Originally described in 1869 based on pathologic examination [52], HCM is present in 1 in 500 of the general population and the most common genetically transmitted cardiomyopathy. HCM can be caused by more than 1,400 different mutations [53] and is usually transmitted in an autosomal dominant pattern. Familial HCM describe a phenotype of thickened myocardium (≥15 mm) in the absence of increased afterload (such as hypertension or aortic stenosis) or other explanations for the thickened myocardium (see Table 16.1). A genetic abnormality in gene loci encoding sarcomere proteins is often present (Table 16.2), and over 1,400 gene variations have been linked to HCM. However, in more than 50 % of probands tested, a causative gene cannot be identified [54], underscoring the complexity and variability of the genetics in HCM. Figure 16.1 illustrates the structure of proteins involved in HCM-causing mutations. Mutations in two genes—MYH7 and MYBPC3—account for as many as 75 % of HCM gene-positive individuals [11]. A small subgroup of gene-positive HCM patients has two or more sarcomere protein gene mutations, which may be associated with an earlier onset and/or more rapid disease progression [55, 56]. The utilization of genetic testing is increasing. We believe the most useful applications of genetic testing are twofold: (1) in patients with a clinical suspicion of HCM, the disease can be confirmed, and (2) in family members of an affected gene-positive HCM patient, the presence of the gene defect can be confirmed or excluded. The latter situation provides assurance to gene-negative family members preventing unnecessary serial testing of these individuals, reducing stress, anxiety, and health-care costs [54]. In contrast, patients who are diagnosed with HCM in childhood or adolescence will need to be followed closely for the development of LVH. Whatever the genetic constellation, the clinical phenotype is highly variable, even within families of the same gene mutation, ranging from an asymptomatic course without macroscopic evidence for disease to an individual who has severe and rapid progressive LVH and cardiomyopathy and possibly early sudden cardiac death [54]. Figure 16.2 shows necropsy specimens from the hearts of two patients with HCM: one who had asymmetric septal hypertrophy and one who had concentric LVH. Some studies have identified high-risk [57, 58] and low-risk [59] mutations; however, conflicting reports exist [60] regarding the prognostic capability for predicting SCD. At present there is a lack of consensus about the role of genetic testing in predicting the magnitude or progression of LVH or the development of LVOT gradients, mitral regurgitation, or the clinical course and status as well as the need for strategies to prevent sudden death such as an implantable cardiac defibrillator (ICDs) [54, 61]. The relatively high cost of genetic testing, the inability to detect a disease-causing mutation in phenotypically affected patients (up to 50 %), and genetic variations of uncertain significance remain a challenge when using genetic testing in clinical practice [54].

As seen in Fig. 16.3, HCM is associated with cardiomyocyte hypertrophy, myofiber and myofibrillar disarray with more or less pronounced interstitial fibrosis, and an abnormal microvasculature with intimal hyperplasia and medial thickening are characteristic of HCM. The magnitude of myofiber disarray in HCM is quantitatively increased in comparison with other conditions with LVH [62]. Animal models including the use of transgenic mice [63, 64], transgenic rabbit [65], Maine coon cats [66], and zebrafish [67] are being used to study the molecular mechanisms that translate a genetic defect into the hypertrophic phenotype. Several of these mechanisms have been proposed as being responsible for the clinical phenotype of HCM patients, and it is thought to be likely that HCM is a multifactorial disease:

