HCMR - Novel Markers of Prognosis in Hypertrophic Cardiomyopathy
试验速览
- 阶段
- 不适用
- 状态
- 进行中（未招募）
- 入组人数
- 2,750
- 试验地点
- 44
- 主要终点
- Aborted sudden cardiac death
研究概览
简要总结
Hypertrophic cardiomyopathy (HCM) is the most common monogenic heart disease and the most frequent cause of sudden cardiac death (SCD) in the young. It is characterized by unexplained left ventricular hypertrophy (LVH), diffuse and patchy fibrosis, and myofibrillar disarray. While the majority of patients remain asymptomatic, prognosis is poor in a subset who present with SCD or progress to heart failure (HF). Current methods to predict risk of these adverse events and to target therapy are limited. Current medical therapy does not protect against SCD, nor does it prevent development of HF. Therefore, the identification of novel risk markers would help develop therapeutic targets aimed at altering the phenotypic expression to impact the natural history, especially SCD and HF. Cardiovascular magnetic resonance (CMR) is emerging as a powerful tool for diagnosis and risk stratification in HCM including assessment of LV mass and pattern of hypertrophy. Late gadolinium enhancement by CMR is a marker of focal myocardial fibrosis which is thought to underlie the arrhythmogenic substrate as well as promote development of HF. The investigators hypothesize that HCM patients with a higher primary outcome event rate can be identified by novel CMR findings. The majority of cases of HCM are autosomal dominant and about 60% are caused by mutations in genes encoding cardiac sarcomeric proteins. However, the relationship between genetic mutation, disease phenotype, and clinical outcomes remains poorly understood. The investigators hypothesize that HCM patients with sarcomeric HCM mutations will have a higher primary outcome event rate and more marked myocardial pathology on CMR than those without. Furthermore, there may be a link between sarcomeric mutations and fibrosis, as mutation carriers with overt HCM as well as those without hypertrophy have elevated markers of collagen turnover. The investigators therefore hypothesize that serum biomarkers of collagen metabolism in HCM will predict outcomes. Thus, the Specific Aim is to develop a predictive model of cardiovascular outcomes in HCM by: 1) using exploratory data mining methods to identify demographic, clinical, and novel CMR, genetic and biomarker variables associated with the outcomes and 2) develop a score from the predictive model that can be used to assess risk given a patient's combination of risk factors, thus establishing the evidence base to enable clinical trial design to reduce morbidity and mortality in HCM in a cost-effective manner.
详细描述
2.2 Rationale Presently used risk predictors in HCM for the clinical outcomes of SCD and HF are still insufficient and limit clinical trials and institution of novel therapies in this disease. This large scale, prospective clinical registry will systematically answer the important question whether, through addition of a combination of advanced CMR phenotyping, genetic and biomarker analysis, risk stratification in HCM could be substantially improved over presently used clinical risk predictors. Emerging novel blood, genetic, and CMR markers offer the paradigm-shifting promise of reliably identifying those at risk. In addition, this will be the largest genotyped population of HCM available to correlate with comprehensive CMR and biomarker evaluation. This will allow unique opportunities to evaluate genotype-phenotype correlations and compare specific genetic subsets in a manner that has not been possible in the past. This study will also establish a predictive model that can be used to assess risk given a patient's combination of risk factors. This will help to select patients for future clinical trials to prevent SCD and HF. In addition, it will identify surrogate endpoints to monitor treatment response in HCM. In this way, the evidence base will be established in HCM to enable clinical trial design to reduce morbidity and mortality in HCM in a cost-effective manner.
3 OBJECTIVES The Specific Aim of this study is to develop a predictive model of cardiovascular outcomes in hypertrophic cardiomyopathy by: 1) using exploratory data mining methods to identify demographic, clinical, and novel CMR, genetic and biomarker variables associated with the outcomes and 2) develop a score from the predictive model that can be used to assess risk given a patient's combination of risk factors, thus establishing the evidence base to enable clinical trial design to reduce morbidity and mortality in HCM in a cost-effective manner.
To understand the relationship between these novel risk markers in HCM and clinical outcome, the investigators propose a natural history study of 2750 patients with clinically diagnosed HCM studied at baseline with collection of demographic data, clinical risk factors, as well as novel markers from CMR, genotyping, and serum biomarkers of collagen turnover and myocardial injury, enrolled over a 2-year period and followed for 3-5 years (mean of 4 years). The study will be powered to identify risk markers in a Cox model (imaging, serum, and genetic beyond standard clinical risk factors) with a hazard ratio of 1.5 or greater for the primary endpoint, which will be cardiac death (including SCD and HF death), aborted SCD (appropriate discharge of an implantable cardioverter-defibrillator), and need for heart transplantation. Secondary endpoints include all-cause mortality, ventricular tachyarrhythmias, hospitalization for heart failure, atrial fibrillation, and stroke. This study will enable establishment of a predictive model that will help to identify patients at risk as well as patients for future clinical trials to prevent SCD and HF. In addition, it will identify surrogate endpoints to monitor treatment response in HCM.
4 STUDY DESIGN 4.1 Selection of the Study Population
Patient characteristics:
研究设计
- 研究类型
- Observational
- 观察模型
- Case Only
- 时间视角
- Prospective
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients aged 18-65 with an established diagnosis of HCM defined as unexplained LVH defined as any segment ≥15mm thick, without a predisposing cause.
- •Signed informed consent
排除标准
- •Prior septal myectomy or alcohol septal ablation
- •Prior myocardial infarction
- •Incessant ventricular arrhythmias
- •Inability to lie flat,
- •Contraindication to CMR including pacemakers, defibrillators, intraocular metal, certain types of intracranial aneurysm clips, severe claustrophobia,
- •Stage IV/V chronic kidney disease with glomerular filtration rate <30 ml/min,
- •Diabetes mellitus with end organ damage
- •Pregnant female
- •Inability to provide informed consent
结局指标
主要结局
Aborted sudden cardiac death
时间窗: 5 years
Includes appropriate ICD firing (sustained ventricular tachycardia, rate\>200bpm, or ventricular fibrillation)
Cardiac death
时间窗: 5 years
Sudden cardiac death and heart failure death
left ventricular assist device placement
时间窗: 5 years
Heart transplantation
时间窗: 5 years
次要结局
- All-cause mortality(5 years)
- Hospitalization for heart failure(5 years)
- Atrial fibrillation(5 years)
- Ventricular tachyarrhythmias(5 years)
- Stroke(5 years)
研究者
Christopher Kramer
Ruth C. Heede Professor of Cardiology, Professor of Radiology
University of Virginia