Myocardial and Pericardial Disease

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Myocardial Disease

Overall, myocardial disease can be subdivided into two types: primary and secondary myocardial disease. Whereas the primary type most commonly has a genetic cause, secondary myocardial diseases are mostly acquired but may be precipitated by a genetic background.

Primary myocardial disease

Five different groups of primary myocardial disease exist; which are defined as ‘diseases of the myocardium with impaired cardiac function’, also referred to as cardiomyopathies.

• Hypertrophic cardiomyopathy (HCM)
• Dilated cardiomyopathy (DCM)
• Restrictive cardiomyopathy (RCM)
• Arrythmic cardiomyopathy (ACM)
• Unclassified cardiomyopathy (UCM)

Hypertrophic cardiomyopathy

The modern description of hypertrophic cardiomyopathy (HCM) dates from 1958. The essential characteristics of HCM are unexplained hypertrophy of the left ventricle in the absence of causative other cardiac or systemic disorders. Distinctive features further comprise myocyte disarray, familial occurrence, and an association with sudden cardiac death (SCD).

Epidemiology

The prevalence of the HCM phenotype was found to be approximately 0.2%, or 1 in 500, in several epidemiological studies. This frequency is notably higher than its occurrence in daily clinical practice. Hence, a large amount of patients remains undiagnosed, most probably without symptoms of inferences for their prognosis.

Genetics

Table 1. sarcomeric genes associated with HCM
α-tropomyosin cardiac troponin T troponin I myosin-binding protein C regulatory myosin light chain regulatory myosin light chain cardiac actin titin titin α-myosin heavy chain

The identification of the genetic background of HCM resulted in the hypothesis that HCM is a disease of the sarcomere; the contractile unit of the cell. First, mutations were found in the cardiac B-myosin heavy chain gene, while later on other sarcomeric proteins were found to play a role in HCM (Table 1).

It was shown that macroscopic hypertrophy of the myocardium is not essential for neither diagnosis nor prognosis, as mutations for example in troponin T may lead to only minor or no hypertrophy, whereas it is associated with a high incidence of SCD. Nowadays HCM is viewed upon as a genetic disorder, inherited mainly autosomal dominant; with an incomplete and age-related penetrance. Pathological findings then include myocardial hypertrophy, small-vessel disease and myocyte disarray with or without fibrosis.

The prevalence of HCM in the adult population is approximately 1 in 500. But as in only 60% of HCM patients mutations in the abovementioned known sarcomeric genes are present, non-sarcomeric variants of HCM, ‘phenocopies’, have gained interest. Part of these may actually be explained by unidentified defects in sarcomeric genes, but it is unlikely that this adds up to the missing 40%.

The characteristics of phenocopies of HCM differ from sarcomeric HCM; increased incidence of conduction disease and progression to cavity dilation and heart failure. Left ventricular hypertrophy in young children is known not to be caused by sarcomeric HCM, but rather by metabolic disorders and syndromes with equivocal extracardiac features. These diseases may be causal to non-sarcomeric HCM cases. As they include Anderson-Fabry disease [ESC4] and Danon disease, recognition and diagnosis of phenocopies of HCM may alter familial counselling, clarify the presence of extracardiac features, and may even influence treatment.

Pathophysiology

Left ventricular outflow tract obstruction

The subdivision of HCM into obstructive and non-obstructive forms is of clinical relevance, and is based on the presence or absence of a LV outflow tract gradient under resting and/or provocated conditions. These gradients result in a loud apical systolic ejection murmur. The obstruction results in increased intraventricular pressures, impairing LV function by increasing myocardial wall stress and oxygen demand. The obstruction is located either sub-aortic or mid-cavity, where the sub-aortic location is most common, and is caused by systolic anterior motion (SAM) of the mitral valve and mid-systolic contact with the ventricular septum.

SAM is thought to be facilitated by either an abnormal valvular apparatus loose enough to allow movement, or a hemodynamic force with an anterior component during systole. A drag-effect probably attributes to SAM, which refers to the force exerted by a fluid in the direction of the flow. Apart from its role in sub-aortic obstruction, SAM also results in concomitant mitral regurgitation, with the jet directed posteriorly.

