Introduction
Heart failure is the most common cause of hospitalization in the Medicare age population. Both systolic and diastolic abnormalities of cardiac performance result in the heart failure syndrome. The associated cardiomyopathies resulting in clinical heart failure are still being defined with regard to their incidence and prevalence.
Unusual cardiomyopathies are typically characterized as such because they are believed to occur very infrequently, and represent a small portion of those individuals with nonischemic cardiomyopathy. This definition carries with it a geographic-specific implication. That is, cardiomyopathies around the world differ in their incidence and prevalence. Chagas disease, for example, would be unusual in the Midwestern United States, but would be quite usual in heart failure clinics in South America.
Many unusual cardiomyopathies have been seen with increasing frequency in the United States. This increase is likely due to improved imaging techniques, and increased sensitivity of the heart failure cardiologist to the true prevalence of these cardiomyopathies. Two such causes of heart failure are isolated left ventricular noncompaction (LVNC) and cardiac amyloidosis. Both of these cardiomyopathies have been associated with various genetic abnormalities, but because genetic testing is still prohibitively expensive, genetic tests are not routinely performed on individuals who present with congestive heart failure. Perhaps in the future, genetic testing will be incorporated to better characterize first the diagnosis and second the prognosis that is associated with these illnesses. Although standard treatments for congestive heart failure should be applied to both LVNC and cardiac amyloidosis, certain nuances in the diagnosis of LVNC and cardiac amyloidosis and in the treatment of individuals with LVNC or cardiac amyloidosis require further characterization. A keen awareness of the specifics of the pathophysiologic state is essential in both entities since patients can remain phenotypically silent and only manifest decompensation in the presence of another physiologic or environmental stressor.
The purpose of this review is to offer insight into the incidence and prevalence of the unusual cardiomyopathies, which may be much more usual than previously thought. In addition, the aim is to focus on the differences between these specific causes of congestive heart failure and the more common causes of both heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF).
Left Ventricular Noncompaction
Initially described as a pathologic finding seen in congenital heart defects, LVNC was characterized as abnormal coronary distribution by Grant [1] in the early 1900s. The presence of thickened myocardium with multiple trabeculations and deep clefts was known to congenital heart disease specialists as a rare association of the myocardium that resulted from the arrest of maturation of the fetal heart tube [2].
The fetal heart tube is the first stage of development of the cardiovascular system in utero. As the fetus grows and matures, the heart develops multiple trabeculations, which significantly increase the cardiac mass without requiring epicardial coronary flow as the primary source for myocardial oxygen and nutrients. At about 8 weeks of gestation, trabecular remodeling begins to occur. In this stage the trabeculations began to coalesce to form normal endocardial structures, including the papillary muscles.
As coronary arteries develop through angiogenesis, further remodeling of the myocardium occurs such that a two-layered ventricular wall is formed. The first layer is the compacted layer with a spiral arrangement of ventricular myocytes; and the second, noncompacted or trabeculated layer, has more random myocyte organization and subsequently generates less organized contractile force. Compaction occurs from epicardium to endocardium and from the base to the apex of the heart. An arrest in the compaction process for any reason will therefore be variable among individuals, but LVNC will always involve the endocardial surface of the apex of the left ventricle since this is the last area to undergo compaction [3]. The ratio of the compacted to noncompacted layers of the heart governs the performance characteristic of the adult heart and is one of the diagnostic criteria used to characterize LVNC [4]. When the noncompacted layer of the myocardium is excessive and occurs in the absence of any other congenital cardiac abnormality, the patient is said to have isolated LVNC.
There have been many hypotheses as to why the ventricular myocardial remodeling process is arrested. LVNC is associated with 15 abnormal genes, including those coding for sarcomeric, mitochondrial, cytoskeletal, and Z line proteins [5]. LVNC patterns of inheritance that have been noted include X-linked, autosomal dominant, autosomal recessive, and mitochondrial patterns. The most frequently identified gene abnormalities are those of sarcomeric protein genes coding for β-myosin heavy chain and α-actin. There is an undulating phenotype in LVNC such that affected individuals can suddenly become worse with little warning [6]. Initially it was thought that LVNC affected 0.12 in 100,000 individuals [7]. This prevalence was similar to what was described in hypertrophic cardiomyopathy when it was initially characterized. Today, with increasing imaging capability and genetic screening, hypertrophic cardiomyopathy is thought to affect one in 500 individuals. LVNC has very similar genetics, and may well be on the spectrum between dilated cardiomyopathy and hypertrophic cardiomyopathy [8]. Investigators today believe that LVNC may account for as many as 4%–5% of all individuals with HFrEF [8]. Considering dilated cardiomyopathy accounts for 40% of all HFrEF, LVNC is not such an uncommon diagnosis.
