype that includes arrhythmia, myocardial ischemia, diastolic dysfunction, abnormal vascular responses and high risk for sudden death.

3. The identification of a dynamic pressure gradient in the subaortic area, which divides the LV cavity into a high-pressure apical region and a lower-pressure subaortic region, made HCM to be termed by many researchers “idiopathic hypertrophic subaortic stenosis” (IHSS), or “muscular subaortic stenosis”. It is now well established that not all the patients with hypertrophic cardiomyopathy have automatically left ventricle outflow obstruction, thus today the term HCM is world wide considered more appropriate.

Prevalence. Etiological Considerations

1. Several extensive studies have established the HCM prevalence of 0.2% to 0.5% of the general population.

2. The concepts concerning the causes of HCM had a dynamic evolution; extensive studies of the late 20 years were dedicated to this subject. Let’s review the most important steps of the HCM etiological approach: Early clinical studies have provided persuasive data concerning the inherited determinism of

the disease, based on the reports of families with a high incidence of premature sudden death, left ventricular hypertrophy, and subaortic stenosis. The proportion of presumably genetic determination was initially considered in about 30% of cases, without a precise description of

the inherited defect, suggested to be an abnormal susceptibility to development of HCM. For the rest of cases, various etiologies have been proposed:

a. Abnormal high sympathetic stimulation, or high myocardial responsiveness to circulating catecholamines (decreased neuronal uptake and metabolism of norepinephrine). These changes are probably not of primary pathophysiological significance, highly likely are secondary phenomena.

b. Myocardial ischemia induced by abnormal thick-wall intramural coronary arteries, trigger factor for fibrosis and compensatory hypertrophy. Several other mechanisms have been suggested as causes of myocardial ischemia in patients with HCM (table XIX-2), but the predominant mechanism, or a general ischemic pattern was still impossible to be established. Ischemia seems to be more likely the consequence rather than the cause of HCM.

c. Primary abnormality of collagen, responsible for myocardial disarray. Several studies revealed a striking increase of both scar-type and matrix connective tissue in hypertrophic cardiomyopathy. The extensive scarring and the pronounced interstitial and intercellular matrix connective tissue may contribute to the increased ventricular chamber stiffness and impaired relaxation in this disease (Factor 1991).

d. Abnormal handling of calcium ion by the myocardium (high diastolic calcium sequestration leading to increased diastolic stiffness).

Increased myocardial oxygen demand Reduced myocardial perfusion1. Myocardial hypertrophy.2. Diastolic dysfunction.3. Myocyte disarray.4. Left ventricular outflow obstruction.5. Arrhythmia.

1. Small vessel disease.2. Abnormal vascular responses.3. Myocardial bridges.4. Increased coronary vascular resistance.

Table XIX-2: Potential mechanisms of myocardial ischemia in HCM.

When the advanced genetic technology became available for prospective clinical genetic studies using 2-D echocardiography, the proportion of genetic involvement (autosomal-dominant defect) was established in 50% to 60% of cases.

The latest reports, based on extensive and detailed genetic studies confirmed the inherited determination for HCM in more than 80% of cases. It is now well established the direct relationship between the mutations in the genes for beta cardiac myosin heavy chain, alpha-tropomyosin, angiotensin converting enzyme (ACE), or cardiac troponin T and the HCM occurrence (Watkins 1995). Based on these evidences, familial HCM was classified into:

a. CM1: defect on chromosome 14q1 (b -myosin).b. CM2: defect on chromosome 1 (troponin T) – mild hypertrophy, but poor prognosis.c. CM3: defect on chromosome 15 (a tropomyosin) – good prognosis.d. CM4: defect on chromosome 11 (myosin-binding protein C).e. CM5: defect on chromosome 7 (associated with Wolff-Parkinson-White).

3. Supplementary arguments for the genetic determinisms have been provided by the evidence that HCM develops during periods of rapid somatic growth, sometimes during the first year of life, but more typically during adolescence (Maron 1986). There are no reports for de novo myocardial hypertrophy between ages 30 to 55, but “inappropriate” left ventricular hypertrophy in patients older than 60 years is well described (Topol 1985, Fay 1990, Chikamori 1990, Lewis 1994). The morphological, functional, and prognosis differences of the disease in the elderly suggest a

polygenic response to hypertrophic stimuli, or an age-dependent expression of sarcomeric protein mutations (Niimura 1997).