The sub-aortic gradient and associated LV pressure increase are pathophysiologic and are prognostically important in patients with HCM. LVOTO is an independent predictor for HCM-related death, progression of the disease in terms of New York Heart Association (NYHA) class III or IV, and death due to heart failure and stroke. A gradient threshold of 30 mmHg is prognostically important, but a further increase is not associated with increased risks. Chronic outflow tract obstruction results in an increase in LV wall stress, myocardial ischemia and fibrosis, and justifies intervention in severely symptomatic patients when optimal medical management is insufficient.

HCM patients can be divided into hemodynamic subgroups based on the representative peak instantaneous gradient as assessed with continuous wave Doppler: 1) obstructive gradient under basal (resting) conditions equal to or greater than 30 mm Hg (2.7 m/s by Doppler), 2) latent (provocable) obstructive—gradient less than 30 mm Hg under basal conditions and equal to or greater than 30 mm Hg with provocation 3) nonobstructive—less than 30 mm Hg under both basal and (provocable) conditions. LV outflow gradients are routinely measured noninvasively with continuous wave Doppler echocardiography. To define latent gradients during and/or immediately following exercise for the purpose of major management decisions, treadmill or bicycle exercise testing in association with Doppler echocardiography is probably the most physiologic and preferred provocative test, given that HCM-related symptoms are typically elicited with exertion. Intravenous administration of dobutamine is undesirable.

Diastolic dysfunction

HCM is, in contrast to other cardiomyopathies, characterized by diastolic dysfunction (both active and passive phases), while systolic function is preserved. The passive relaxation during filling of the ventricle is hampered by an increased chamber stiffness, increasing filling pressures and decreasing myocardial blood flow. Isovolumetric relaxation in early diastole is prolonged in HCM. Diastolic dysfunction may well lie at the basis of heart failure in nonobstructive HCM with preserved systolic function.

Ischemia

Myocardial hypertrophy disrupts the subtle equilibrium of myocardial blood flow. Patients with HCM show an increased baseline flow velocity compared to healthy individuals; reflecting a decreased microvascular resistance to adapt to the increase in oxygen demand. Consequently, coronary flow reserve is decreased. Apart from the changes in the coronary microcirculation, systolic extravascular compression might play a role. Most importantly, HCM results in a progressive mismatch between muscle tissue and vascular growth, resulting in a high risk of myocardial ischemia especially for the subendocardial layers. The presence of myocardial ischemia is an important determinant of progression of the disease as is promotes scarring and remodelling of the ventricle.

Arrhythmia

Myocardial fibrosis associated with HCM is an important arrhythmogenic substrate. Functional consequences of HCM may provide the trigger for ventricular arrhythmias, i.e. ischemia and LVOTO, resulting in non-sustained ventricular tachycardia in approximately 20% of patients. Other functional consequences as diastolic dysfunction, mitral regurgitation, as well as LVOTO are associated with atrial fibrillation (AF) which is observed in 20-25% of HCM patients.

Wall thinning and cavity dilation

Thinning of the LV wall is present frequently in patients with severe LVH and may account for the lack of marked LVH in the elderly. While mechanisms of LV remodelling in HCM are still to be defined, cavity dilation and hampered systolic function occur in less than 5% of patients.

Clinical diagnosis

Echocardiography

Two-dimensional echocardiography is the easiest diagnostic modality for assessment of HCM, but cardiac magnetic resonance imaging (CMR) may be used when echocardiography is inconclusive, or when more detailed anatomic information is needed for clinical decision making.

Echocardiographic characteristics include thickening of the left ventricular wall without cavital dilatation, and a normal or hyperdynamic left ventricular chamber. Although some of its synonyms are misleading, left ventricular outflow tract obstruction is not an invariable characteristic of HCM, and although the cut-off for maximal wall thickness is 15 mm for HCM, some underlying mutations are associated with only minor LVH but a high risk of sudden cardiac death. Systolic-anterior motion of the mitral valve is another typical echocardiographic characteristic of HCM.