Some X-linked cardiomyopathies that resemble LVNC, such as Barth syndrome, exist in children but have not been seen in the adult population because of the limited survival of individuals with X-linked cardiomyopathies [9].
Epigenetic changes in DNA methylation, chromatin remodeling, or histone posttranslational modification have also been implicated in the development of LVNC. Some maternal conditions that would result in fetal hypoxia have been shown in animal models to cause such epigenetic changes [10]. Similar changes have also been noted with maternal use of cocaine. Some controversy is emerging as to whether LVNC can be acquired in the adult. Adults who meet the diagnostic criteria by echocardiography for LVNC may have no heart failure signs or symptoms at all. These individuals appear to have the LVNC genotype but as yet have not phenotypically manifested the classic LVNC characteristics. Other investigators propose these affected individuals have enough compacted myocardium to remain asymptomatic, but another environmental or morphologic insult can result in heart failure from LVNC simply by increasing the demand on myocardial performance, or by further expressing epigenetic alterations to contractile or ultrastructural proteins [8].
Myocardial ischemia may also have a profound effect in converting someone with asymptomatic LVNC to someone with HFrEF [6]. The arrested coronary artery development and the susceptibility of large trabeculations to myocardial ischemia from capillary collapse as a result of increased left ventricular end-diastolic pressure can begin the cycle of impaired cardiac performance leading to increased left ventricular end-diastolic pressure, which in turn causes more ischemia and then more heart failure. Epicardial coronary lesions in patients will hasten the process.
Failure of the ventricular myocardium to further compact alters the contraction properties of the heart in addition to the morphologic appearance on echocardiography and left ventriculography. Diagnosis of this condition is challenging since a slightly off-axis echo resembles LVNC [4]. The altered organization of a larger proportion of ventricular myocytes results in an abnormal twisting of the left ventricle during systole and therefore is more easily identified by echocardiographic imaging techniques such as tissue Doppler imaging with speckled tracking and strain rate [11]. These new echocardiographic findings help to provide further differentiation between true LVNC and a hypertrabeculated heart. Many echocardiographers unfortunately fail to routinely use these diagnostic tools when evaluating a patient with HFrEF.
Diagnosis of LVNC
Patients with LVNC usually present with congestive heart failure; however, ventricular tachycardia, sudden cardiovascular death, and systemic embolic events are not uncommon presentations for patients with noncompaction [6]. As many as 10% of patients may be identified on pathologic examination of an explanted heart at the time of cardiac transplantation.
Familial manifestation occurs in roughly 25% of patients, so an in-depth family history is essential when one is evaluating patients with HFrEF. Although sorting out a family history is a seemingly easy task, many individuals believe a family member died of a “heart attack” rather than congestive heart failure or sudden cardiac death. Specific mention of an enlarged heart or circumstances surrounding a sudden cardiac death may provide very useful clues to the identification of a familial manifestation of LVNC. Current recommendations state that first-degree relatives of patients with LVNC should be screened with echocardiography [11].
Echocardiography continues to be the mainstay of diagnosis of noncompaction [12]. However, technical challenges result in multiple echocardiograms being performed before the diagnosis is made. Often confused with an idiopathic dilated cardiomyopathy, LVNC has a visible noncompacted layer that is at least two times as thick as the compacted layer [4]. The first challenge is to differentiate an echocardiogram that is obtained in a slightly off-axis fashion and appears hypertrabeculated from a properly obtained echocardiogram showing LVNC. The next major challenge occurs as the sonographer can make adjustments during the echocardiogram acquisition to show less of the spongy endocardial surface, resulting in an echocardiogram that looks more like that corresponding to conventional dilated cardiomyopathy (Figures 1 and 2).
The Left Panel Shows an Apical Four-chamber View of a Patient with Dilated Cardiomyopathy.
The ejection fraction was thought to be 15%–20% with global hypokinesis. The right panel show a view of the same patient now with an improved endocardial definition obtained with use of Optison (GE Healthcare, Marlborough, MA, USA) (perflutren protein-type A microspheres injectable suspension, USP).
The Left Panel Shows an Apical Four-chamber View of an Echocardiogram with an Inappropriately Low Gain Setting, which was Interpreted as Showing Dilated Cardiomyopathy.
