outcomes (procedural approaches, benefits, mortal-ity). The importance of ongoing studies is high.
Paul R. Scully, MBBS Thomas A. Treibel, PhD Marianna Fontana, PhD Guy Lloyd, MD Michael Mullen, MD Francesca Pugliese, PhD Neil Hartman, PhD Philip N. Hawkins, PhD Leon J. Menezes, BM BCh *James C. Moon, MD *Barts Heart Centre St Bartholomew’s Hospital West Smithfield
London EC1A 7BE United Kingdom
E-mail:j.moon@ucl.ac.uk https://doi.org/10.1016/j.jacc.2017.11.037
Ó 2018 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Please note: Dr. Scully is supported by a British Heart Foundation Clinical Research Training Fellowship (FS/16/31/32185). Dr. Pugliese has received research support from Siemens Healthineers, and this work forms part of the translational research portfolio of the NIHR Cardiovascular Biomedical Research Centre at Barts Heart Centre, which is supported and funded by the NIHR. Dr. Menezes is supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre. Dr. Lloyd has received speaker fees from Edwards Lifesciences; and a research grant from Medtronic. Dr. Mullen has been a consultant for Edwards Lifesciences. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. (A study investigating the role of occult cardiac amyloid in the elderly with aortic stenosis [ATTRact-AS];NCT03029026)
R E F E R E N C E S
1.Gillmore JD, Maurer MS, Falk RH, et al. Nonbiopsy diagnosis of cardiac transthyretin amyloidosis. Circulation 2016;133:2404–12.
2.Tanskanen M, Peuralinna T, Polvikoski T, et al. Senile systemic amyloidosis affects 25% of the very aged and associates with genetic variation in alpha2-macroglobulin and tau: a population-based autopsy study. Ann Med 2008;40:232–9.
3.Castaño A, Narotsky DL, Hamid N, et al. Unveiling transthyretin cardiac amyloidosis and its predictors among elderly patients with severe aortic stenosis undergoing transcatheter aortic valve replacement. Eur Heart J 2017; 38:2879–87.
4.Treibel TA, Fontana M, Gilbertson JA, et al. Occult transthyretin cardiac amyloid in severe calcific aortic stenosis: prevalence and prognosis in patients undergoing surgical aortic valve replacement. Circ Cardiovasc Imaging 2016;9:e005066. 5.González-López E, Gallego-Delgado M, Guzzo-Merello G, et al. Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fraction. Eur Heart J 2015;36:2585–94.
Cardiac Resynchronization
Therapy for End-Stage
Hypertrophic Cardiomyopathy
The Need for Disease-Specific Criteria
Cardiac resynchronization therapy (CRT) is a well-established treatment for patients with heart failure (HF) with reduced left ventricular ejection fraction (LVEF), whereas its role in patients with preserved LVEF is controversial at best (1). Hypertrophic car-diomyopathy (HCM) is characterized by normal or enhanced LVEF, even in patients with severe FIGURE 1 Cardiac Amyloid in Aortic Stenosis
An 88-year-old woman with severe aortic stenosis.(A) DPD scintigraphy fused single-photon emission tomography/computed tomography illustrating cardiac tracer retention suggestive of cardiac amyloid, with large bilateral pleural effusions.(B) Fluoroscopy demonstrating the 26-mm Edwards Sapien 3 valve (Edwards Lifesciences, Irvine, California) in situ during the transcatheter aortic valve replacement. Note the pre-existing dual-chamber pacemaker leads.
Letters J A C C V O L . 7 1 , N O . 4 , 2 0 1 8
J A N U A R Y 3 0 , 2 0 1 8 : 4 6 3 – 7 3 464
congestive symptoms. About 5% to 7% of patients with HCM, however, develop systolic dysfunction with LVEF values <50% and as low as 25% to 30%, subtended by extensive myocardial fibrosis (“end-stage”)(2). In this subset, CRT appears a reasonable option, but the limited data available show conflicting results (1,3), possibly because eligibility criteria are undefined and variably extrapolated from systolic HF. Whether dilated cardiomyopathy (DCM) criteria apply to HCM is unresolved. Therefore, we aimed to evaluate the effects CRT on symptomatic status and outcome in end-stage HCM in a tertiary referral center.
We evaluated patients with HCM consecutively seen from 2000 to 2016; patients with storage or metabolic disease were excluded. We identified 61 patients with end-stage HCM, of whom 13 (21%) received CRT (7 females, age at diagnosis 29 10 years). Patients with CRT were <1% of the total cohort.