Echocardiography is the standard method to screen for HCM because it has a good sensitivity for detecting global or focal hypertrophy. Therefore it is also the test of choice to follow affected individuals, who carry a diagnosis of HCM as well as screening their family members who are at risk for the development of HCM. Furthermore, Doppler echocardiography provides essential hemodynamic data identifying abnormal LV filling, LVOT gradients at rest and during exercise, and mitral regurgitation, which is associated with LVOT gradients and systolic anterior motion of the mitral valve (SAM). Echocardiography is also an essential method to monitor the mechanisms of symptoms, the risk of sudden death, as well as the effects of treatment, and the changes in resting and exertional LVOT gradients, mitral regurgitation, diastolic function, and pulmonary artery systolic pressure. Because of its better resolution and lower inter-study-variability than echocardiography [17, 18], MRI is increasingly being used to evaluate HCM patients; in addition, MRI has better spatial resolution, is less operator dependent, and is not affected by chest wall configuration or body habitus. Furthermore, late gadolinium enhancement (LGE) can detect the presence, the pattern of distribution, and the extent of myocardial fibrosis, which is a marker for potential ventricular arrhythmias [88]. However, the importance of quantification of cardiac fibrosis as an indication for primary prevention of sudden death with implantable defibrillators is controversial and focus of ongoing research. While MRI has greater sensitivity to detect abnormal wall thickness and provide precise quantification, its high cost and poor tolerability in some patients limit its use for longitudinal follow-up. In addition, echocardiography is superior to MRI for the assessment of mitral regurgitation, quantification of LV outflow tracts, pulmonary artery systolic pressure, and left ventricular filling pressures.

Endomyocardial biopsy with histologic evaluation of myocyte appearance and myofiber orientation is useful for excluding other infiltrative cardiomyopathies which can mimic HCM as detailed in Table 16.1. As previously discussed, genetic testing is helpful to confirm clinical suspicion of HCM and to exclude a known gene defect in family members of an affected individual, which obviates the need for serial long-term follow-up. At present, genetic testing is not a reliable method to predict future development of the disease in phenotypically normal but gene-positive individuals or for the prediction of disease progression and severity in HCM patients [54].

Cardiac amyloidosis causes a progressive increase in heart wall thickness that is not due to myocardial hypertrophy but rather to extracellular amyloid deposition [89]. This extracellular deposition of amyloid fibrils is composed of an autologous protein which has a beta sheet fibrillar confirmation. While the two main forms of amyloidosis, light chain (AL) and TTR amyloidosis, are the most common, there are more than 30 related amyloidosis proteins capable of forming amyloid fibrils [90, 91]. Cardiac involvement in amyloidosis can be rapidly progressive, and it is the most common cause of death in AL amyloidosis and a major determinant of prognosis. AL amyloid frequently involves the heart, liver, kidney, peripheral and autonomic nervous system, as well as the GI tract [89, 90]. Most patients are diagnosed in the fifth decade of life, and about 50 % have cardiac involvement. CHF augurs a poor prognosis with a survival of only 6 months in untreated patients. Death is usually due to progressive CHF or sudden death due to asystole or electromechanical dissociation.

For TTR amyloidosis, there is a hereditary and nonhereditary form, the latter of which is known as senile amyloid (SA). The hereditary form is autosomal dominant with a 50 % likelihood that the offspring will inherit the disease. TTR generally manifests in the third to fifth decades as cardiac amyloid, neuropathy, or both, depending on the specific molecular abnormality. Senile amyloidosis is related to the breakdown of abnormal TTR. SA generally affects the heart in men in their seventh or eighth decade of life [92]. CHF is often the first manifestation of SA.

Amyloidosis has protean manifestations due to organ infiltration, and symptoms are often nonspecific. Amyloid may present as CHF, progressive wasting, or as a peripheral neuropathy. The finding of low voltage in the electrocardiogram and thick LV walls in the echocardiogram known as voltage-mass discordance is a useful clue to the diagnosis of amyloid in a CHF patient [89]. Cardiac MRI with abnormal gadolinium uptake may also be indicative of cardiac amyloid [93]. Technetium pyrophosphate radionuclide scans may show homogenous uptake of the heart in cases of TTR and SA due to the binding of the P component of the amyloid fibrils [89]. Once there is clinical suspicion of amyloid, a tissue diagnosis should be made. This can be done with a needle biopsy of the abdominal fat or biopsy of another involved tissue. However, in cases with suspected cardiac amyloid, an endomyocardial biopsy may be needed [93]. For AL, amyloid blood and urine are also assessed with immunofixation to detect abnormal proteins which can be quantified by a free light chain assay. In the presence of these abnormal proteins, a bone marrow biopsy should be done to assess the severity of plasma cell dyscrasia [90]. In the absence of AL amyloid, blood testing can be done for a mutation of TTR. If this is negative, SA is the most likely diagnosis. In ambiguous cases, special staining of the biopsy specimens can elucidate the type of amyloid.