PathologyA. Macroscopic appearance:

Myocardial hypertrophy involving especially the LV myocardium and the interventricular septum (fig. XIX-2). Right ventricular hypertrophy alone is unreported. Increased total cardiac weight.

The cut surface of involved myocardium shows abnormally short and broad muscle fibers running in different directions.

Abnormal intramural coronary arteries. Dilated left atrium (due to functional mitral insufficiency). Thickened anterior mitral leaflet, increased leaflet area and elongation of the leaflets or

anomalous papillary muscle insertion (Klues 1992).

MARON Classification (1981):Type I: Hypertrophy confined to the anterior portion of the interventricular septum (10%).Type II: Hypertrophy involving the anterior and posterior septum (entire septum) (20%).Type III: Hypertrophy involving the anterior and posterior septum as well as the lateral free wall (52%).

Type IV: Hypertrophy involving left ventricular regions other than the anterior septum and the posterior free wall (18%).

Fig. XIX-1: Maron Classification (Adapted from Maron B.J., Wolfson J.K., Ciro E., Spirito P., Relation of electrocardiographic abnormalities and patterns of left ventricular hypertrophy identified by two-dimensional echocardiography in patients with hypertrophic cardiomyopathy. Am J Cardiol 1981; 48: 418-428).

B. Microscopic appearance. The cardinal microscopic feature of HCM is myocyte disarray:

Loss of the normal parallel arrangement of myocytes.

Myocytes arranged in circles around foci of connective tissue.

Marked variation in diameter and nuclear size of myocytes.

Abnormal intercellular contacts. Disrupted myofibrillar

architecture within cells.

Type IType I

Type IIType II

Type IIIType III

Type IVType IV

Anterior mitral leaflet

Posterior mitral leaflet

RV cavity

Anterior part of the

ventricular septum

LA

AO

LV free wall

Various degrees of myocardial fibrosis (from extensive scarring to discrete diffuse interstitial pattern).

Abnormal small intramural arteries (thick wall and reduced lumen) within fibrotic areas (more frequent in the interventricular septum).

N.B ! * Disarray itself is not a specific characteristic of HCM (may be also found in congenital heart disease, hypertension, aortic stenosis, coronary artery disease, or cor pulmonale), but in this disease is typically more extensive. * A cardiac phenotype similar to that seen in HCM is described in association with a number of rare, genetically determined disorders: Friedreich’s ataxia (chromosome 9), neurofibromatosis (chromosome 17), hereditary spherocytosis (chromosome 14), aniridia with catalase deficiency (chromosome 11), and Noonan’s syndrome (chromosome 12).

Pathophysiology The most characteristic pathophysiological abnormality in HCM, even in obstructive types, is not systolic but rather diastolic dysfunction.

A. Diastolic dysfunction1) Hypertrophy induces marked reduction of LV compliance and inside volume, resulting

diminished diastolic filling. 2) The increased end-diastolic left ventricle pressure leads to subsequent elevated LA, pulmonary

venous, and pulmonary capillary pressures, responsible for LA enlargement and dyspnea. In these conditions, the atrial systole becomes very important for LV filling, explaining why atrial fibrillation is assessed like a severe condition in patients with HCM.

B. Systolic dysfunction (hypercontractile LV function + dynamic outflow obstruction)1) Hypercontractile status of the LV determines a rapid, powerful, and high volume ejection during

the first half of the systolic period (~ 80% of the systolic output). This rapid ventricular emptying is the explanation of the characteristic high ejection fraction of HCM.

2) The high speed ejected flow leads to anterior mitral leaflet attraction toward the septum (Venturi effect). This systolic anterior motion – SAM – of the leaflet is responsible for the dynamic obstruction and incomplete mitral leaflet coaptation in mid-systole (mitral regurgitation). The sequence of events in systole is eject/obstruct/leak.