The right panel shows a short-axis view from cardiac magnetic resonance imaging of the same individual, demonstrating the thick endocardial layer 2.3 times the thickness of the thin compacted layer, confirming the diagnosis of left ventricular noncompaction.
In addition, the use of tissue Doppler imaging, speckle tracking, and longitudinal and circumferential strain provides valuable insight into whether a heart is simply hypertrabeculated or is affected with LVNC [9].
In any echocardiographic study where LVNC is suspected, prudent use of intravenous contrast medium is very helpful in outlining the true endocardial surface, and this technique is well suited for showing deep clefts that occur in the noncompacted layer [12]. The presence of clefts all from the endocardial surface to the compacted layer is one of the criteria used to diagnose LVNC. Table 1 presents a modification of the criteria of Jenni et al. [4] for the echocardiographic diagnosis of isolated LVNC.
Echocardiographic Diagnosis of LVNC
| 2D echocardiography | Absence of coexisting cardiac abnormality. |
| Excessive and prominent trabeculations with deep recesses seen at an end-systolic frame in parasternal short and apical views. | |
| A two-layered myocardial wall with the thick layer 2 or more times the thickness of the thin layer | |
| Color Doppler echocardiography | Evidence of blood flow into the trabecular recesses |
| 3D/4D echocardiographic imaging | Trabeculae and deep recesses clearly seen in the 3D rendering |
| Contrast imaging | Blood flow deep into the recesses confirming the thick/thin layer ratio noted above |
Cardiac magnetic resonance imaging (CMRI) has emerged as the diagnostic modality of choice for LVNC [13]. This is because CMRI has significantly increased contrast and improved spatial resolution when compared with echocardiography. As with echocardiography, the determination of two distinct layers of myocardium is important. The spongiform layer should be 2.3 times the thickness of the compacted layer in diastole. Again, the apex and lateral walls are the most frequently involved areas. Delayed hyperenhancement of the myocardial trabeculae has also been associated with a more advanced stage of clinical decompensation in patients with LVNC [14].
More recently, cardiac CT has also been described as a sensitive and specific tool in the diagnosis of LVNC. A noncompacted layer greater than 2.3 times the diameter of the compacted layer in diastole seen on CT angiography is diagnostic of LVNC with a similar predictive value to CMRI [15]. Since the use of cardiac CT angiography continues to gain popularity as an imaging modality to define the coronary anatomy in dilated cardiomyopathy, protocols to also visualize the left ventricular cavity to exclude LVNC are currently being refined.
LVNC Treatment
The treatment of LVNC that has resulted in HFrEF is similar to that of other cardiomyopathies, with beta blockers and ACE inhibitors as the mainstay of therapy. Because of the intratrabecular recesses, systemic anticoagulation should be considered in individuals who have a significantly reduced ejection fraction related to LVNC [16].
The prognosis for recovery of patients with LVNC is less robust than that of the general population with dilated cardiomyopathy. Patients who have progressed to advanced stages of heart failure should be monitored closely and considered for advanced heart failure treatments such as cardiac transplantation and ventricular assist systems if they manifest signs and symptoms of end-organ dysfunction, or if the physician needs to reduce ACE inhibitor or beta blocker therapy because of hypotension.
Infiltrative Cardiomyopathy (Amyloidosis)
Infiltrative cardiomyopathies, in general, represent a group of diseases that are characterized by restrictive cardiac physiology. Often the ejection fraction is preserved yet patients have severe limitations in their exercise tolerance. As with most restrictive heart disease, any increase in heart rate will significantly worsen the heart failure state. Infiltrative cardiomyopathy is one of the severest forms of HFpEF. Cardiac amyloidosis can result from multiple different pathologic abnormalities, and the severity and time course of the disease are quite variable among these types [17].
Immunoglobulin amyloidosis is the first type and is characterized by systemic overproduction of immunoglobulin light chain protein. The conditions commonly associated with this overproduction are plasma cell dyscrasias, Waldenstrom macroglobulinemia, and multiple myeloma [18].
Familial amyloidosis is a genetic abnormality associated with the transthyretin gene. There have been more than 70 different mutations of the genes coding for transthyretin, and the defect is transmitted in an autosomal dominant fashion [19]. Other proteins also can be affected by these mutations and can contribute to the heterogeneity of familial amyloidosis [18].
Senile systemic amyloidosis usually involves the atria of the heart, and patients often exhibit very few symptoms. It has been recognized recently, however, that significant heart failure symptoms can result from senile amyloidosis, and the disease process can persist for many years [20]. Recent reviews suggest senile amyloidosis is far more common than initially thought. The disease may be present in up to 80% of 80-year-olds [20], and may result in symptoms in 25% of people older than 80 years [20, 21]. Atrial fibrillation and other conduction abnormalities are also seen in patients with senile amyloidosis [22].