Cardiac amyloidosis can be clinically distinguished from HCM by the progressive nature of LVH secondary to progressive amyloid deposition. In HCM the ECG demonstrates LVH, whereas in amyloid, the ECG voltage is low and progressively decreases with amyloid infiltration as wall thickness increases due to the amyloid infiltration [93]. The clinical presentation of cardiac amyloid reflects myocardial infiltration. Initially there is impaired diastolic dysfunction and which generally progresses to systolic dysfunction [89]. Patients often develop right- and left-sided heart failure as well as atrial and ventricular arrhythmias [94, 95]. When CHF is seen in association with other organ involvement suggesting amyloid infiltration such as macroglossia, carpal tunnel syndrome, easy bruising and bleeding, autonomic neuropathy, nephrotic syndrome, and cachexia, amyloid should strongly be considered.

On echocardiography, amyloid may mimic HCM by the presence of asymmetric septal hypertrophy. Cardinal echocardiographic findings in amyloid to suggest the diagnosis are a sparkling appearance of the myocardium, progressive diastolic dysfunction, increased wall thickness of the LV, RV septum in the absence of systemic or pulmonary hypertension, and the intra-atrial septum and bi-atrial dilation. Strain and strain rate imaging show impaired myocardial function which progresses over time [93].

Treatment which is similar for all amyloidosis involving the heart requires management of the cardiac-related complications. Most patients develop CHF with volume overload and thus should be on a low-sodium diet (1–2 G of sodium per day). Patients should monitor their weights daily as well as their edema and ascites. Diuretics are the mainstay of therapy for CHF due to amyloid [89]. In addition certain cardiac drugs such as digoxin and calcium channel blockers are generally contraindicated as they might bind to the P component of the amyloid fibrils which can result in digoxin toxicity and in the case of calcium channel blockers severe and even fatal hypotension. Beta blockers are generally not useful in amyloid as they promote bradycardia as well as hypotension. Afterload reduction is often problematic due to autonomic dysfunction and systemic or orthostatic hypotension [89]. Chronic oral anticoagulation is warranted in patients with atrial fibrillation to reduce the risk of systemic embolization and stroke. TTR has a proclivity for cardiac conduction disturbances and bradycardia so that pacemaker therapy is useful in this setting. It is unclear if defibrillators are effective in preventing sudden death in these patients as sudden death may be due to asystole or electromechanical dissociation [94, 95].

The most common type of AL amyloid produced by plasma cells in the bone marrow may be treated by autologous bone marrow transplantation or chemotherapy with thalidomide, melphalan, dexamethasone, bortezomib, lenalidomide, and bendamustine or with a combination of these medications [90]. AL amyloid therapy is focused on reducing or eliminating plasma cell production of free light chains. Response to therapy can be in part assessed by reduction in the cardiac biomarker for CHF (BNP). A 30 % reduction in levels is indicative of a positive response; however, progressive renal failure can cause increases in BNP and limit the utility of the BNP level for assessing the response to therapy [91].

Melphalan-dexamethasone is a standard regimen which is generally well-tolerated [96], but its effectiveness in patients with advanced cardiac disease is limited [91], with median survivals being between 10 and 18 months. Recently, bendamustine, an alkylating agent with a unique mechanism of action, has shown potential promise as a therapeutic agent. However, the data is limited on improving survival.

Combination therapy with immunomodulating drug thalidomide with dexamethasone and cyclophosphamide has shown benefits on end-organ responsiveness in 33 % of patients; however, toxicity occurs in up to 60 % of patients. The second-generation drug lenalidomide and third-generation agent pomalidomide in combination with dexamethasone are being assessed [90]. In small studies, 40–50 % of patients appear to be responders. The addition of alkylating agents increases the response rate but also the drug toxicity [91].

Protease inhibitor drugs such as bortezomib, ixazomib, and carfilzomib are being tested [97]. These drugs have been shown to be effective in reducing the production of free fibrillar light chains [98]. The newer protease inhibitors ixazomib and carfilzomib appear to have a greater protease inhibitor effect and less toxicity. These drugs are currently being evaluated in clinical trials [97].