Study Design and Rationale of EXPLORER-HCM Ho, Carolyn Y.; Olivotto, Iacopo; Jacoby, Daniel ...
Circulation. Heart failure,
06/2020, Letnik:
13, Številka:
6
Journal Article
Recenzirano
Odprti dostop
Background: Obstructive hypertrophic cardiomyopathy (oHCM) is characterized by unexplained left ventricular (LV) hypertrophy associated with dynamic LV outflow tract obstruction. Current medical ...therapies are nonspecific and have limited efficacy in relieving symptoms. Mavacamten is a first-in-class targeted inhibitor of cardiac myosin, which has been shown to reduce LV outflow tract obstruction, improve exercise capacity, and relieve symptoms of oHCM in the PIONEER-HCM phase 2 study. Methods: EXPLORER-HCM is a multicenter, phase 3, randomized, double-blind, placebo-controlled trial to investigate the efficacy and safety of mavacamten in treating symptomatic oHCM. Eligible adults with oHCM and New York Heart Association Functional Class II or III are randomized 1:1 to receive once-daily, oral mavacamten, or matching placebo for 30 weeks. The primary composite functional end point is clinical response at week 30 compared to baseline defined as either (1) an increase in peak oxygen consumption ≥1.5 mL/kg/min and reduction of at least one New York Heart Association class; or (2) an improvement of ≥3.0 mL/kg/min in peak oxygen consumption with no worsening of New York Heart Association class. Secondary end points include change in postexercise LV outflow tract gradient, New York Heart Association class, peak oxygen consumption, and patient-reported outcomes assessed by the Kansas City Cardiomyopathy Questionnaire and a novel HCM-specific instrument. Exploratory end points aim to characterize the effect of mavacamten on multiple aspects of oHCM pathophysiology. Conclusions: EXPLORER-HCM is a phase 3 trial in oHCM testing a first-in-class, targeted strategy of myosin inhibition to improve symptom burden and exercise capacity through reducing LV outflow tract obstruction. Results of this trial will provide evidence to support the first disease-specific treatment for HCM. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03470545.
The primary endpoint was developed following discussions with the US Food and Drug Administration, and was defined as either a 1·5 mL/kg per min or greater increase in peak oxygen consumption (pVO2) ...with at least one New York Heart Association (NYHA) class improvement, or a 3·0 mL/kg per min or greater increase in pVO2 with no worsening of NYHA class. Even after surgical myectomy and alcohol septal ablation, improvements in pVO2 remain uncertain to this day, despite the indisputable clinical benefits of both procedures.2 Overall, the effect of mavacamten in obstructive hypertrophic cardiomyopathy appeared considerable,1 particularly because the primary endpoint was achieved in patients who were predominantly in functional NYHA class II (72% of patients) and would not have been candidates for septal reduction therapies. ...in a broad perspective, surgical myectomy and alcohol septal ablation should not be considered a panacea for patients with hypertrophic cardiomyopathy, and ideal results are far from guaranteed outside a limited number of centres that have experienced high patient volumes.3,4 Therefore, effective medical therapies such as mavacamten might be particularly important as an alternative in many settings.
Abstract
Aims
Risk stratification algorithms for sudden cardiac death (SCD) in hypertrophic cardiomyopathy (HCM) and regional differences in clinical practice have evolved over time. We sought to ...compare primary prevention implantable cardioverter defibrillator (ICD) implantation rates and associated clinical outcomes in US vs. non-US tertiary HCM centres within the international Sarcomeric Human Cardiomyopathy Registry.
Methods and results
We included patients with HCM enrolled from eight US sites (n = 2650) and five non-US (n = 2660) sites and used multivariable Cox-proportional hazards models to compare outcomes between sites. Primary prevention ICD implantation rates in US sites were two-fold higher than non-US sites (hazard ratio (HR) 2.27 1.89–2.74), including in individuals deemed at high 5-year SCD risk (≥6%) based on the HCM risk-SCD score (HR 3.27 1.76–6.05). US ICD recipients also had fewer traditional SCD risk factors. Among ICD recipients, rates of appropriate ICD therapy were significantly lower in US vs. non-US sites (HR 0.52 0.28–0.97). No significant difference was identified in the incidence of SCD/resuscitated cardiac arrest among non-recipients of ICDs in US vs. non-US sites (HR 1.21 0.74–1.97).
Conclusion
Primary prevention ICDs are implanted more frequently in patients with HCM in US vs. non-US sites across the spectrum of SCD risk. There was a lower rate of appropriate ICD therapy in US sites, consistent with a lower-risk population, and no significant difference in SCD in US vs. non-US patients who did not receive an ICD. Further studies are needed to understand what drives malignant arrhythmias, optimize ICD allocation, and examine the impact of different ICD utilization strategies on long-term outcomes in HCM.