3) The septum asymmetrical hypertrophy acts as a supplementary obstructive component, continuously narrowing the outflow tract of the LV.

4) As a result of dynamic or possible anatomic subaortic obstruction, a pressure gradient develops inside the LV cavity. Gradient recording is precious information concerning the severity of disease (40-50 mm Hg implies surgical solution).

5) Diminished ejection during mid and late systole leads to premature partial closure of the aortic valve, which may be assessed by S2 splitting. In severe obstructions there is a delayed closure, leading to a reverse (paradoxical) S2 splitting.

6) In late stages, as a result of a gradual deterioration in left ventricular function, progressive myocardial wall thinning may occur, associated with an increase in left ventricular dimensions, severely reducing the systolic performance. This pattern is particularly difficult to differentiate from dilative cardiomyopathy.

Clinical Features

Patients with hypertrophic cardiomyopathy frequently have dyspnea, chest pain, arrhythmias, unexplained syncope, hemodynamic abnormalities, and are prone to sudden death. Usually, the age of diagnosis is around 20 to 30 years, or in elderly. Symptoms:

1. Dyspnea is the most common symptom, ranging from exertional induced (90% of cases), to orthopnea. It results as a consequence of elevated end diastolic LV pressure, which leads to pulmonary hypertension.

2. Angina pectoris.3. Syncope in hypertrophic cardiomyopathy is explained as a result of low input-low output

failure induced by a sudden increase in heart rate in the presence of a low filling volume.4. Palpitations – due to powerful contractions and arrhythmias.

Patients may be asymptomatic at the time of diagnosis (accidental echocardiographic evidence of HCM), but usually complains of symptoms during exercise. The clinical pattern is similar with aortic stenosis, making the differentiation more difficult.

Physical examination:1. Abnormal forceful apical impulse, laterally displaced, and sometimes a presystolic apical

impulse (forceful atrial systole) result in a double apical impulse.2. Rapid upstroke to the arterial pulse, followed by a secondary peak, reflecting

hyperdynamic left ventricular contraction.3. S1 and S2 are usually normal, but splitting of S2 may be observed (paradoxical if severe

outflow gradient).4. Presence of S4 (reflecting atrial systole into a poorly compliant left ventricle) and, less

frequent than in aortic stenosis, presence of S3.5. SYSTOLIC MURMUR, which has two components: ejection through the subaortic

“funnel shaped” area, and mitral regurgitation.The dynamic subaortic stenosis systolic murmur:

Harsh, crescendo-decrescendo ejectional murmur. Starts well after the S1 (mid-systole). Best heard at the left sternal edge and end-apexian. Radiating to the aortic and mitral areas but not into the neck or axilla.

* Physiological and pharmacological maneuvers that decrease afterload or venous return (standing, Valsalva’s, amyl nitrate) increase the intensity of the murmur, whereas interventions that increase afterload and venous return (squatting and phenylephrine) reduce it.The mitral regurgitation murmur:

Pansystolic. Best heard over apical area. Axillary radiation.

* In patients with marked mitral regurgitation, a diastolic rumbling murmur may be present (increased transmitral flow).6. Exercise hypotension has been documented in hypertrophic cardiomyopathy. It is not the

result of an inability to augment cardiac output but instead relates to an inappropriate and exaggerated decrease in systemic vascular resistance (abnormal peripheral vascular responses to exercise) at high work loads (hemodynamic instability).

Paraclinical Investigations

I. ECG is usually abnormal, even in asymptomatic patients (see also table XIX-2):1. ST-segment and T-wave abnormalities.2. Giant negative T-waves in midprecordial leads – HCM involving the apex.3. Abnormal Q waves (pseudo-infarct pattern) usually in inferior and lateral leads, occur in

25% to 50% of patients. Many mechanisms for Q waves in HCM have been suggested, including massive septal hypertrophy, abnormal septal activation, and myocardial ischemia.

