Clinicopathological profiles of progressive heart failure in hypertrophic cardiomyopathy

Paola Melacini, Cristina Basso, Annalisa Angelini, Chiara Calore, Fabiana Bobbo, Barbara Tokajuk, Nicoletta Bellini, Gessica Smaniotto, Mauro Zucchetto, Sabino Iliceto, Gaetano Thiene, Barry J Maron, Paola Melacini, Cristina Basso, Annalisa Angelini, Chiara Calore, Fabiana Bobbo, Barbara Tokajuk, Nicoletta Bellini, Gessica Smaniotto, Mauro Zucchetto, Sabino Iliceto, Gaetano Thiene, Barry J Maron

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.

Figures

Figure 1
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
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
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
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
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.

References

    1. Maron BJ, Towbin JA, Thiene G, Antzelevitch C, Corrado D, Arnett D, Moss AJ, Seidman CE, Young JB. American Heart Association; Council on Clinical Cardiology, Heart Failure and Transplantation Committee; Quality of Care and Outcomes Research and Functional Genomics and Translational Biology Interdisciplinary Working Groups; Council on Epidemiology and Prevention. Contemporary definitions and classification of the cardiomyopathies. Circulation. 2006;113:1807–1816. .
    1. Maron BJ. Hypertrophic cardiomyopathy: a systematic review. JAMA. 2002;287:1308–1320. .
    1. Elliott PM, Poloniecki J, Dickie S, Sharma S, Monserrat L, Varnava A, Mahon NG, McKenna WJ. Sudden death in hypertrophic cardiomyopathy: identification of high risk patients. J Am Coll Cardiol. 2000;36:2212–2218. .
    1. Spirito P, Bellone P, Harris KM, Bernabo P, Bruzzi P, Maron BJ. Magnitude of left ventricular hypertrophy and risk of sudden death in hypertrophic cardiomyopathy. N Engl J Med. 2000;342:1778–1785. .
    1. Schiller NB, Shah PM, Crawford M, DeMaria A, Devereux R, Feigenbaum H, Gutgesell H, Reichek N, Sahn D, Schnittger I. Recommendations for quantitation of left ventricle by two-dimensional echocardiography. American Society of Echocardiography Committee on Standards, Subcommittee on Quantitation of Two-Dimensional Echocardiograms. J Am Soc Echocardiogr. 1989;2:358–367.
    1. Panza JA, Petrone RK, Fananapazir L, Maron BJ. Utility of continuous wave Doppler echocardiography in the noninvasive assessment of left ventricular outflow tract pressure gradient in patients with hypertrophic cardiomyopathy. J Am Coll Cardiol. 1992;19:91–99.
    1. Maron BJ, Spirito P, Green KJ, Wesley YE, Bonow RO, Arce J. Noninvasive assessment of left ventricular diastolic function by pulsed Doppler echocardiography in patients with hypertrophic cardiomyopathy. J Am Coll Cardiol. 1987;10:733–742.
    1. Kirkpatrick JN, Vannan MA, Narula J, Lang RM. Echocardiography in heart failure. J Am Coll Cardiol. 2007;50:381–396. .
    1. Paulus WJ, Tschöpe C, Sanderson JE, Rusconi C, Flachskampf FA, Rademakers FE, Marino P, Smiseth OA, De Keulenaer G, Leite-Moreira AF, Borbély A, Edes I, Handoko ML, Heymans S, Pezzali N, Pieske B, Dickstein K, Fraser AG, Brutsaert DL. How to diagnose diastolic heart failure: a consensus statement on the diagnosis of heart failure with normal left ventricular ejection fraction by the Heart Failure and Echocardiography Associations of the European Society of Cardiology. Eur Heart J. 2007;28:2539–2550. .
    1. Maron BJ, Roberts WC. Quantitative analysis of cardiac muscle cell disorganization in the ventricular septum of patients with hypertrophic cardiomyopathy. Circulation. 1979;59:689–706.
    1. Basso C, Thiene G, Corrado D, Buja G, Melacini P, Nava A. Hypertrophic cardiomyopathy and sudden death in the young; pathologic evidence of myocardial ischemia. Hum Pathol. 2000;31:988–998. .
    1. Angelini A, Calzolari V, Thiene G, Boffa GM, Valente M, Daliento L, Basso C, Calabrese F, Razzolini R, Livi U, Chioin R. Morphologic spectrum of primary restrictive cardiomyopathy. Am J Cardiol. 1997;80:1046–1050. .
    1. Shirani J, Pick R, Roberts WC, Maron BJ. Morphology and significance of the left ventricular collagen network in young patients with hypertrophic cardiomyopathy and sudden cardiac death. J Am Coll Cardiol. 2000;35:36–44. .