Graphical Abstract
Over the last 50 years, the epidemiology of hypertrophic cardiomyopathy (HCM) has changed because of increased awareness and availability of advanced diagnostic tools. We aim to describe the temporal ...trends in age, sex, and clinical characteristics at HCM diagnosis over >4 decades.
We retrospectively analyzed records from the ongoing multinational Sarcomeric Human Cardiomyopathy Registry. Overall, 7286 patients with HCM diagnosed at an age ≥18 years between 1961 and 2019 were included in the analysis and divided into 3 eras of diagnosis (<2000, 2000-2010, >2010).
Age at diagnosis increased markedly over time (40±14 versus 47±15 versus 51±16 years,
<0.001), both in US and non-US sites, with a stable male-to-female ratio of about 3:2. Frequency of familial HCM declined over time (38.8% versus 34.3% versus 32.7%,
<0.001), as well as heart failure symptoms at presentation (New York Heart Association III/IV: 18.1% versus 15.8% versus 12.6%,
<0.001). Left ventricular hypertrophy became less marked over time (maximum wall thickness: 20±6 versus 18±5 versus 17±5 mm,
<0.001), while prevalence of obstructive HCM was greater in recent cohorts (peak gradient >30 mm Hg: 31.9% versus 39.3% versus 39.0%,
=0.001). Consistent with decreasing phenotypic severity, yield of pathogenic/likely pathogenic variants at genetic testing decreased over time (57.7% versus 45.6% versus 38.4%,
<0.001).
Evolving HCM populations include progressively greater representation of older patients with sporadic disease, mild phenotypes, and genotype-negative status. Such trend suggests a prominent role of imaging over genetic testing in promoting HCM diagnoses and urges efforts to understand genotype-negative disease eluding the classic monogenic paradigm.
Myocardial fibrosis is a key pathologic feature of hypertrophic cardiomyopathy (HCM). However, the fibrotic pathways activated by HCM-causing sarcomere protein gene mutations are poorly defined. ...Because lysophosphatidic acid is a mediator of fibrosis in multiple organs and diseases, we tested the role of the lysophosphatidic acid pathway in HCM. Lysphosphatidic acid receptor 1 (LPAR1), a cell surface receptor, is required for lysophosphatidic acid mediation of fibrosis. We bred HCM mice carrying a pathogenic myosin heavy-chain variant (403
) with
-ablated mice to create mice carrying both genetic changes (403
LPAR1
) and assessed development of cardiac hypertrophy and fibrosis. Compared with 403
LPAR1
, 403
LPAR1
mice developed significantly less hypertrophy and fibrosis. Single-nucleus RNA sequencing of left ventricular tissue demonstrated that
was predominantly expressed by lymphatic endothelial cells (LECs) and cardiac fibroblasts.
ablation reduced the population of LECs, confirmed by immunofluorescence staining of the LEC markers Lyve1 and Ccl21a and, by in situ hybridization, for
and
.
ablation also altered the distribution of fibroblast cell states. FB1 and FB2 fibroblasts decreased while FB0 and FB3 fibroblasts increased. Our findings indicate that
is expressed predominantly by LECs and fibroblasts in the heart and is required for development of hypertrophy and fibrosis in an HCM mouse model. LPAR1 antagonism, including agents in clinical trials for other fibrotic diseases, may be beneficial for HCM.
Truncations of Titin Causing Dilated Cardiomyopathy Herman, Daniel S; Lam, Lien; Taylor, Matthew R.G ...
New England journal of medicine/The New England journal of medicine,
02/2012, Letnik:
366, Številka:
7
Journal Article
Recenzirano
Odprti dostop
Titin, an important protein in the sarcomere, is the largest human protein. This study identified mutations in the titin gene that result in a truncated protein as important causes of dilated ...cardiomyopathy.
Gene mutation is an important cause of cardiomyopathy. Mutations in eight sarcomere-protein genes cause hypertrophic cardiomyopathy, detected in 40 to 70% of patients.
1
,
2
Variations in more than 40 genes, most of which encode components of the sarcomere, the cytoskeleton, or the nuclear lamina, have been shown or posited to cause dilated cardiomyopathy.
3
,
4
Clinical evaluation identifies 30 to 50% of patients with dilated cardiomyopathy as having a relative who is affected or likely to be affected,
5
–
7
implicating a genetic cause. However, pathogenic mutations have been found in only 20 to 30% of patients.
8
TTN,
the gene encoding titin, . . .
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