At CRT implantation (age 49 12 years), 8 pa-tients were in New York Heart Association (NYHA) functional class II and 5 patients in class III/IV. Cardiopulmonary exercise testing was performed in 8 patients, showing marked VO2reduction (average
52% of predicted). Left bundle branch block (LBBB) was present in 12 of 13 patients with average QRS duration of 173 27 ms, and LVEF was 42 12% (2 patients were implanted despite EF>50% due to refractory HF and marked intraventricular dyssyn-chrony). Nine patients had paroxysmal atrial fibril-lation, evolving into permanent in 6; 4 required ablate-and-pace. The CRT group showed a higher proportion of LBBB compared with end-stage pa-tients without CRT (12 of 13 vs. 9 of 48; p< 0.01); no difference was seen in NYHA functional class, age, LVEF, and diuretics dose.
At 1 year, 7 patients (54%) improved $1 NYHA functional class, 3 reported no change, and 2 worsened$1 class. No differences were observed in LVEF and left ventricular (LV) volumes. At end of follow-up (5.2 3.1 years after implantation), 6 pa-tients died (46%) due to HF (n¼ 3), cerebral hemor-rhage, cardiorenal complications, and heart transplant complications. Two patients were alive after heart transplantation. In the 7 CRT responders, symptomatic improvement lasted 2.7 2.5 years. At final evaluation, however, there was no sustained symptomatic improvement compared with baseline. No difference in survival was evident between CRT and no-CRT end-stage patients during comparable follow-up (p ¼ 0.46). Time from onset of NYHA functional class III/IV symptoms to listing in
transplant candidates was also similar (2.1 vs. 1.9 years, respectively; p ¼ 0.73). Two long-term CRT responders (sustained improvement to NYHA func-tional class II) were observed: a 48-year-old woman with LVEF of 32% and LBBB, and a 32-year-old woman with normal systolic function (LVEF 64%) and marked mitral regurgitation associated with LBBB following extensive surgical myectomy.
Patients vaguely fulfilling DCM criteria for CRT implantation are rare in large HCM cohorts and bear an ominous prognosis with an overall mortality or need for transplantation exceeding 50% at 5 years. CRT provided no significant advantage over phar-macological therapy alone, and failed to induce LV reverse remodeling or improvement in systolic func-tion. We did observe transient symptomatic improvement at 1 year, but this effect was not main-tained long term. A likely explanation for lack of CRT efficacy lies in the peculiar pathophysiology of HCM. Imaging and pathology studies(4,5)show that more than one-third of the LV in end-stage patients is replaced byfibrosis, which predominates, but is not confined to, the anteroseptal region and is often diffuse. Such substrate appears hardly amenable to the beneficial effects of CRT. Therefore, DCM criteria combining systolic dysfunction and LBBB are not applicable to HCM patients. The fact that individual responders exist, however, suggests that disease-specific eligibility criteria should be sought, rather than admitting defeat too early over this important therapeutic issue. A case-by-case evaluation of HF symptoms, QRS duration, LV dyssynchrony, and mechanism of mitral regurgitation may help identify patients who will benefit from CRT. Need for perma-nent pacing should prompt consideration for CRT in order to prevent worsening of diastolic function. Most importantly, exploring earlier stages of HCM progression and assessing the burden of fibrosis by cardiac magnetic resonance may be key in patient selection(5). Unfortunately, too few of our patients had cardiac magnetic resonance before CRT (n¼ 5) to address this important issue.
*Francesco Cappelli, MD Sofia Morini, MD Paolo Pieragnoli, MD, PhD Mattia Targetti, MD Pierluigi Stefàno, MD Niccolò Marchionni, MD, PhD Iacopo Olivotto, MD
*Intensive Cardiac Care Unit Cardiothoracovascular Department
Azienda Ospedaliero-Universitaria Careggi [AOUC]
J A C C V O L . 7 1 , N O . 4 , 2 0 1 8 Letters
J A N U A R Y 3 0 , 2 0 1 8 : 4 6 3 – 7 3
Largo Brambilla 3 50134 Florence Italy
E-mail:cappellifrancesco@inwind.it https://doi.org/10.1016/j.jacc.2017.11.040
Ó 2018 by the American College of Cardiology Foundation. Published by Elsevier. Please note: The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
R E F E R E N C E S
1.Auricchio A, Baron-Esquivias G, Bordachar P, et al. 2013 ESC guidelines on cardiac pacing and cardiac resynchronization therapy. Eur Heart J 2013;34: 2281–329.
2.Pasqualucci D, Fornaro A, Castelli G, et al. Clinical spectrum, therapeutic options, and outcome of advanced heart failure in hypertrophic cardiomyop-athy. Circ Heart Fail 2015;8:1014–21.
