Physiologic or pathologic hypertrophy: how can we know?

Abstract

Pathologic left ventricular hypertrophy due to hypertrophic cardiomyopathy is typically diagnosed based on compatible clinical and imaging findings. In a subset of patients however, the diagnosis is unclear, either due to the finding of concentric hypertrophy raising the possibility of physiologic hypertrophy due to athlete’s heart or due to the potential of so-called hypertrophic cardiomyopathy ‘phenocopies’, which include Anderson-Fabry disease and cardiac amyloidosis. We review each of these diseases, highlighting important distinguishing features, the knowledge of which should permit the resolution of such diagnostic dilemmas.

Keywords::

• Anderson-Fabry disease
• athlete’s heart
• cardiac amyloidosis
• hypertrophic cardiomyopathy
• left ventricular hypertrophy

Left ventricular hypertrophy (LVH) may be due to a physiologic response to increased load, pathologic hypertrophy due to hypertrophic cardiomyopathy (HCM) or be mimicked by myocardial infiltration. While in most instances, a patient’s clinical presentation and morphologic features make this distinction clear, it remains a challenge in many patients. Given the important prognostic and therapeutic differences associated with these conditions, having a practical template to distinguish them is of great clinical importance. In this editorial, we outline the relevant historical, clinical, imaging and pathological features of each of these conditions, the appreciation of which is elemental to their distinction.

Physiologic hypertrophy: athlete’s heart

The recognition that systematic athletic training can lead to specific circulatory and cardiac morphological adaptations extends over 100 years [1,2]. Athlete’s heart may be associated with ventricular enlargement and hypertrophy [3]. The vast majority of athletes will have only a mild absolute increase in left ventricular (LV) wall thickness (≤12 mm); however, in some the increase may be more substantial, up to 16 mm [1,2,4]. Importantly, however, such significant increases are rare, occurring in <2% of highly trained athletes and should not be present in persons with less vigorous activity. The type of athletic training also has a major influence on the possible magnitude of change in LV thickness, with the most extreme increases having been observed in specific sports including rowing, cycling, cross-country skiing, distance running and swimming [1,2,4]. Notably, isometric sports such as weight lifting and wrestling are not associated with increases in wall thickness beyond the accepted normal range [1,2,4]. Furthermore, female athletes rarely have increases in LV wall thickness >11 mm; thus a finding of even relatively mild degrees of LVH in a woman should prompt consideration of a pathological cause [2].

Other important historical details to ascertain include the absence of cardiac symptoms and family history of cardiomyopathy or sudden cardiac death. Similarly, the physical examination should be unremarkable, save for perhaps resting bradycardia. Although most athletes have ECGs that are within normal limits, an abnormal ECG is found in approximately 40% [2]. Compatible changes include increased QRS voltages, early repolarization patterns, diffuse T-wave inversion and deep Q waves [2]. As such, the overlap with pathological ECG patterns is too great to help definitively distinguish the cause of LVH.

Echocardiographic findings to note include the absolute LV wall thickness rarely being >12 mm [4] with a relatively symmetric distribution of hypertrophy [1]. An enlarged LV end-diastolic dimension (>55 mm) is typical, whereas a small cavity dimension (<45 mm) is highly inconsistent and should prompt consideration of pathology [2]. The LV filling pattern is invariably normal in trained athletes [1].

Should the diagnosis of athlete’s heart remain unclear, cardiopulmonary testing may be useful, with a VO₂ max >45–50 ml/kg/min or >110–120% of predicted in favor of physiologic change [2,5]. In addition, a trial of deconditioning may be pursued with regression of LV wall thickness of greater than 2 mm within 3 months, supporting a diagnosis of athlete’s heart [6,7]. With its high spatial resolution and tomographic imaging capability, cardiac magnetic resonance (CMR) is ideally suited to documenting such changes. Finally, athletes should not demonstrate late gadolinium enhancement (LGE) on contrast-enhanced CMR and, therefore, the identification of LGE should prompt an alternate diagnosis [2,7,8].

Pathologic hypertrophy: HCM

HCM is the most common genetic disease of the heart with a prevalence of approximately 0.2% (1:500). It is caused by mutations in genes encoding sarcomeric proteins with the classic phenotype being characterized by a hypertrophied, non-dilated LV in the absence of another disease capable of producing the degree of hypertrophy evident [2,3]. Given its autosomal dominant pattern of inheritance, a family history of cardiomyopathy or sudden cardiac death may be present. Clinically, symptoms of chest pain, dyspnea, presyncope or syncope are frequently present with or without LV outflow tract obstruction (LVOTO) [3].

The ECG, while abnormal in 75–90% of HCM patients, does not have diagnostic features of the disease [9]. The characteristic echocardiographic finding is asymmetric septal hypertrophy, with the average reported wall thickness being approximately 20 mm [1]. However, an important minority of patients show relatively mild LVH (13–15 mm) and, in fact, any wall thickness is compatible with the presence of the genetic substrate [2]. As in athlete’s heart, the anterior ventricular septum is usually the region of maximal wall thickening; however, this is not invariably the case. About 7% of patients have dominant apical hypertrophy and about 10% have concentric LVH [10]. In patients with HCM, the LV is typically small and hyperdynamic and dynamic LVOTO at rest or with provocation is present in about 70% of patients [9]. Tissue Doppler annular velocities are typically reduced and LV myocardial mechanics show abnormalities of systolic and diastolic function [11,12].

