Restrictive cardiomyopathies are a cluster of distinct myocardial diseases with a similar pathophysiology of myocardial muscle stiffening and impaired ventricular filling. The phenotypic expression of this group of cardiomyopathies may be quite different, ranging from hereditary, infiltrative, dilated, or hypertrophic cardiomyopathy (Table 72.1). However, the characteristic pathophysiology of restrictive cardiomyopathy is similar and represented by a rapid rise in intraventricular pressure with a small increase in volume.¹ The diastolic volumes may be preserved or reduced. Usually, it may be associated with preserved biventricular systolic function; however, it may change late in the course of disease. Anatomically, the hallmarks of this group of disorders include substantial atrial dilatation and normal or reduced left ventricular size in the absence of pericardial disease. Depending on the stage of presentation and severity of disease, the anatomic features may vary widely. In its classic form, the restrictive pattern of ventricular filling may be apparent in the form of a diastolic “dip and plateau” on the hemodynamic tracing. Advanced stages of diastolic dysfunction with restrictive filling patterns may be apparent on echocardiography. The etiology of restrictive cardiomyopathy can be genetic, inherited, or acquired. Compared to other forms of cardiomyopathy, restrictive cardiomyopathies are less common and more likely to be underdiagnosed. As a heterogeneous group of disorders (Table 72.1) with varying degrees of restrictive physiology, the diagnosis can be challenging and requires a high degree of suspicion. An important differential diagnosis of restrictive cardiomyopathy is constrictive pericarditis, which has significant overlap in presentation and clinical features. A thickened pericardium may be seen in constrictive pericarditis on imaging, but 18% of patients with constrictive pericarditis may not have a thickened pericardium. Advanced echocardiographic techniques can sometimes help differentiate between the two, but endomyocardial biopsy may be needed in specific cases. Similarly, often, several diagnostic modalities need to be employed to specifically identify the cause of restrictive cardiomyopathy (Algorithm 72.1), as discussed in later subsections.

Epidemiology, pathogenesis, diagnostic, and management approaches are discussed in more detail under each subsection of some of the common forms of restrictive cardiomyopathies.

Sarcoidosis is a systemic, multiorgan disease of uncertain etiology involving noncaseating granulomas, most commonly involving the lungs. Other organs involved include eyes, the nervous system, skin, and myocardium. While cardiac involvement was historically thought to occur in only 5% of pulmonary sarcoid cases, the prevalence is much higher, ranging up to 25% in recently reported autopsy studies.² Cardiac sarcoid is frequently underdiagnosed and requires a high degree of suspicion. While the most common presentation leading to a diagnosis may be sudden cardiac death, cardiac sarcoid may present as heart block, ventricular arrhythmias, ventricular aneurysms, and restrictive or dilated cardiomyopathy.

Cardiac sarcoidosis is more prevalent among African Americans and women in the United States; the annual incidence is 10.9 per 100,000 among whites and 35.5 per 100,000 among African Americans.³ Outside the United States, the highest prevalence is reported among Scandinavians and Japanese. It is uncommon to observe sarcoidosis in patients who are young (<15 years of age) or older (>70 years of age).

Multiple environmental and genetic factors have been postulated as contributing factors to the development of sarcoidosis. Geographic, seasonal, and occupational clustering suggests possible infectious, environmental, or occupational etiologies. Recent evidence suggests an immunologic response to an unidentified antigen, which is triggered in genetically susceptible individuals. Association with human leukocyte antigen (HLA)—specifically HLA DQB1*0601 and HLADRB1*—has been reported.⁴,⁵

Most often, granulomatous involvement of the myocardium is patchy, rendering the utility of endomyocardial biopsy limited in detecting granulomas. The granulomas are composed of macrophages, histiocytes, and lymphocytes and result in myocardial edema, granulomatous infiltration, and fibrosis. The most common cardiac sites for granulomas are the basal septum, atrioventricular (AV) node, bundle of His, ventricular free walls, and papillary muscles. In cases of severe disease, especially presenting as dilated cardiomyopathy, granulomas maybe absent, and extensive fibrosis may be present instead. Although left ventricular dysfunction is common, it not uncommon to have right ventricular dysfunction, especially in patients with sarcoid-related pulmonary hypertension. Cardiac sarcoid can masquerade as arrhythmogenic right ventricular
dysplasia, including aneurysm formation and predominant right ventricular involvement.

Initial workup (Algorithm 72.2) involves the electrocardiogram (ECG), which may be abnormal in patients with clinically manifest cardiac disease.¹⁰ Findings may include fragmentation of the QRS complex, right bundle branch block, left bundle branch block, or varying degrees of heart block. Rarely, pathologic Q waves or epsilon waves may occur.

Echocardiography may be helpful in those with symptomatic disease but can be normal in clinically silent cardiac sarcoidosis or even in cases of sudden cardiac death. Echocardiographic abnormalities can be seen in 14% to 56% of patients with cardiac sarcoidosis.¹¹ Unfortunately, these findings can be variable and not specific to cardiac sarcoidosis. They commonly include ventricular diastolic and/or systolic dysfunction, regional wall motion abnormalities in a noncoronary pattern, basal septal thinning, and discrete aneurysms.