4. Short PR interval with a slurred QRS upstroke, associated with Wolff-Parkinson-White syndrome.

5. Various types of arrhythmias. Atrial fibrillation occurs especially in individuals with marked LA enlargement. Loss of atrial systole can result in catastrophic hemodynamic collapse in patients with significant impairment of diastolic filling. Ventricular tachyarrhythmias may lead to sudden death.

6. Conduction disturbances (bundle blocks especially) are uncommon but may cause syncope.

II. Chest X-ray:1. LV hypertrophy – prominent left inferior cardiac arch.2. LA enlargement.3. Pulmonary stasis.

III. Echocardiography (see also table XIX-2):1. Assessment of the LV hypertrophy severity and localization. 2. Asymmetric septal hypertrophy detection and quantification (septal-to-free wall thickness

ratio > 1,3). Reduced septal motion (< 5 mm) and thickening ( > 11 mm) during systole.3. Systolic anterior motion of the mitral valve (SAM).4. Normal aortic valve (differential diagnosis with AS).5. Doppler assessment of the left intraventricular pressure gradient.6. Small left ventricular cavity.7. Normal or increased motion of the posterior wall.8. Partial mid to late systolic closure of the aortic valve.9. LA dilatation.

IV. Carotidogram – “spike and dome” pattern

V. Cardiac Catheterization: Echocardiography has largely replaced cardiac catheterization in the diagnosis of HCM. Catheterization provides more accurate information concerning the intracardiac pressures (increased left ventricular end-diastolic pressure), including the intraventricular pressure gradient, the severity of mitral regurgitation, and allows the assessment of coronary atherosclerosis in patients with chest pain.

VI. Radionuclide Scaning, MRI, and Positron Emission Tomography are modern techniques providing useful information about the structural and functional condition of the myocardium, allowing a detailed overview of the disease characteristics.

VII. Genetic tests. The inherited character of HCM has been demonstrated step by step by molecular and genetic investigations, which confirmed the clinical and epidemiological suppositions. In a historical perspective, it’s obvious that progresses in genetical techniques have changed several times the etiological approach concerning HCM. According to this evidence, it’s natural to consider that routine genetic testing will become generally available to clinicians in the near future.

Modern Diagnosis Criteria Positive diagnosis for HCM, today, is mostly paraclinical, but clinical data suggest and/or complete the general presentation of the patient. It is obvious that echocardiography alone, or combined with ECG and genetic testing may provide the diagnosis. Several criteria for HCM positive diagnosis have been proposed across the last 40 years; in 1997 McKenna developed a simplified and practical approach for HCM assessment, using echocardiographical and ECG evidences.

N.B ! It is proposed that diagnosis of HCM in first-degree relatives of patients with the disease would be fulfilled in the presence of one major criterion, or two minor echocardiographic criteria, or one minor echocardiographic plus two minor electrocardiographic criteria.

Major MinorEchocardiography1. Left ventricular walls thickness 13

mm in the anterior septum or posterior wall or 15 mm in the posterior septum or free wall.

2. Severe SAM (septal leaflet contact).

1. Left ventricular wall thickness of 12 mm

in the anterior septum or posterior wall or of 14 mm in the posterior septum or free wall.

2. Redundant MV leaflets.

Electrocardiography1. LVH + Repolarization changes

(Romhilt & Estes).2. T wave inversion in leads I and aVI

(3 mm) (with QRS-T wave axis difference 30°), V3–V6 (3 mm) or II and III and aVF (5 mm).

3. Abnormal Q waves (>40 ms or >25% R wave) in at least 2 leads from II, III, aVF (in the absence of left anterior hemiblock), V1–V4; or I, aVL, V5–V6.

1. Complete BBB or (minor) interventricular

conduction defects (in LV leads).2. Minor repolarization changes in LV leads.

3. Deep S in V2 (>25 mm).

4. Unexplained syncope, chest pain, dyspnea Table XIX-3: Proposed new diagnostic criteria for HCM in first-degree relatives of affected patients From McKenna WJ, Spirito P, Desnos M, et al. Experience from clinical genetics in hypertrophic cardiomyopathy. Proposal for new diagnostic criteria in adult members of affected families. Heart 1997; 77:130–132.

