In the majority of patients with chronic heart failure (HF), clinical deterioration is caused by one factor or a combination of factors (Table 3.1). In de novo cases (acute HF), acute cardiac injury (either due to myocardial infarction [MI] or myocarditis) is the prevalent cause, although a sudden rise in afterload (uncontrolled blood pressure) or preload (intravenous fluid loading), extreme tachycardia or hypotension (as in acute anemia or sepsis) can result in cardiac compromise. Knowledge of the etiology is crucial in determining the optimal therapeutic strategy.
TABLE 3.1 Causes of heart failure | |
Common • Ischemic heart disease • Arterial hypertension • Valvular heart disease • Primary cardiomyopathy • Diabetes mellitus | Rare • Thyroid disease • Severe anemia • Cardiotoxicity • Peripartum cardiomyopathy • Stress-provoked cardiomyopathy |
Less common • Infection and inflammation (myocarditis) • Persistent arrhythmia (tachycardiomyopathy) • Congenital heart disease • Severe lung disease (cor pulmonale) • Substance abuse (alcohol) | |
Ischemic heart disease
Ischemic heart disease is the commonest cause of left ventricular (LV) dysfunction and HF. It is characterized by a constant or intermittent decrease in coronary perfusion, caused by significant narrowing of the lumen of coronary arteries. This leads to a mismatch between the rate of oxygen delivery and the rate of its utilization by the cardiac muscle.
Coronary ischemia is usually due to coronary artery disease (CAD), in which an atherosclerotic lesion (plaque) develops within the wall of the coronary artery; when unstable, the plaque ruptures causing acute coronary occlusion and subsequent MI (Figure 3.1). Predisposing factors for the development of CAD are shown in Table 3.2.
Figure 3.1 Coronary artery disease: development of an atherosclerotic lesion (plaque) in a coronary artery wall. CD39, cluster of differentiation 39; LDL, low-density lipoprotein; NO, nitric oxide; PGI2, prostaglandin I2 (prostacyclin).
TABLE 3.2 Predisposing factors for developing coronary artery disease | |
• Older age • Male sex • Family history • Smoking | • Hyperlipidemia • Arterial hypertension • Diabetes mellitus • Obesity |
Ischemic and non-ischemic cardiomyopathy. Ischemic cardiomyopathy is the term widely used to encompass coronary ischemia and MI with resulting myocardial scarring. In some patients, however, the degree of LV dysfunction is out of proportion to the magnitude of CAD. Such patients require further testing (invasive or non-invasive), as those with non-ischemic cardiomyopathy (i.e. not related to CAD) often present with typical angina, while those with CAD may have silent (asymptomatic) ischemia.
Over the past 25 years, mortality rates from acute coronary syndromes (MI and unstable angina) have declined, mainly as a result of improved and timely therapy to open the occluded artery (e.g. fibrinolysis, angioplasty, stenting). However, at the same time the rate of new presentation with HF has increased, indicating that many survivors of MI are left with or subsequently develop significant LV systolic dysfunction; some reports have indicated that more than 60% of individuals over 65 will develop HF within 2 years of MI.
The treatment of patients with non-ischemic cardiomyopathy (caused by infection, drugs, alcohol, arrhythmia etc.) and coexistent obstructive CAD is challenging, because the natural history of these patients is not predictable. The prognosis in many cases depends on the extent of CAD (number of vessels involved) and the presence of inducible coronary ischemia and myocardial scarring.
Arterial hypertension
Hypertension frequently develops between 35 and 60 years of age. In the developed world, arterial hypertension affects around 20% of the adult population. Although most have no identifiable cause (i.e. idiopathic hypertension), a family history of hypertension is common, so the proposed etiology includes interaction between polygenic mutations and environmental triggers. Secondary causes, which contribute to the development of hypertension in about 5% of cases, include primary adrenal disease (hyperaldosteronism, hypercortisolemia, pheochromocytoma), hyperthyroidism, renal causes (including renal artery stenosis and parenchymal disease), sleep-disordered breathing, drugs, alcohol and others.
Hypertension and heart failure. Elevated arterial blood pressure (BP) is a common cause of LV hypertrophy (LVH) and may lead to LV diastolic and systolic dysfunction and overt HF. The development of LVH is associated with adverse outcomes and worse prognosis. The risk of developing HF increases with the degree of BP elevation; for example, a person with a BP of 160/100 mmHg or greater is twice as likely to develop HF as a person with a BP below 140/90 mmHg. Moderate elevations contribute to risk in the long term.