CMR is particularly useful for the identification of segmental hypertrophy of the apex and anterolateral wall, which are less reliably visualized by echocardiography [7]. It can also identify additional morphologic markers associated with HCM including elongated mitral valve leaflets, anomalous papillary muscles, myocardial crypts and Gruner (apical-basal muscle) bundles [7,13]. The average reported prevalence of LGE in HCM is 65%, and virtually any pattern and location of LGE can be observed, although the finding of diffuse LGE within the septum is very suggestive of the disease [7,8].

The most definitive evidence for HCM is the detection of a disease causing genetic mutation. Unfortunately, its absence does not exclude the diagnosis, as a definite pathogenic mutation is detected in only 40% of patients with phenotypic expression of the disease [7].

Infiltrative disorders: Anderson-Fabry disease

Anderson-Fabry disease (AFD) is an X-linked lysosomal storage disease characterized by α-galactosidase deficiency [14]. This inborn error of metabolism leads to the accumulation of glycosphingolipids in multiple organs, with cardiac involvement seen in >60% of patients [14,15]. Correct diagnosis is vital, as the infiltration can be arrested with enzyme replacement therapy. About 1% of patients referred to an HCM clinic will be found to have AFD.

Given the pattern of inheritance, men are primarily affected, while women may represent symptomatic or asymptomatic carriers of the disease [16]. Skin lesions, corneal deposits and a history of acroparesthesias, hypohidrosis and heat, cold or exercise intolerance should be sought out [14]. A history of renal, nervous system or gastrointestinal disease may also be present [14,16] Importantly, an atypical cardiac variant of the disease exists in men with low residual α-galactosidase activity, with the main manifestation of LVH and mild proteinuria; thus, the absence of systemic findings should not exclude the disease [14,17].

The principle echocardiographic finding is concentric LVH, although eccentric hypertrophy and focal hypokinesis and thinning of the basal inferolateral wall have also been described [16]. The main functional abnormality is impaired LV diastolic filling consistent with impaired relaxation [18]. However, in AFD, this may progress to restrictive physiology, which is rarely the case with HCM. In addition, a recent study has demonstrated that AFD patients with LVH show abnormally low global longitudinal and circumferential strain and loss of the normal base-to-apex circumferential strain gradient. In contrast, patients with HCM show low global longitudinal strain but compensate with an increase in circumferential strain, with preservation of base-to-apex gradient [15]. Although CMR studies in AFD are lacking, the presence of LGE has been reported in up to 50% of patients in a unique distribution involving the basal inferolateral wall [7,16,18].

The endomyocardial biopsy findings in AFD include myocyte vacuolation and dense bodies of globotriaosylceramide; however, this procedure is rarely necessary as the disease is readily diagnosed by determining the α-galactosidase activity in plasma or peripheral leukocytes and/or the demonstration of a familial genetic mutation [14,16].

Infiltrative disorders: cardiac amyloidosis

Amyloidosis is a clinical disorder caused by the infiltration of organs by insoluble deposits of abnormal fibrils, arising from a diverse group of disease processes [18,19] However, only transthyretin and monoclonal immunoglobulin light chain amyloidosis commonly cause significant cardiac disease, mostly dominated by right-sided symptoms, including peripheral edema, hepatomegaly, ascites and elevated jugular venous pressure [19]. Systemic findings include peripheral and autonomic neuropathies and in monoclonal immunoglobulin light chain amyloidosis, macroglossia, carpal tunnel syndrome, purpura, nephrotic syndrome and gastrointestinal symptoms [16,19]. Importantly, systemic symptoms can be variable and lone cardiac involvement is possible [18].

The absence of high ECG voltages in a patient with LVH should immediately raise the suspicion of infiltrative diseases, of which amyloid is the most common [16,18,19]. A pseudoinfarction pattern and conduction delays are also frequently observed [19]. Increased echogenicity of the thickened myocardium, with a ‘sparkling’ appearance, is the classic echocardiographic finding. However, this is less characteristically demonstrated using modern echocardiographic imaging, in which tissue harmonics have been applied. LV thickening is typically concentric, although both eccentric thickening and LVOTO have also been reported. Other findings may include thickening of the RV, valves and interatrial septum, enlarged atria and pericardial effusion [16,18]. Diastolic dysfunction is the fundamental abnormality, initially presenting as an abnormal relaxation pattern, with progression to a restrictive pattern [18]. Strain assessment may allow the detection of early impairments in LV function (i.e., when conventional echocardiographic measures are still normal) and have superior predictive value [16,18]. Considering CMR, the demonstration of concentric LV thickening combined with global subendocardial LGE is highly specific for cardiac amyloidosis [7].

Confirmatory diagnosis ultimately requires histologic analysis of tissue. Congo red staining identifies amorphous pink deposits on light microscopy, which exhibit apple-green birefringence under polarized microscopy [19].

Summary

Pathologic hypertrophy of the heart due to HCM can usually be diagnosed by the severity and distribution of asymmetric hypertrophy. Family history, clinical presentation, genetic studies and imaging with CMR and advanced echocardiography are almost always sufficient to distinguish HCM from Athlete’s heart. Rarely, deconditioning is required to distinguish Athlete’s Heart from mild concentric hypertrophy due to HCM. When assessing patients with more significant hypertrophy thought to be due to HCM, it is important to remember that infiltrative disorders may be the cause in 1–2% of patients. Such phenocopy disease can usually be distinguished by genetic testing, α-galactosidase activity, CMR patterns of LGE and endomyocardial biopsy.

Financial & competing interest disclosure

The authors were supported by the Richard and Edith Strauss Canada Foundation and the Halpern Hypertrophic Cardiomyopathy Fund. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript.

No writing assistance was utilized in the production of this manuscript.