Complications Sudden unexpected death can be the first clinical manifestation of hypertrophic cardiomyopathy and is the most devastating feature of the natural history of the disease. Clinical features associated with an increased risk of sudden death include non-sustained ventricular tachycardia, syncope, a family history of sudden death, and an abnormal exercise blood pressure response.

Other possible complications include thromboembolism, infective endocarditis, conduction system disease, and progressive course toward ventricular dilatation and failure. The localization of vegetation formation in infective endocarditis on HCM are: the “contact lesion”, which is a mural plaque on the septal endocardium at the site of anterior mitral valve mid-systolic contact, atrial aspect of mitral valve, and ventricular aspect of the aortic valve.

Differential Diagnosis The most important differentiation must be done with valvular aortic stenosis (table XVI-3), but any situation of “unexplained” left ventricular hypertrophy should be considered (table XIX-4).

Primary genetic disorders characterized by LVH

Exaggerated “physiological” response

Metabolic disorders

Noonan’s syndrome.Friedreich’s ataxia.Lentiginosis.

Athlete’s heart.Obesity.

Infants of diabetic mothers.Amyloid.Glycogen storage disease.Mitochondrial myopathy.Phaeochromocytoma.Fabry’s disease.

Table XIX-4: Possible causes of “unexplained” left ventricular hypertrophy (LVH), which must be differentiated from HCM.

Natural History The majority of HCM patients develop a slow, age-related progression of symptoms, as a result of gradual deterioration in left ventricular function, unless a dramatic event doesn’t occur (sudden death). Extensive studies revealed that annual mortality of HCM is approximately 2% per annum in adults, reaching a maximum of 4% to 6% during childhood and adolescence.

RESTRICTIVE CARDIOMYOPATHYRESTRICTIVE CARDIOMYOPATHY

Definition: Noncompliance of the myocardium, caused by changes in its composition, which is characterized by restrictive filling with a normal or decreased diastolic volume of either or both ventricles. The disease may be idiopathic or associated with other diseases. The definition excludes “specific heart muscle diseases” of known cause or associated with disorders of other systems, such as disorders of the myocardium caused by systemic or pulmonary hypertension, coronary heart disease, valvular heart disease or congenital heart disease

Etiology and Classification: Restrictive cardiomyopathy is the least common of the cardiomyopathies and it is composed of myocardial and endocardial diseases.

I. Primary Restrictive Cardiomyopathy1. Endomyocardial Fibrosis.2. Loeffler`s Cardiomyopathy.3. Idiopathic Restrictive Cardiomyopathy.

II. Secondary Restrictive CardiomyopathyA) Infiltrative Disease:

1. Amyloidosis.2. Sarcoidosis.3. Postirradiation Therapy.

B) Storage Disease:1. Hemochromatosis.2. Glycogen Storage Disease.3. Fabry`s Disease.

Pathology: A wide range of pathological aspect may be noted in restrictive cardiomyopathy, some of them related to the specific etiology, other common to all causes, responsible for abnormal diastolic behavior.

1. Myocardial fibrosis2. Mild to moderate hypertrophy.3. Interstitial infiltration (amyloidosis determines a firm rubbery consistency of the heart).4. Endocardial fibrotic shell with extension into the myocardium.5. Biatrial dilatation (often contains trombi).6. Normal or mild decreased ventricular cavities size.7. Both ventricles are affected, usually LV more than RV (higher pressures), except tropical

endomyocardial fibrosis, in which the right ventricle may be predominantly involved.

Pathophysiology The hallmark of the restrictive cardiomyopathy is the diastolic dysfunction, determinated by the markedly increased stiffness of the myocardium or endocardium, which causes the ventricular pressure to rise dramatically with only small changes in volume causing an upward shift of the left ventricular pressure–volume relationship and a “dip and plateau” or “square root” hemodynamic pattern.

1. The noncompliance of the myocardium restricts LV filling, which results in increased LV filling pressure and reduced stroke output.