Echocardiographic diagnostic criteria for HCM are:

Major:

• LV wall thickness ≥13 mm in the anterior septum or ≥15 mm in the posterior septum or free wall
• Severe SAM (septum–leaflet contact)

Minor:

• LV wall thickness of 12mm in the anterior septum or posterior wall or of 14mm in the posterior septum or free wall
• Moderate SAM (no septum–leaflet contact)
• Redundant mitral valve leaflets

Electrocardiography

Electrocardiographic signs of HCM are typical as the increase in myocardial tissue increases the QRS complexes. Therefore a typical ECG characteristic of HCM is that it meets voltage criteria for LVH and shows changes in repolarization.

Electrocardiographic diagnostic criteria for HCM are:

Major:

• Left ventricular hypertrophy and repolarization changes
• T-wave inversion in leads I and aVL (≥3mm) (with QRS–T wave axis difference ≥30°), V3–V6 (≥3mm) or II and III and aVF (≥5mm)
• Abnormal Q (>40 ms or >25% R wave) in at least two leads from II, III, aVF (in absence of left anterior hemiblock), V1–V4; or I, aVL, V5–V6

Minor:

• Complete bundle branch block or (minor) interventricular conduction defect (in LV leads)
• Minor repolarization changes in LV leads
• Deep S V2 (>25mm)

The diagnosis is confirmed when either 1 major or 2 minor echocardiographic criteria, or 1 minor echocardiographic and 2 minor electrocardiographic criteria are present. Specificity of these criteria relies significantly on the a-priori chance of HCM, and is therefore only relevant in first-degree relatives of index cases with confirmed HCM.

Medical treatment

Asymptomatic patients should only receive drugs when severe LVH is present. Verapamil is the treatment of choice, improving diastolic filling and relaxation of the ventricle, decreasing diastolic filling pressures.

In symptomatic patients, first line medical treatment consists of a calcium-channel blocker. Verapamil is the first choice, but diltiazem may be used as an alternative. Second, beta-blockers may be used when symptoms prevail, and can be used solitarily or in combination with a calcium-channel blocker. In severely symptomatic patients, diuretics may be used with caution, as a small drop in filling pressure may reduce stroke volume and cardiac output dramatically in HCM patients. A combination can be made with either calcium-channel blockers or beta-blockers.

Patients presenting with ventricular tachyarrhythmia or supraventricular atrial fibrillation amiodarone may be used, and may even improve symptoms and prognosis in HCM patients. Disopyramide has negative inotropic action and results in peripheral vasoconstriction and may improve symptoms.

Invasive treatment of obstructive HCM

In patients where maximal medical treatment does not control the symptoms, invasive debulking of the myocardial septum may be considered when a marked outflow gradient is present. Treatment options comprise percutaneous alcohol septal ablation, or surgical septal myectomy.

Surgical myectomy has shown excellent long-term result, but 15-20% of patients may suffer from ventricular remodelling and dilatation of the left ventricle. Since the introduction of alcohol ablation, surgical myectomy is reserved for patients with HCM with concomitant disease that independently warrants surgical correction, such as coronary artery bypass grafting of valve repairs, in whom surgical myectomy can be performed as part of the operation (Guideline AHA 2011).

Septal ablation is considered eligible in patients with outflow tract gradients of more than 30 – 50 mmHg at rest or 60-100 mmHg after provocation. By injection of 1-3 mL of pure alcohol over 5 minutes into the first or second septal branch, a small myocardial infarction is created. Furthermore, the alcohol induces septal hypokinesis, thereby reducing the outflow tract gradient. This gradient may resoilve immediately, or it may take weeks to months. When the outflow tract obstruction persists, patients can be treated a second time.

Dual chamber pacing

In patients with medically refractory symptoms, whom are suboptimal candidates for invasive septal reduction treatment, permanent dual chamber pacing may be considered. Pacing may alleviate symptoms by decreasing the outflow tract pressure gradient. However, maintaining a reduction in gradient requires pre-exitation of the right ventricular apex and distal septum, and complete ventricular caption. For optimal results, this should therefore be performed in highly experienced centers only.

