Neuregulin-1 (NRG-1) is a paracrine factor released by microvascular endothelial cells that has cardioprotective effects in animal models of heart failure. However, circulating NRG-1 has not been studied in human heart disease. We used a novel immunoassay to test whether circulating NRG-1beta is associated with disease severity and clinical outcomes in chronic heart failure.
Methods and Results
Serum NRG-1beta was quantified in 899 outpatients in the Penn Heart Failure Study, a referral cohort representing a broad spectrum of systolic heart failure. Circulating NRG-1beta was significantly elevated in patients with worse disease severity (median, 6.2 ng/mL for New York Heart Association class IV versus 4.4 ng/mL for class I; P=0.002).
In adjusted models, NRG-1beta was independently associated with an increased risk of death or cardiac transplantation over a median follow-up of 2.4 years (adjusted hazard ratio, 1.58; 95% confidence interval, 1.04 to 2.39; P=0.03 comparing fourth versus first NRG-1beta quartile). Associations with outcome differed by heart failure cause and symptom severity, with the strongest associations observed in patients with ischemic cardiomyopathy (interaction P=0.008) and New York Heart Association class III/IV symptoms (interaction P=0.01).
These findings were all independent of brain natriuretic peptide, and assessment of NRG-1beta and brain natriuretic peptide jointly provided better risk stratification than each biomarker individually in patients with ischemic or New York Heart Association class III/IV heart failure. Conclusions-Circulating NRG-1beta is independently associated with heart failure severity and risk of death or cardiac transplantation.
These findings support a role for NRG-1/ErbB signaling in human heart failure and identify serum NRG-1beta as a novel biomarker that may have clinical applications.
"Neuregulin-1{beta} Is Associated With Disease Severity and Adverse Outcomes in Chronic Heart Failure"
Circulation. 2009 Jul 13; Ky B, Kimmel SE, Safa RN, Putt ME, Sweitzer NK, Fang JC, Sawyer DB, Cappola TP
Hypertension (HTN) is a risk factor for dementia, and animal studies suggest that centrally active angiotensin-converting enzyme (ACE) inhibitors (those that cross the blood-brain barrier) may protect against dementia beyond HTN control.
METHODS:
Participants in the Cardiovascular Health Study Cognition Substudy with treated HTN and no diagnosis of congestive heart failure (n = 1054; mean age, 75 years) were followed up for a median of 6 years to determine whether cumulative exposure to ACE inhibitors (as a class and by central activity), compared with other anti-HTN agents, was associated with a lower risk of incident dementia, cognitive decline (by Modified Mini-Mental State Examination [3MSE]), or incident disability in instrumental activities of daily living (IADLs).
RESULTS:
Among 414 participants who were exposed to ACE inhibitors and 640 who were not, there were 158 cases of incident dementia. Compared with other anti-HTN drugs, there was no association between exposure to all ACE inhibitors and risk of dementia (hazard ratio [HR], 1.01; 95% confidence interval [CI], 0.88-1.15), difference in 3MSE scores (-0.32 points per year; P = .15), or odds of disability in IADLs (odds ratio [OR], 1.06; 95% CI, 0.99-1.14).
Adjusted results were similar. However, centrally active ACE inhibitors were associated with 65% less decline in 3MSE scores per year of exposure (P = .01), and noncentrally active ACE inhibitors were associated with a greater risk of incident dementia (adjusted HR, 1.20; 95% CI, 1.00-1.43 per year of exposure) and greater odds of disability in IADLs (adjusted OR, 1.16; 95% CI, 1.03-1.30 per year of exposure) compared with other anti-HTN drugs.
CONCLUSIONS:
While ACE inhibitors as a class do not appear to be independently associated with dementia risk or cognitive decline in older hypertensive adults, there may be within-class differences in regard to these outcomes. These results should be confirmed with a randomized clinical trial of a centrally active ACE inhibitor in the prevention of cognitive decline and dementia.
"Angiotensin-converting enzyme inhibitors and cognitive decline in older adults with hypertension: results from the cardiovascular health study"
Arch Intern Med. 2009 Jul 13; 169(13): 1195-202Sink KM, Leng X, Williamson J, Kritchevsky SB, Yaffe K, Kuller L, Yasar S, Atkinson H, Robbins M, Psaty B, Goff DC
Endothelin-1 (ET-1) has been implicated in many cardiovascular diseases, including acute heart failure (AHF) due to myocardial ischemia. Previously we described the oral endothelin-converting enzyme (ECE) inhibitor, PP36, and in this study, we investigated its cardioprotective effect in more detail, and examined the role of PP36 in the neurohormonal activation in rats that had been subjected to acute myocardial ischemia due to the microsphere embolization of coronary microcirculation.
PP36 treatment (3.5x10-5 M/kg/day) led to a significant four-fold decrease in hypertensive response when big-ET-1 was administered to healthy, conscious rats. ECE inhibition did not affect mortality during the first 48 hours after ischemia initiation.
Systemic hemodynamic, heart function, and neurohormonal activation were analyzed in the healthy control group, the acute heart failure group, and the AHF+PP36 group two days after acute heart failure induction. In conscious rats in the AHF+PP36 group, mean arterial pressure (MAP) was restored and became similar to that of the MAP of the control group.
In anesthetized rats, in the AHF+PP36 group, MAP was not restored and was 22% lower than the MAP of the control group. Myocardial contractility was partially restored and cardiac relaxation significantly improved after PP36 application. Further analysis of cardiac output and peripheral resistance in anesthetized rats revealed no differences between the acute heart failure group and the AHF+PP36 group.
There were no differences in plasma ET-1 concentration, serum angiotensin converting enzyme activity, and in the adrenal glands' catecholamine content between the acute heart failure group and the AHF+PP36 group. However, rats in the AHF+PP36 group demonstrated a 60% decrease in cardiac endothelial nitric oxide synthase (eNOS) protein expression, and a 56% reduction of myocardial norepinephrine release, when compared with the acute heart failure group's animals.
These results suggest that PP36 can preserve heart function during the recovery from acute ischemic injury, and may modulate the cardiac norepinephrine release and eNOS protein level.
"Endothelin-converting enzyme inhibition in the rat model of acute heart failure: heart function and neurohormonal activation"
Exp Biol Med (Maywood). 2009 Jul 13; Rufanova VA, Pozdnev VF, Kalenikova EI, Postnikov AB, Storozhilova AN, Masenko VP, Gomazkov OA, Medvedev OS, Medvedeva NA
