Clinicopathological profiles of progressive heart failure in hypertrophic cardiomyopathy

Abstract

Aims: Hypertrophic cardiomyopathy (HCM) is an important cause of heart failure-related disability over a wide range of ages. Profiles of severe progressive heart failure symptoms and death, or heart transplantation deserve more complete definition within large patient cohorts.

Methods and results: Clinical and morphological features of heart failure were assessed in 293 consecutive HCM patients over a median follow-up of 6 (inter-quartile range 2-11) years. Gross and histopathological features were analysed in 12 patients for whom the heart was available for inspection. Of the 293 patients, 50 (17%) developed severe progressive heart failure, including 18 who died or were transplanted. Three profiles of heart failure were identified predominantly associated with: (i) end-stage systolic dysfunction (ejection fraction <50%) (15; 30%); (ii) left ventricular (LV) outflow obstruction at rest (11; 22%); and (iii) non-obstructive with preserved systolic function (24; 48%). Overall, atrial fibrillation (AF) contributed to heart failure in 32 patients (64%) among the three profiles. Compared with other patients, those non-obstructive with preserved systolic function had earlier onset of heart failure symptoms mainly due to diastolic dysfunction, and the most accelerated progression to advanced heart failure and adverse outcome (P = 0.04). Thrombi were identified in the left atrial appendage of five gross heart specimens all belonging to patients with AF, including three of which were unrecognized clinically and had previously embolized. Extensive myocardial scarring with LV remodelling was evident in all end-stage patients; no or only focal scars were present in other patients.

Conclusion: Profiles of advanced heart failure in HCM are due to diverse pathophysiological mechanisms, including LV outflow obstruction and diastolic or global systolic ventricular dysfunction. Atrial fibrillation proved to be the most common disease variable associated with progressive heart failure. Recognition of the heterogeneous pathophysiology of heart failure in HCM is relevant, given the targeted management strategies necessary in this disease.

Figure 1

Time lines shown for the three hypertrophic cardiomyopathy patient subgroups and disease profiles associated with severe, progressive heart failure. Patient ages at intervals describe clinical evolution. FU, follow-up.

Figure 2

End-stage systolic dysfunction. A 59-year-old transplanted male patient with a troponin T mutation [#5 (Table 3); #3 (Table 4)]. (A) Four-chamber view at end-diastole showing dilatation of both atria [transverse left atrial (LV) dimension = 70 mm], left ventricular (LV) enlargement (i.e. 62 mm), and mild hypertrophy [septal (VS) thickness; 13 mm]; ejection fraction was 30%. (B) Heart removed at transplantation. Note thinning of basal and mid-ventricular septum (12 mm) compared with distal LV. (C) High power of boxed area in (B). Greyish areas (arrows) are indicative of septal scarring. (D) Area of septum shown in (C). Extensive replacement fibrosis is associated with abnormal intramural arterioles. Trichrome stain ×60. RA, right atrium; RV, right ventricle.

Figure 3

Non-obstructive hypertrophic cardiomyopathy with preserved systolic function (and atrial fibrillation). A 60-year-old male patient with a β-myosin heavy chain mutation [#39 (Table 3); #9 (Table 4)]. (A) Four-chamber view at end-diastole showing severe dilatation of both atria [transverse dimension of left atrium (LA), 90 mm], normal-sized left ventricle (LV) and right ventricle (RV), and mild LV hypertrophy (ventricular septum, VS; 18 mm) as well as preserved systolic function. (B) Heart removed at transplantation. (C) Histological section of left ventricular free wall (LVFW) showing the absence of replacement fibrosis. Trichrome stain ×3. (D) High-power view of area in box in (C) showing increased interstitial fibrosis. Trichrome stain ×40. (E) Thrombus within LA appendage (arrow). RA, right atrium.

Figure 4

Non-obstructive hypertrophic cardiomyopathy with preserved systolic function. Restrictive form of heart failure due to diastolic dysfunction in sinus rhythm. A 28-year-old woman with troponin I mutation [#45 (Table 3); #12 (Table 4)]. (A) Four-chamber view in end-diastole showing dilatation of both atria (left atrium, LA = 53 mm), normal-sized ventricles, and mild ventricular septal (VS) thickening (17 mm). (B) Pulsed Doppler waveform with evidence of restrictive filling: E/A >2; deceleration time < 150 ms. (C) long-axis left ventricular (LV) plane with mild VS hypertrophy (17 mm); atria missing due to transplantation. (D and E) LV free wall (D) and septum (E) showing diffuse myocardial disarray, mild interstitial fibrosis, and intramural small vessel disease. Trichrome stain ×40. LVFW, left ventricular free wall; RA, right atrium; RV, right ventricle.

Figure 5

Non-obstructive hypertrophic cardiomyopathy with preserved systolic function. A 12-year-old girl with massive septal hypertrophy in sinus rhythm with a myosin-binding protein C mutation [#42 (Table 3); #11 (Table 4)]. (A) Parasternal long-axis view at end-diastole, showing marked septal hypertrophy (30 mm) and normal-sized left ventricular (LV) cavity. (B) Explanted heart, showing massive asymmetric hypertrophy of ventricular septum (VS), and absence of grossly visible scars. (C and D) Sections of left ventricular free wall (LVFW) (C) and VS (D) showing myocyte hypertrophy and disarray, and increased interstitial fibrosis. Trichrome stain, ×20 and ×40.