Prognosis and outcome

Table 2. Risk factors for SCD
Major	Possible
Cardiac arrest (ventricular fibrillation) Spontaneous sustained ventricular tachycardia Family history of premature sudden cardiac death Unexplained syncope LV thickness ≥ 30mm Abnormal exercise blood pressure Nonsustained ventricular tachycardia (Holter)	Atrial fibrillation Myocardial ischemia LV outflow tract obstruction High-risk mutation Intense (competitive) physical exertion

In general, symptoms of HCM increase with age. Mortality rates have been reported to account between 2 and 3% per year. Most importantly, patients with HCM may be at high risk of sudden cardiac death, which may even be the disease presentation in particular in asymptomatic or mildy symptomatic young patients. HCM is the most common cause of SCD in young people, including athletes. The pathophysiological basis for this predilection is unclarified, and although SCD is most frequent in young people less than 30 to 35 years old, a risk for SCD extends beyond mid-life. Although HCM presentation and expression is heterogeneous, and its relatively low prevalence, clinical markers as shown in Table 2 may identify patients at high risk for SCD. Patients at an unacceptably high risk of SCD are eligible for ICD implantation.

Dilated cardiomyopathy

Dilated cardiomyopathy (DCM) is a primary myocardial disease characterized by ventricular dilatation (one or both ventricles) and impaired myocardial contractility. The impairment of myocardial function cannot be explained by abnormal loading conditions alone, such as valve disease or systemic hypertension. In at least 50% of patients with DCM, its cause cannot be determined which is referred to as idiopathic DCM. DCM is a condition which causes and presentations are highly variable. The diagnosis of idiopathic DCM should only be made after exclusion of the specific cardiomyopathies with a dilated phenotype.

Epidemiology

The prevalence of DCM is approximately 36 per 100 000.

Genetics

The genetic background of DCM is not as clear as in HCM. Although previously thought to be sporadic, genetic transmission is now thought to account for 30-40% of cases. Multiple genes have been identified that are linked with the occurrence of DCM. Genetic disease may account in part for the primary forms of DCM, but importantly, genetic predisposure may well lead to DCM in case of exposure to precipitating factors such as (emotional) stress, excessive alcohol use or stress upon the cardiovascular system; secondary DCM.

The expression of DCM in the familial form is frequently incomplete, and hence its prevalence has been severely underestimated. Even minor abnormalities may progress into overt DCM, and accurate clinical screening of (asymptomatic) relatives is mandatory for identification of familial DCM cases.

Pathophysiology

Figure 1. Process of cardiac remodelling

Probably facilitated by a genetic predisposure, DCM can be precipitated by a wide variety of factors including arterial hypertension, myocarditis, or tachyarrhythmias. A subsequent increase in wall stress combined with activation of neurohumoral pathways induces complex cellular and molecular maladaptation. Programmed cell death finally leads to a decrease in the number of functioning cardiomyocytes. This process of cardiac remodelling in itself results in systolic and/or diastolic dysfunction leading to increased wall stress, thereby creating the vicious circle of systolic dysfunction.

The failing myocardium has several distinct factors promoting apoptosis of cardiomyocytes in vitro; cathecholamins, wall stress, angiotensin II, nitric oxide and inflammatory cytokines. Hence, medical management of DCM aims at antagonizing these pathways, reducing stress signalling in and remodelling of the failing heart.

Clinical diagnosis

The most common first manifestation of DCM is heart failure, in which clinical symptoms do not differ from heart failure of other causes. An important feature of the physical examination is a gallop rhythm of S3 and S4, invariably present in DCM. S3 and S4 may fuse in tachycardic patients with new onset of heart failure. Special attention should focus upon excluding valvular heart disease as a cause, and the possibility of right-sided involvement should be considered.

Diagnostic testing in DCM should focus on identification of reversible causes, and includes plasma biomarkers, noninvasive imaging, electrocardiography and exercise testing.