Pathological changes found in patients with LVH include an increase in the size of cardiac myocytes, progressive fibrosis, vascular changes of small arterioles with medial hypertrophy, and perivascular fibrosis.
The magnitude of LVH in response to a trigger such as hypertension depends not only on a direct response to the shear stress of raised pressure, but also the effect of changes in the levels of neurohormones, growth factors and cytokines. The reason why some hypertensive individuals progress directly to symptomatic LV systolic dysfunction without evidence of a significant cardiac event (MI) or diastolic HF is unknown.
Optimal BP control is an essential element of therapy in hypertensive heart disease. Evidence is emerging that tighter BP control (< 130/80 mmHg) is associated with reduction of LVH and cardiovascular events. Nonetheless, the role of tighter BP control remains controversial in the population as a whole and in certain subgroups, in particular diabetics and the elderly. Secondary causes of hypertension (including sleep-disordered breathing and renal artery stenosis) need to be ruled out in individuals with resistant hypertension and recurrent presentation with acute HF and elevated BP.
Valvular heart disease
Aortic valve stenosis. The most common cause of aortic valve stenosis is age-related valve degeneration, a result of ongoing inflammation with lipid deposition and progressive calcification. Congenital bicuspid aortic valve stenosis may be found in middle-aged populations. Rheumatic fever remains an important cause of aortic valve stenosis in areas of lower socioeconomic status.
Progressive aortic stenosis leads to exertional symptoms, such as dyspnea, chest pain and syncope, and the development of congestive HF. The emergence of symptoms heralds a worse prognosis (50% survival for 2–3 years) and dictates the need for aortic valve replacement. Historically, poor surgical candidates were managed medically or palliated with balloon valvuloplasty. However, the emergence of transcatheter aortic valve implantation (TAVI) with acceptable initial results provides an alternative for patients for whom corrective surgery is not appropriate.
Aortic valve stenosis and left ventricular dysfunction. Patients with severe aortic valve stenosis and LV systolic dysfunction (ejection fraction < 40%) are a challenging group to manage. They often present with a relatively low pressure gradient on echocardiography but with severe symptoms of HF. Importantly, the cause of HF (i.e. primary valvular disease versus primary myopathic process) has to be determined first, as the therapeutic options are different (surgery versus medical treatment). Patients without appropriate contractile reserve (on stress echocardiography) generally have a poor prognosis with either medical or surgical management, but may still benefit from aortic valve replacement.
Aortic valve regurgitation can be acute or chronic. Acute regurgitation, which presents with acute dyspnea and HF, is a cardiac emergency. Causes include perforation of aortic cusps in the course of bacterial endocarditis, proximal extension of a dissecting aortic aneurysm, trauma or dehiscence of an aortic prosthesis. Chronic regurgitation results from congenital, infective (syphilis), rheumatic or degenerative causes. Symptoms include progressive dyspnea, angina and symptoms of HF. Symptomatic patients have a much higher mortality rate than asymptomatic patients, and the severity of preoperative symptoms is a strong determinant of survival after valve replacement.
Mitral valve regurgitation is one of the commonest valvular diseases leading to HF. It poses a major diagnostic and therapeutic dilemma, as the distinction between organic (primary) and functional (secondary) causes, and thus the need for surgery, is not always obvious (Table 3.3).
TABLE 3.3 Causes of mitral valve regurgitation | |
Primary (organic) • Rheumatic heart disease • Valve prolapse • Valvular degenerative disease • Chordal rupture due to endocarditis, trauma or myocardial infarction | Secondary (functional) • Apical displacement of the papillary muscles (due to global LV remodeling) • Dilation of mitral annulus (in dilated cardiomyopathy) • Inferior LV wall remodeling (after infarction with displacement of the posterior papillary muscle) |
LV, left ventricular. | |
Acute regurgitation – rupture of the papillary muscle or chordae tendineae due to endocarditis, cardiac ischemia or trauma – is a cardiac emergency. It manifests with severe dyspnea at rest, chest pain and symptoms of pulmonary edema. Chronic regurgitation leads to progressive breathlessness, initially on effort, with the development of symptoms of HF. Atrial arrhythmias are common. Symptomatic patients with severe primary mitral regurgitation are treated with surgery (valve repair or replacement).
