To Supplement or Not: A Role for Antioxidant Vitamins in the Management of Heart Failure?
There is an epidemic of heart failure occurring in advanced industrial nations. The number one diagnosis for payment by Medicare in the US is heart failure. Because heart failure is increasingly prevalent among the elderly, and because the population of individuals older than age 65 years is increasing rapidly in the US, patients with heart failure will become ever more common in the US in the near future. Although etiology or symptoms may vary among individuals, the most common clinical presentation for heart failure involves reduced exercise tolerance, elevated blood levels of B-type natriuretic peptide, and reduced cardiac output. Entities leading to heart failure include unmanaged hypertension, ischemia, valvular disease, myocarditis, and chemotherapy-induced cardiomyopathy. Under the microscope, failing hearts often show a small fraction of apoptosis (suicide) of cardiomyocytes (cardiac muscle cells), and many cardiomyocytes become enlarged. In parallel with these changes in cardiomyocytes, fibrosis (scarring) is evident in the myocardium, with proliferation of fibroblasts and altered production of extracellular matrix protein. This process leads to stiffness of the cardiac muscle and reduced myocardial systolic and diastolic function.
Progression of heart failure involves activation of the neurohormonal and renin-angiotensin-aldosterone systems, resulting in increased catecholamine and angiotensin II levels in the circulation. Catecholamines, including epinephrine and norepinephrine, bind to β-adrenergic receptors, whereas angiotensin II binds to angiotensin receptors AT1 or AT2. These receptors are located across the plasma membrane of cardiomyocytes, and their activation initiates a cascade of signaling events inside the cells. Normally, these signaling events regulate cardiac muscle contraction and relaxation. Prolonged and intense activation of β-adrenergic or angiotensin II signaling contributes to remodeling of the atria and the ventricles, shown under the microscope as enlargement of cardiomyocytes, all of which precede the clinical onset of symptoms of heart failure.
Oxidative stress has been associated with the development and progression of heart failure. Catecholamines can undergo auto-oxidation, thereby generating oxygen free radicals, also known as reactive oxygen species (ROS). ROS can attack important molecules inside cardiomyocytes, thereby impairing the biochemical function of these molecules, for example, DNA, RNA, and proteins. There is a plasma membrane-associated oxidase, nicotinamide adenine dinucleotide phosphate oxidase or NAD(P)H oxidase, which can be activated by angiotensin II in cardiomyocytes. In neutrophils, NAD(P)H oxidase activation is important for generation of ROS needed to destroy invading microorganisms. In cardiomyocytes, activation of this oxidase results in excessive ROS levels. Additional sources of oxidants include ischemia or ischemic reperfusion injury. Whereas ischemia can inhibit the production of cellular antioxidant enzymes and impair mitochondrial respiration, resulting in an increased production of oxidants, reperfusion activates xanthine oxidase, which produces additional quantities of oxidants. Some chemotherapeutic drugs, for example, doxorubicin, undergo redox cycling when entering into cells, thereby producing oxidants. Moreover, inflammatory responses also result in ROS generation. At the cellular level, ROS can create enough damage to induce cell death, or initiate signaling events leading to fibrosis or hypertrophy of cardiomyocytes.
Patients diagnosed with systolic or diastolic heart failure show elevated biomarkers of oxidative stress. Congestive heart failure patients show elevated production of prostaglandins, increased blood levels of lipid oxidation products, and a reduced reservoir of antioxidants. Ventricular dilation in ischemic and valvular heart disease patients correlates with the level of the oxidative stress measured with the biomarker of oxidant stress, 8-iso-prostagladin F2 alpha. The degree of biomarker oxidative stress or loss of antioxidant reservoir corresponds to the severity of heart failure as well as to the degree of increased morbidity or mortality. Interestingly, human hearts can respond to oxidative stress by elevating the activity of antioxidant enzymes. Numerous animal models have been developed showing increased oxidative stress with heart failure. Animals supplemented with or engineered to overexpress antioxidant enzymes actually demonstrate protection of the heart in various types of heart failure. These results led to the speculation that antioxidant supplements might be beneficial for heart failure patients.
Unfortunately, clinical trials of antioxidant vitamins in patients at risk for heart failure or with clinical heart failure have failed to show clear prevention of heart failure or reduction of the mortality rate associated with heart failure. Although diets rich in antioxidant vitamins reduce the risk of coronary heart disease and eventual heart failure, administering vitamin E or vitamin C to high-risk coronary disease or congestive heart failure patients has not produced positive outcomes. However, several pharmacological agents currently used for the treatment of heart failure, such as the angiotensin-converting enzyme inhibitors captopril and ramipril, the angiotensin receptor blocker telmisartan, the aldosterone receptor antagonist eplerenone, and the β-blockers nebivolol, carvedilol, and metoprolol all exhibit antioxidant activity. To what degree the antioxidant properties of these agents play a beneficial role in their pharmacological use is unknown at this time. It is unclear why antioxidant vitamins that are effective in animal models of heart failure fail to provide benefit in patients with heart failure. Perhaps the dosage or the timing of administration of these agents in humans is inappropriate. Consequently, the ultimate role of ROS suppression in heart failure patients requires considerable further investigation.
The take-home message for the clinician is that antioxidant vitamins have not as yet been shown to be of benefit in the management of heart failure, despite clinical investigation and widespread use of these compounds sold over the counter or through the Internet. Our message to heart failure patients with respect to these agents is: Caveat emptor—Let the buyer beware!! These agents have not yet been proven to be beneficial and are not ready for “prime time” utilization.
As always, we are happy to respond to any questions or comments on the blog at amjmed.org.
To read this article in its entirety please visit our website.
-Qin M. Chen, PhD, Joseph S. Alpert, MD (Editor in Chief, The American Journal of Medicine)
This article originally appeared in the August 2016 issue of The American Journal of Medicine.