Echocardiography is an important diagnostic modality in DCM, as it can be used to assess both the size and shape of the LV, but also to determine LV function by assessing the LV ejection fraction (EF). Furthermore, valvular heart disease or pericardial abnormalities can be excluded. CMR evaluation may contribute to identification of specific cardiomyopathic conditions, especially when echocardiographic images are suboptimal. Cardiopulmonary exercise testing is a measure of the cardiac response to exertion, and is an established risk factor in DCM patients. Furthermore, the combination of anaerobic threshold and ventilatory efficiency is a reliable predictor for 6-month mortality. Dilatation of the ventricular cavity results in myocyte stretch. In response, B-type natriuretic peptide is released, which is a neurohorme that can be used to evaluate progression of DCM and to guide medical treatment. High plasma concentrations (twice the ULN) are furthermore associated with increased long term mortality.

Electrocardiography does not provide an accurate diagnostic mean in DCM, but can identify several features associated with impaired prognosis, or identify contributing factors to DCM. Where sinus tachycardia is frequently present, non-specific ST-segment or T-wave changes, as well ass changes in P-wave morphology may well be present.

AF is an important feature associated with high mortality; its control may contribute to optimalise cardiac output. Furthermore, the presence of AF may indicate tachycardia-induced cardiomyopathy. 24-hour Holter monitoring can reveal a decreased heart rate variability or complex ventricular arrhythmias which are associated with a high risk for mortality. Finally, prolonged QTc intervals are associated with high mortality.

Management of DCM

Management of symptoms and progression of DCM, coincide with treatment options as described in the management of heart failure. Hence, also in DCM, diuretics and neurohumoral antagonists provide the basis for management of symptoms, and preventive cardio defibrillator or pacemaker implantation is indicated in selected patients with DCM. Most importantly surgical or percutaneous correction of underlying conditions facilitating progression of DCM, such as coronary artery disease, valvular heart disease or congenital abnormalities is warranted.

Specific dilated cardiomyopathies

It is important to note that there are several causes of secondary DCM. A foursome of these are of utmost importance to recognize early on, as accurate diagnosis influences the patients treatment strategy and chance for recovery.

Tako-tsubo (Stress)

Tako-tsubo (octopus pot) cardiomyopathy is an acute cardiomyopathy precipitated by exposure to high doses of cathecholamines. It is most common in middle-aged women, and is usually completely reversible wit supportive care. Diagnostic features include electrocardiographic signs of myocardial infarction, without angiographic evidence of coronary artery disease. A distinctive feature is the presence of apical and midventricular systolic dysfunction in which the base of the heart is relatively spares, which is referred to as apical ballooning. Endomyocardial biopsy may mimic myocardial infarction, and demonstrates contraction band necrosis, but may be useful to exclude myocarditis.

Peripartum cardiomyopathy

Peripartum cardiomyopathy is defined as ‘a cardiomyopathy manifesting between the last month of pregnancy and 6 months post partum’. Most probably, inflammatory factors play a prominent role in its aetiology, but it remains to be fully elucidated. The initial period may feature severe hemodynamic compromise, but if patients survive this period long-term prognosis is excellent, although these women are at higher risk of reccurrence with a subsequent pregnancy.

Peripartum cardiomyopathy

Peripartum cardiomyopathy is defined as ‘a cardiomyopathy manifesting between the last month of pregnancy and 6 months post partum’. Most probably, inflammatory factors play a prominent role in its aetiology, but it remains to be fully elucidated. The initial period may feature severe hemodynamic compromise, but if patients survive this period long-term prognosis is excellent, although these women are at higher risk of reccurrence with a subsequent pregnancy.

Alcoholic cardiomyopathy

Alcoholic cardiomyopathy is a dose-related disorder that resembles idiopathic DCM. Cessation of alcohol use results in an improvement of the disease. Not only does alcohol have a direct toxic effect on the myocardium, excessive alcohol use also increases risk for other comorbidities that increase cardiovascular risk such as systemic hypertension.

Prognosis and outcome

DCM has a highly variable clinical course. Approximately half of DCM patients respond well to contemporary heart failure medication, and an minority of patients show a healing course. Conversely, a subgroup can be identified with a highly unfavourable clinical course, not responsive to heart failure medication and rapidly progressing to inotropy- or LVAD dependency. Overall, 5-year survival rates approximates 30%.