Secondary mitral valve regurgitation (in patients with cardiomyopathy and CAD) is primarily a disease of the LV myocardium. Therapies that promote the reversal of LV remodeling, such as myocardial revascularization, beta-blocker therapy and cardiac resynchronization, should be instituted first. New percutaneous techniques for poor surgical candidates have emerged but require long-term data. Surgery should be considered in selected cases.
Mitral valve stenosis. The prevalence of mitral valve stenosis has declined in developed countries as a result of early recognition and treatment of rheumatic fever (its main cause). However, the resurgence of the disease has been observed in areas of lower socioeconomic status. Mitral valve stenosis causes progressive dyspnea and palpitations. Untreated, it leads to severe pulmonary hypertension and may result in right-sided HF characterized by peripheral edema and abdominal distension. Percutaneous (valvuloplasty) or surgical (valve replacement) treatment is required.
Tricuspid valve regurgitation often accompanies advanced left-sided heart or pulmonary disease, due to annular dilation and non-closure of the valve leaflets. Rare causes of structural tricuspid valve regurgitation include endocarditis, rheumatic heart disease and trauma. Isolated severe tricuspid valve regurgitation may lead to right ventricular dysfunction and symptoms of right-sided HF. Symptoms of left-sided heart or pulmonary disease are prominent in most secondary cases.
Pulmonary valve stenosis is usually congenital, either isolated or part of a more complex congenital heart disease (e.g. tetralogy of Fallot). Symptoms include dyspnea and progressive right-sided HF.
Pulmonary valve regurgitation often occurs after surgical repair of a narrowed right ventricular outflow tract (with or without native valve excision) in patients with congenital heart disease (e.g. tetralogy of Fallot). Isolated significant pulmonary valve regurgitation is rare and caused by either endocarditis or hepatic carcinoid. Symptoms include right-sided HF and arrhythmia.
Patient prosthesis mismatch. All prosthetic valves are, to some degree, stenotic. Underestimating the size of the prosthesis at the time of aortic valve replacement may lead to persistence of LVH and retard negative LV remodeling. Patient prosthesis mismatch during aortic valve replacement contributes to increased cardiac mortality rates, especially in patients with depressed LV function.
Cardiomyopathies
Cardiomyopathies are cardiac diseases in which the myocardium is a primary target of the pathological processes, characterized by abnormal chamber size and wall thickness or functional contractile dysfunctions. In ‘primary cardiomyopathies’ the cause is myocardial specific, whereas ‘secondary cardiomyopathies’ have a pre-existing cardiac (valvular disease, coronary ischemia, congenital heart disease or arrhythmia) or systemic (arterial hypertension, infective, hormonal or metabolic) cause.
Several classifications of cardiomyopathies have been proposed. In 2006, the American Heart Association introduced a classification based on the etiology (genetic, acquired or mixed). In 2008, the European Society of Cardiology published its revised definition based on phenotype (dilated, hypertrophic, restrictive, arrhythmogenic right ventricular dysplasia and unclassified; Table 3.4). In 2013, the World Heart Federation proposed the MOGE(S) nosology system, which integrates both phenotype description and genetic information:
• M – morphology
• O – organs involved
• G – genetic inheritance
• E – etiology
• S – stage plus NYHA functional status.
TABLE 3.4 Classification of primary cardiomyopathies | ||
Genetic | Mixed | Acquired |
• Hypertrophic • Arrhythmogenic RV cardiomyopathy/dysplasia • Isolated LV non-compaction • Glycogen storage diseases – Danon disease – Pompe disease • Conduction defects • Mitochondrial myopathies • Ion channel disorders – Long QT syndrome – Brugada syndrome – Short QT syndrome – CPVT – Asian SUNDS | • Dilated • Restrictive (non-hypertrophied and non-dilated) | • Inflammatory (myocarditis) • Stress-provoked (tako-tsubo) • Peripartum • Tachycardia-induced • Infants of insulin-dependent diabetic mothers |
CPVT, catecholaminergic polymorphic ventricular tachycardia; LV, left ventricular; RV, right ventricular; SUNDS, sudden unexpected nocturnal death syndrome. Adapted from Maron BJ et al. 2006. American Heart Association Scientific Statement. | ||
The MOGE(S) system is supported by an online app at http://moges.biomeris.com/moges.html.