    1. Harris KM, Spirito P, Maron MS, Zenovich AG, Formisano F, Lesser JR, Mackey-Bojack S, Manning WJ, Udelson JE, Maron BJ. Prevalence, clinical profile, and significance of left ventricular remodeling in the end-stage phase of hypertrophic cardiomyopathy. Circulation. 2006;114:216–225. .
    1. Maron MS, Olivotto I, Betocchi S, Casey SA, Lesser JR, Losi MA, Cecchi F, Maron BJ. Effect of left ventricular outflow tract obstruction on clinical outcome in hypertrophic cardiomyopathy. N Engl J Med. 2003;348:295–303. .
    1. Maron BJ, Spirito P, Shen WK, Haas TS, Formisano F, Link MS, Epstein AE, Almquist AK, Daubert JP, Lawrenz T, Boriani G, Estes NA, III, Favale S, Piccininno M, Winters SL, Santini M, Betocchi S, Arribas F, Sherrid MV, Buja G, Semsarian C, Bruzzi P. Implantable cardioverter-defibrillators and prevention of sudden cardiac death in hypertrophic cardiomyopathy. JAMA. 2007;298:405–412. .
    1. Olivotto I, Maron MS, Adabag AS, Casey SA, Vargiu D, Link MS, Udelson JE, Cecchi F, Maron BJ. Gender-related differences in the clinical presentation and outcome of hypertrophic cardiomyopathy. J Am Coll Cardiol. 2005;46:480–487. .
    1. Biagini E, Coccolo F, Ferlito M, Perugini E, Rocchi G, Bacchi-Reggiani L, Lofiego C, Boriani G, Prandstraller D, Picchio FM, Branzi A, Rapezzi C. Dilated-hypokinetic evolution of hypertrophic cardiomyopathy: prevalence, incidence, risk factors, and prognostic implications in pediatric and adult patients. J Am Coll Cardiol. 2005;46:1543–1550. .
    1. Yacoub MH, Olivotto I, Cecchi F. ‘End-stage’ hypertrophic cardiomyopathy: from mystery to model. Nat Clin Pract Cardiovasc Med. 2007;4:232–233. .
    1. Olivotto I, Cecchi F, Casey SA, Dolara A, Traverse JH, Maron BJ. Impact of atrial fibrillation on the clinical course of hypertrophic cardiomyopathy. Circulation. 2001;104:2517–2524. .
    1. Carasso S, Yang H, Woo A, Vannan MA, Jamorski M, Wigle ED, Rakowski H. Systolic myocardial mechanics in hypertrophic cardiomyopathy: novel concepts and implications for clinical status. J Am Soc Echocardiogr. 2008;21:675–683.
    1. Geske JB, Sorajja P, Nishimura RA, Ommen SR. Evaluation of left ventricular filling pressures by Doppler echocardiography in patients with hypertrophic cardiomyopathy: correlation with direct left atrial pressure measurement at cardiac catheterization. Circulation. 2007;16:2702–2708. .
    1. Rakowski H, Carasso S. Quantifying diastolic function in hypertrophic cardiomyopathy: the ongoing search for the holy grail. Circulation. 2008;116:2262–2265. .
    1. Fuster V, Rydén LE, Cannom DS, Crijns HJ, Curtis AB, Ellenbogen KA, Halperin JL, Le Heuzey JY, Kay GN, Lowe JE, Olsson SB, Prystowsky EN, Tamargo JL, Wann S, Smith SC, Jr, Jacobs AK, Adams CD, Anderson JL, Antman EM, Halperin JL, Hunt SA, Nishimura R, Ornato JP, Page RL, Riegel B, Priori SG, Blanc JJ, Budaj A, Camm AJ, Dean V, Deckers JW, Despres C, Dickstein K, Lekakis J, McGregor K, Metra M, Morais J, Osterspey A, Tamargo JL, Zamorano JL. American College of Cardiology; American Heart Association Task Force; European Society of Cardiology Committee for Practice Guidelines; European Heart Rhythm Association; Heart Rhythm Society. ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation. Europace. 2006;8:651–745.
    1. Maron BJ, Olivotto I, Bellone P, Conte MR, Cecchi F, Flygenring BP, Casey SA, Gohman TE, Bongioanni S, Spirito P. Clinical profile of stroke in 900 patients with hypertrophic cardiomyopathy. J Am Coll Cardiol. 2002;39:301–307. .
    1. Richard P, Charron P, Carrier L, Ledeuil C, Cheav T, Pichereau C, Benaiche A, Isnard R, Dubourg O, Burban M, Gueffet JP, Millaire A, Desnos M, Schwartz K, Hainque B, Komajda M for the EUROGENE Heart Failure Project. Hypertrophic cardiomyopathy. Distribution of disease genes, spectrum of mutations, and implications for a molecular diagnosis strategy. Circulation. 2003;107:2227–2232. .
    1. Ashrafian H, Watkins H. Reviews of translational medicine and genomics in cardiovascular disease: new disease taxonomy and therapeutic implications. Cardiomyopathies: therapeutics based on molecular phenotype. J Am Coll Cardiol. 2007;49:1251–1264. .

Source: PubMed

Sponzoři a spolupracovníci

Zdravotní podmínky

Drogové intervence

3
Předplatit