The onset of clinical heart failure (HF) is associated with poor prognosis even today, and unfortunately the incidence of HF is projected to continue to increase in the coming decades. Therefore, organizations such as the American College of Cardiology (ACC) and American Heart Association (AHA) have identified the prevention of HF as a major need and therefore have commenced efforts aimed at preventing HF. Early initiatives included a new system of HF classification which identified at risk individuals as Stage A (those with risk factors such as hypertension and diabetes) or Stage B (those with some structural myocardial changes [for example, left ventricular hypertrophy] but without manifest HF). However, such systems of classification identified the majority (~65-75%) of a middle-aged population as Stage A or B. Recently we have shown that HF risk prediction can be improved using cardiac troponin T measured with a novel high-sensitivity assay (hs-cTnT) and N-terminal pro-B-type natriuretic peptide (NT-proBNP). Furthermore, hs-cTnT seems to identify individuals at higher risk among those with established risk factors (such as hypertension) for HF. In preliminary results, we have shown that individuals with systolic blood pressure of 120- 129 mm Hg and elevated hs-cTnT have a higher rate of incident HF than those with systolic blood pressure of 150-159 mm Hg and undetectable hs-cTnT. Therefore, we believe that by using hs-cTnT to estimate HF risk we can identify individuals in whom aggressive modification of risk factors such as high blood pressure will be associated with a favorable risk-benefit ratio. Our objective/specific aim therefore is to evaluate if treatment of selected subjects with Stage A or B HF (i.e., those with hs-cTnT >5 ng/L and an estimated 10-year HF hospitalization risk of >5%) who have reasonably well- controlled blood pressure with antihypertensive agents (carvedilol or spironolactone) will be associated with improvement of surrogate markers associated with incident HF (i.e., speckle-tracked cardiac and vascular strain). Carvedilol and spironolactone were chosen for the following reasons: a) they are not routinely used as first-line antihypertensive agents; b) beta-blockade was associated with decreases in hs-cTnT in our preliminary analysis of subjects with established HF; and c) the mechanism of actions of carvedilol and spironolactone provide a sound scientific rationale for use in prevention of HF. Using a prospective open-label blinded end point (PROBE) design, we propose to randomize 210 subjects aged >40 years with systolic blood pressure between 125-150 mm Hg, cardiac troponin T (measured with a novel high- sensitivity assay) level >5 ng/L, and 10-year HF risk >5% (estimated using a validated laboratory model including demographic factors, NT-proBNP, and hs-cTnT) to receive carvedilol (nonselective beta-blocker), spironolactone (aldosterone antagonist), or usual care for 18 months. The primary end point will be change in global longitudinal systolic myocardial strain estimated using 2D speckle tracking. Additionally, changes in vascular strain and biomarkers will be evaluated. This study will help us identify whether both or either of the medications can be further tested in large randomized clinical trials to prevent the incidence of HF.

Public Health Relevance

Despite advances in cardiovascular care, prevalence of heart failure (HF) is steadily increasing. The increase in HF rates poses enormous challenges, as once an individual becomes symptomatic or requires hospitalization with HF, the prognosis remains poor. Therefore, prevention of HF is essential. HF prevention is a critical issue for the veteran population, in whom HF risk factors that include common medical conditions such as hypertension and diabetes are highly prevalent. However, not everyone with these risk factors develops HF. Using novel blood tests, we propose to identify and treat veterans at higher HF risk to see if we can stabilize or improve ultrasound measures known to be associated with HF risk. If successful, this will be of significant benefit to the veterans in whom HF risk in the comng decades is very high.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
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Clinical Trials - B (CLNB)
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Michael E Debakey VA Medical Center
United States
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Nambi, Vijay; Deswal, Anita; Ballantyne, Christie M (2018) Prevention of ""Failure"": Is It a Failure of Prevention? Circulation 137:106-108