Secondary amyloidosis is a condition resulting from systemic inflammation from other disease types such as rheumatoid arthritis, chronic lung disease, inflammatory bowel disease, and other diseases associated with chronic inflammation. Long-term overproduction of acute-phase reactants in these syndromes results in amyloid protein deposition in the heart, with the advanced stages having significant restrictive cardiomyopathy [18].
Hemodialysis-associated amyloidosis results from β2-microglobulin deposition in patients who are receiving long-term hemodialysis as renal replacement therapy. This protein deposition is usually seen in bones and joints; however, evidence is emerging that amyloid protein deposition does occur in the heart [23, 24] and over years could be responsible for heart failure associated with this type of systemic amyloidosis.
Cardiac Amyloidosis Diagnosis
Endomyocardial biopsy has been the gold standard for the diagnosis of cardiac amyloidosis [17]. It is not necessary to perform a heart biopsy when the clinical and echocardiographic findings are present in an individual with biopsy-proven amyloid from another tissue. Subcutaneous fat pad biopsy has a sensitivity of 70% for detecting systemic amyloid [25]. The search for a noninvasive diagnostic modality for cardiac amyloidosis has improved dramatically with the emergence of CMRI; this noninvasive modality has taken a definitive position as the noninvasive diagnostic modality of choice for amyloidosis of the heart [26]. The specificity of CMRI is quite high; the current limitation is the sensitivity of detecting the amyloid infiltrates when they are small with less clinical impact.
Two-dimensional echocardiography remains a first-line diagnostic tool because of the ubiquitous use of this modality in patients with heart failure symptoms [22, 27]. Like other forms of HFpEF, amyloidosis is associated with impaired filling seen with standard and tissue Doppler assessments. The glistening or speckle pattern noted in the left ventricular walls and extensive atrial enlargement should raise concern for the presence of amyloidosis. In the presence of significant left ventricular hypertrophy on such an echocardiogram, an ECG with low voltage in the limb leads is very specific for the presence of cardiac amyloidosis (Figure 3) [28].
The Left Panel Shows an Echocardiogram in the Apical Four-chamber View in a Patient with Systemic Amyloidosis Related to a Primary Blood Dyscrasia that was Diagnosed by Tissue Biopsy in Multiple Other Organs.
The right panel shows a parasternal long-axis view of a patient with severe restrictive symptoms, significant left ventricular hypertrophy, and low voltage on the ECG.
Treatment of cardiac amyloidosis remains very challenging and focuses primarily on the treatment of any underlying disease state resulting in amyloid protein deposition. Numerous clinical trials are currently ongoing looking for pharmacologic agents that will reduce amyloid protein deposition. Cardiac transplantation remains controversial in systemic amyloidosis because of the reoccurrence of amyloid protein deposition in the transplanted heart.
Volume control with diuretics is also fairly difficult since patients with this degree of restriction require elevated filling pressures to maintain any reasonable cardiac output. Maintenance of the slow heart rate is important in the treatment of these individuals; however, because conduction abnormalities can result from amyloid protein deposition, caution must be taken to avoid significant bradycardia and heart block.
Digitalis glycosides should be avoided in amyloidosis because of the preferential binding to amyloid protein, and increased clinical effects even at therapeutic blood levels [29].
Conclusion and Take-Home Message
Uncommon cardiomyopathies such as LVNC and cardiac amyloidosis may not be as uncommon as had previously been thought. In fact, these disease states represent a fairly significant portion of individuals seen in an advanced heart failure practice for HFrEF and HFpEF, respectively. It is important to remember these clinical entities when one is evaluating patients with heart failure. A thorough history, including a family history, and physical examination and routine diagnostic tools such as echocardiography continue to be the diagnostic armamentarium of the heart failure cardiologist. Further evaluation of individuals with dilated cardiomyopathy or severe restrictive cardiomyopathy should include CMRI, since this diagnostic tool has proven to be both sensitive and specific for LVNC and very specific for the presence of cardiac amyloidosis.
As genetic testing evolves, and cost of genetic testing falls, the use of routine genetic testing in heart failure and cardiomyopathy may prove to be of substantial benefit. Furthermore, as our understanding of the microRNA changes in all heart failure patients improves, heart failure patients may be able to have personalized medical therapies to alter their disease progression.