2. The dynamic aspect of the LV filling pressure is strongly suggestive for the disease, even not patognomonic: deep and rapid decline in ventricular pressure at the onset of diastole, with a rapid and important rise to a plateau in early diastole (“dip and plateau” or “square root” sign) (fig. XIX-2). Even high, the amplitude of plateau phase is usually less than one-third of the peak RV systolic pressure. In constrictive pericarditis the amplitude is higher than this value.

Fig. XIX-2: Pressure catheterism aspect in restrictive cardiomyopathy. Note the “dip and plateau” diastolic pattern.

RESTRICTIVE CARDIOMYOPATHY

NORMAL

AO

LV

LA

AO

LV LA

3. The right atrial pressure tracing shows prominent x and y waves, resulting in the characteristic “M” or “W” aspect (fig. XIX-3), a and v waves are often of same high amplitude.

4. Elevation of the pulmonary venous pressure, responsible for dyspnea. Pulmonary artery pressure > 45 mm Hg helps differentiating from constrictive pericarditis.

5. Typically, in restrictive cardiomyopathy, the LV is slightly more affected than RV, resulting in the differences between the filling pressures (LV filing pressure > 5 mm Hg, than RV one), accentuated by exercise (in constrictive pericarditis both ventricles are equally affected).

6. The systolic function usually is normal in early stages of the disease, but in time, as the myocardial structural abnormalities progresses, systolic function may become compromised.

N. B! * The general hemodynamic aspect is decline in cardiac output + pulmonary stasis (differentiation from constrictive pericarditis)

Clinical FeaturesSymptoms

Both left-sided and right-sided congestive heart failure exercise induced symptoms in early stages (the cardiac output cannot be increased by tachycardia without subsequent further compromising ventricular filing), dyspnea at rest, and low cardiac output symptoms (fatigue), in advanced cases.

Exertional chest pain is usually absent. Palpitation due to arrhythmias is commonly present.

Physical examination reveals signs of global heart failure: High jugular venous pressure with diastolic collapse (Friedreich`s sign), and elevation of the

jugular venous pressure with inspiration (Kussmaul’s sign). Hepatic distention, ascites, peripheral edema, and anasarca are seen in advanced cases. Palpable apical impulse (apical retraction, as in constrictive pericarditis is not seen). Presence of S3 and/or S4.

InvestigationsI. ECG shows low QRS voltages, nonspecific ST-segment and T-wave abnormalities, atrial fibrillation (LA enlargement), ventricular arrhythmias, or heart block (often the cause of death).II. Chest X-ray reveals signs of pulmonary vascular congestion and normal or slightly enlarged heart size.III. Echocardiography, including Doppler Tissue Imaging and Color M Mode Doppler is the main laboratory test to diagnose restrictive cardiomyopathy.

Symmetrical thickening of both ventricles, especially the LV. Enlargement of the atria, whilst the ventricular chambers sizes are usually normal. Abnormal high brightness of the myocardium in amyloidosis (“sparkling” aspect). Normal systolic ejection fraction and impaired ventricular filling.

IV. Cardiac catheterization: “Dip and plateau” pattern in ventricular filling. Higher than normal, but not identical values of RA, LA, RV, and LV pressures (constrictive

pericarditis):

Fig. XIX-3: “W” aspect of RA pressure tracing.

1. Left atrial pressure is usually greater than 15 mm Hg.2. Right atrial pressure greater than 7 mm Hg.3. Pulmonary wedge pressure greater than 12 mm Hg. 4. Left-ventricular end diastolic pressure is usually 5 mm Hg higher than the right-sided

pressures (though the absence of this difference does not suggest automatically constriction).5. Pulmonary artery pressure > 45 mm Hg

V. Transvenous endomyocardial biopsy is useful for detailed etiological diagnosis.

VI. MRI and CT scanning may also be useful to exclude pericardial thickness and assess venous filling using phase–flow mapping

N.B !* Increased left ventricular thickness on the echocardiography and decreased QRS voltages on the ECG is highly suggestive of restrictive cardiomyopathy.

Differential diagnosis The most important diagnostic problem with restrictive cardiomyopathy is differentiation from constrictive pericarditis, because the latter has the chance of surgical treatment, which may essentially modify the outcome and prognosis of the patients. The main differentiation features were already discussed, and are also shown in chapter XX. In some cases, only surgical exploration can make the diagnosis.