Hypertrophic cardiomyopathy (HCM) is an autosomal dominant genetic disorder of the heart muscle, in which a multitude of mutated genes encode compromised proteins of the cardiac sarcomere. The reported prevalence in the general population is about 0.2% (1 in 500), although true prevalence may be higher because it is often asymptomatic initially.
At least 11 abnormal sarcomeric genes are implicated, which may partly explain the wide clinical presentation of the disease. Double or triple gene mutations in affected individuals have been identified and are associated with a malignant phenotype. Genetic modifiers could influence the effects of the primary sarcomere mutation leading to either earlier or delayed onset of clinical disease. The penetrance of a sarcomere mutation increases with age; diagnosis tends to be earlier in males. A sedentary lifestyle, and comorbidities such as hypertension, obesity, diabetes and obstructive sleep apnea may have cumulative effects on disease penetrance and severity in older individuals. Patients may present with arrhythmia (including sudden cardiac death), syncope or HF.
The disorder is characterized by an abnormal thickening of the left ventricle (LV septum thickness > 1.5 cm; Figure 3.2), usually in the absence of other conditions that increase ventricular pressure loading (e.g. systemic hypertension, aortic valve disease, the athlete’s heart).
Figure 3.2 Hypertrophic cardiomyopathy: echocardiogram showing abnormal thickening of the septum (arrow). LV, left ventricle.
In pregnancy, there is no convincing evidence that HCM increases risk, but all patients should be offered obstetric and cardiologic care at specialized centers experienced in treating such conditions. Normal delivery is possible, but patients with severe outflow obstruction require special care and possibly Cesarean section.
All patients with HCM require cardiologic referral, and syncope requires urgent investigation. Family members should be screened.
HCM phenocopy. Several other genetic disorders include cardiac hypertrophy as a component. Although cardiac hypertrophy in these conditions may appear similar to HCM on echocardiography the differences are apparent on tissue histology as well as in the pathogenesis of the disease.
Examples of such disorders include:
• hereditary transthyretin-related amyloidosis (ATTR)
• Fabry disease
• glycogen storage disease (PRKAG2, LAMP2, Pompe)
• respiratory chain enzyme defects (mitochondrial cardiomyopathies).
Arrhythmogenic right ventricular cardiomyopathy (ARVC)/dysplasia is an uncommon genetic condition characterized by fibrofatty infiltration of the right ventricle. Both autosomal dominant and recessive inheritance have been described and a number of genes that encode desmosomal proteins have been implicated. It is an important cause of sudden cardiac death, particularly in the young, and is usually due to a ventricular arrhythmia, or patients may manifest signs of right-sided HF and eventually biventricular failure.
The diagnosis of ARVC requires the presence of two out of four major criteria:
• RV dysfunction, dilation or aneurysm formation
• conduction abnormalities (broad QRS in V1–V3, epsilon waves)
• tissue diagnosis
• family history.
Isolated left ventricular non-compaction is an idiopathic form of cardiomyopathy due to intrauterine arrest of myocardial compaction. It was originally described in infants but more recently reported in adults. Both sporadic and familial forms are recognized. There is a spectrum of clinical presentation, and recent clinical reports have suggested that the disorder is associated with the important complications of thromboembolism, congestive HF, ventricular arrhythmias and sudden cardiac death.
Glycogen storage diseases are rare genetic causes of cardiomyopathy. They include Danon disease (also known as lysosomal glycogen-storage disease with normal acid maltase) and Pompe disease (an autosomal recessive disorder characterized by the deficiency of acid alpha-glucosidase, a lysosomal hydrolase).
Dilated cardiomyopathy is characterized by an increase in LV end-diastolic diameter (> 2.7 cm/m2) (Figure 3.3) and reduced LV systolic function (ejection fraction < 45%). Most cases of dilated cardiomyopathy are idiopathic, but 35–50% of cases have a family history. In addition, about 10% of asymptomatic relatives have evidence of unrecognized LV dysfunction.
Figure 3.3 Normal heart (left), and dilated cardiomyopathy (right).
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