Management of cardiac sarcoid revolves around pharmacotherapy for heart failure, immunosuppressants, arrhythmia management, and decision on implantable cardioverter device (ICD) placement. Although there is a paucity of randomized clinical trials in the management of cardiac sarcoid, it is common practice to initiate and optimize guideline-driven medical therapy in those with ventricular systolic dysfunction. Immunosuppressive therapy remains the cornerstone in management strategy.¹⁴ Multiple nonrandomized trials have demonstrated the utility of immunosuppressants in patients with cardiac sarcoid, with steroids being the main agent.¹⁵ Steroids have been beneficial for treating atrial and ventricular tachyarrhythmias and ventricular systolic dysfunction, particularly in early disease before fibrosis is evident on CMRI. Prednisone is the agent of choice and is usually started at 1 mg/kg daily up to 40 mg/day, which is gradually tapered off to a maintenance dose. The level of scar burden and ventricular arrhythmias may predict response to steroids. Methotrexate is the second-line agent that is commonly used concomitantly with steroids in nonresponders or in a steroid-sparing strategy.¹⁶ Other agents that have been reported to be useful include mycophenolate mofetil, anti-tumor necrosis factor α antibodies, azathioprine, cyclophosphamide, infliximab, adalimumab, and rituximab.

Arrhythmia management includes steroids to reduce the risk of ventricular arrhythmia and reverse heart block. The consensus is that ICD implantation is reasonable in patients with ventricular dysfunction (left ventricular ejection fraction <50%) and sustained ventricular arrhythmias, syncope, or sustained ventricular tachycardia on electrophysiologic study.¹⁷ Similarly, pacemaker implantation is considered appropriate among those with second -or third-degree conduction block. A pacemaker/ICD may be considered in those patients requiring a pacemaker for heart block but with concomitant left ventricular dysfunction. The role of ICD in those with preserved ejection fraction is not clear. A strategy for ablation for sustained or recurrent ventricular tachycardia due to cardiac sarcoid has shown to be successful.

For patients with severe left ventricular dysfunction, advanced therapies such as left ventricular assist devices (VADs) and cardiac transplantation should be considered. While the total number of patients undergoing cardiac transplantation because of underlying cardiac sarcoidosis is low, it may be underestimated due to under diagnosis. More importantly, post-transplant outcomes in patients with sarcoidosis are similar to those with other underlying etiologies.¹⁸

Cardiac amyloidosis is a disorder of protein misfolding due to unstable tertiary structures leading to insoluble fibrils that can accumulate in various organs, most notably the myocardium, ultimately leading to clinical heart failure. It is subcategorized according to the type of misfolded protein, and, although there are more than 30 identified proteins that can result in amyloidosis, there are only 5 that typically result in cardiac involvement: immunoglobulin light chain, immunoglobulin heavy chain, serum amyloid A, apolipoprotein A1, and transthyretin.
The vast majority of cases of cardiac amyloidosis can be categorized into either primary light-chain (AL) amyloidosis or transthyretin amyloidosis (ATTR).

The amyloid fibrils found in AL amyloidosis are the result of immunoglobulins that are produced by a clonal plasma cell dyscrasia, such as multiple myeloma. These light chains can be characterized as having either a κ or λ predominant pattern, which can be detected on a serum free light-chain assay. Estimates suggest that there are approximately 3000 new cases of AL amyloidosis every year, and half of patients with AL amyloidosis have evidence of cardiac involvement, highlighting the importance of recognizing the presence of AL amyloidosis.¹⁹ The degree of cardiac involvement is strongly associated with poor survival, with median survival of 6 months for untreated AL cardiac amyloidosis after onset of heart failure.

Conversely, the fibrils formed in ATTR are the result of destabilization of the quaternary protein structure of transthyretin. Transthyretin, previously known as prealbumin, is a protein that is produced by the liver, which circulates in a tetrameric form and transports thyroid hormone and retinol (vitamin A). Through varying mechanisms, the tetramers dissociate into oligomers and monomers, which ultimately deposit in various organ systems, most notably the heart. According to autopsy data, 17% of subjects older than 80 years with heart failure with preserved ejection fraction (HFpEF) demonstrated deposition of transthyretin within cardiac tissue.²⁰ Hereditary ATTR (ATTRh) is secondary to an autosomal dominant condition, which results in an amino acid substitution of transthyretin, subsequently causing tetramer destabilization and formation of amyloid fibrils. ATTRh can result in a primarily familial amyloid polyneuropathy, a predominant familial amyloid cardiomyopathy, or an overlap of the two syndromes. The three principal genetic polymorphisms that result in familial amyloid cardiomyopathy include Val122Ile, Leu111Met, and Ile68Leu. ATTRh is considered to be rare owing to variable penetrance, though an estimated 3% to 4% of persons of African or Caribbean descent are carriers of the Val122Ile mutation.²¹