B. MYOCARDITISB. MYOCARDITIS(Inflammatory Cardiomyopathies)

Definition. Local or diffused inflammations of the myocardium, caused by infectious or noninfectious agents.

* The French pathologist Corvisart, in his 1806 essay Organic Diseases and Lesions of the Heart and Great Vessels, stated his belief that acute “carditis” may cause chronic heart disease.

Etiology:A. Infectious Myocarditis

1. Viral etiology1) Enteroviruses (Coxsackie A and

B, ECHO viruses, Influenza A and B, Poliomyelitis virus)

2) Herpes viruses (Herpes simplex, Varicella-zoster, Epstein-Barr virus, Cytomegalovirus)

3) Adenovirus4) Rubeola5) Coronavirus6) Hepatitis B and C7) Human immunodeficiency virus

2. Bacterial etiology – during septicemias:1) Dipfteria (cardiac damage due to an exotoxin liberation by the Corynebacterium,

which inhibits protein syntesis).2) Salmonella – rare.3) Streptococcus.

4) Meningococcus.5) Clostridia.6) Brucellosis

3. Rickettsial Myocarditis – Q fever (R. burnettii).4. Fungal infections

1) Aspergilosis.2) Actinomycosis.3) Candidiasis (particularly in the immunocompromised host)

5. Protozoal Myocarditis1) Tripanosomiasis (Chagas` Disease, caused by Trypanosoma cruzi, endemic in Central

and South America)2) Toxoplasmosis.3) Malaria.

6. Metazoal Myocarditis:1) Trichinosis.2) Cysticercosis.3) Echinococcus (hidatid cyst).

B. Noninfectious Myocarditis1. Rheumatic fever myocarditis.2. Collagen diseases.3. Sarcoidosis.4. Drug-induced (hypersensitivity mechanism): cocaine, tricyclic antidepressants,

phenothiazines, ampicillin, indomethacin, isoniazid, paracetamol, penicillin, phenylbutazone, streptomycin, tetracycline, and methysergide.

5. Toxic (lead, mercury, phosphorus, antimony, arsenic).6. Scorpion, wasp, and spider stings.7. Physical agents (heat stroke, hypothermia, ionizing radiation)

Pathology – wide spectrum of gross and histological pathological changes, according to the etiology: The gross appearance of heart may be normal, dilated, hypertrophied, or flabby. Interstitial inflammatory reaction. Myocytolysis and/or necrotic spots.

Diagnosis According to Prof. Negoită, four stages must be followed in order to establish an accurate positive diagnosis of myocarditis:

1. Anamnesis: recent preexistence of an infectious episode (influenza, pneumonia, etc).2. Clinical presentation:

Progressive dyspnea, usually following a minor infectious episode; various severity, from exertional to cardiac asthma and APE; often is associated with palpitation, fatigue, and precordial discomfort.

Chest pain may reflect association with pericarditis, or it may have myocardial ischemic pattern.

Fever. Tachycardia, usually out of proportion of fever, even after prolonged rest. Muffled heart sounds, especially S1, and gallop +/-arrhythmic rate. A transient apical systolic murmur may be noted sometimes.

Possible presence of a transient pericardial friction rub. Auscultatory signs of pulmonary congestion. In patients with fulminant disease, low cardiac output syndrome may occur (cold, pale

extremities, oliguria, disturbances of consciousness state). 3. Routine paraclinical investigations:

1) ECG: transient nonspecific ST-T changes; various types of arrhythmias or conduction disturbances, which may be transient, or causative of sudden death.

2) Chest X-ray: Various aspect of heart size (may be normal or enlarged). Pulmonary congestion

3) Echocardiography: wall-motion abnormalities.4) Blood analyses: increased ESR, leukocytosis.

4. Special immunological and histological tests:1) Identification of the etiological agent in blood, pericardial fluid, stool, urine, throat

washing, sputum, cerebral fluid.2) Immunological tests (antidodies, complement-fixation).3) Endomyocardial biopsy in severe cases not responding to sustained treatments.

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