3.Rogers PSD, Marazia A, Chow AW, et al. Effect of biventricular pacing on symptoms and cardiac remodelling in patients with end-stage hypertrophic cardiomyopathy. Eur J Heart Fail 2008;10:507–13.
4.Galati G, Leone O, Pasquale F, et al. Histological and histometric charac-terization of myocardialfibrosis in end-stage hypertrophic cardiomyopathy a clinical-pathological study of 30 explanted hearts. Circ Heart Fail 2016;9: e003090.
5.Olivotto I, Maron BJ, Appelbaum E, et al. Spectrum and clinical significance of systolic function and myocardialfibrosis assessed by cardiovascular magnetic resonance in hypertrophic cardiomyopathy. Am J Cardiol 2010;106:261–7.
Altered HDL Remodeling
and Functionality in
Familial Hypercholesterolemia
Current research is focused on improving high-density lipoprotein (HDL) function rather than simply targeting an increase in high-density lipoprotein-cholesterol (HDL-C) levels(1). The results of several recent studies indicate that stimulation of the HDL-dependent cholesterol efflux from macrophage foam cells mediated by the adenosine– triphosphate-binding cassette (ABC) A1 transporter, considered to be the major atheroprotective property of HDL, is inversely associated with the incidence of cardiovascular disease events(1). Familial hyper-cholesterolemia (FH) is an inherited autosomal dominant disorder mainly caused by mutations in the low-density lipoprotein receptor (LDLR) gene and characterized by high low-density lipoprotein-cholesterol (LDL-C) levels, which often are associated with low HDL-C levels(2). Several studies have re-ported that patients with FH display qualitative abnormalities in the HDL particles that may be critical for HDL remodeling and macrophage cholesterol efflux (2). Furthermore, recent evidence indicates that hypercholesterolemia alters HDL lipidome and
protein cargo in pigs, thereby impairing its ability to promote macrophage cholesterol efflux (3). The potential of HDL particles to be remodeled in nontreated patients with FH and the effect of such remodeling on the HDL-mediated macrophage cholesterol efflux have not been investigated.
In the present study, we evaluated the HDL-associated master remodeling lipid transfer proteins and enzymes, and their potential to alter HDL composition and macrophage cholesterol efflux in nontreated patients with FH with an identified LDLR mutation and in normolipidemic subjects of similar age (51.0 1.21 years of age and 49.8 1.98 years of age in adult subjects, respectively; 15.9 0.64 years of age and 16.1 0.75 years of age in adolescent subjects, respectively) and sex distributions (Table 1). All studied subjects were recruited from the Vascular Medicine and Metabolism Unit of the Sant Joan Uni-versity Hospital and the Department of Biochemistry of the Hospital de la Santa Creu i Sant Pau. The study was performed in accordance with the ethical principles set forth in the Declaration of Helsinki.
As expected (2), adult patients with FH showed higher levels of LDL-C and apolipoprotein (apo) B, whereas HDL-C and apoA-I levels were lower than those of control subjects. Importantly, nontreated patients with FH were also characterized by higher cholesteryl ester transfer protein (CETP) (4,5) and phospholipid transfer protein (PLTP) activities but reduced lecithin-cholesterol acyltransferase (LCAT) activity. The increased lipid transfer activities of CETP and PLTP may explain the higher potential for plasma to convert mature HDL into pre
b
-HDL par-ticles (Table 1). LCAT activity is essential for con-verting unesterified cholesterol into cholesteryl esters, and via this mechanism, LCAT induces the transformation of preb
-HDL into mature spherical HDL. Reduced LCAT may thus contribute to the higher contents of unesterified cholesterol and apoE and the reduced content of apoA-I in mature FH HDL (Table 1). We also determined macrophage cholesterol efflux to apoB-depleted plasmas, which contains mature HDL, the HDL regulatory proteins, and preb
-HDL particles, thereby permitting optimal HDL remodeling and cholesterolflow to HDL. ApoB-depleted plasma from patients with FH displayed an impaired ability to promote macrophage cholesterol efflux under experimental settings that stimulated mainly ABCA1-dependent cholesterol efflux by treating the cells with cyclic adenosine mono-phosphate or that stimulated concerted action of ABCA1/ABCG1-dependent efflux pathways by over-loading the cells with acetylated-LDL (Table 1). Notably, most of these HDL alterations were alsoLetters J A C C V O L . 7 1 , N O . 4 , 2 0 1 8
J A N U A R Y 3 0 , 2 0 1 8 : 4 6 3 – 7 3 466
