Novel and Emerging Therapies for Heart Failure
As heart failure develops, perturbations in energy metabolism in the heart compromise its function. One primary pathological change that occurs in the failing heart is that the ability of cardiac myocytes to derive energy from fatty acids declines. This is a significant problem because fatty acids represent the primary energy source for the healthy heart. Therefore, the decline of cardiac function in heart failure is compounded by inefficient fatty acid utilization (Ingwall 2009; Lopaschuk 2010).
A novel approach to overcoming this barrier of impaired fatty acid metabolism is use of the drug trimetazidine. Trimetazidine boots glucose utilization in the heart, thus lessening the reliance on fatty acids for energy. In a comprehensive analysis of studies including 884 subjects with chronic heart failure, use of trimetazidine was found to reduce hospitalization for cardiac causes by 57%. Moreover, trimetazidine was associated with improved left ventricular ejection fraction, exercise capacity, left ventricular end-diastolic diameter, and New York Heart Association functional classification (Zhang 2012). In another review of published studies including data on 955 heart failure patients, use of trimetazidine was associated with improved left ventricular ejection fraction, left ventricular end-systolic volume, New York Heart Association classification, and exercise capacity. Most impressively, trimetazidine use was associated with a 71% reduction in all-cause mortality and a 58% reduction in cardiovascular events (Gao 2011). The researchers went on to conclude “Trimetazidine might be an effective strategy for treating [heart failure].”
Despite over 40 years of published studies (Brodbin 1968), this little-known, potentially lifesaving heart drug languishes in regulatory limbo in the United States and has not received approval by the Food and Drug Administration (FDA). Marketed as Vastarel MR® in Europe, trimetazidine modulates mitochondrial metabolism to energize and revive compromised heart tissue. A mountain of scientific research shows it has the capability to protect vulnerable, oxygen-deprived heart muscle before a lethal cardiac event takes place. However,concerns about the lack of long-term data on hard endpoints like heart attack and cardiac mortality make the regulatory path to approval a difficult one for this novel drug.
Trimetazidine can cause side effects such as slowed or stiff movements, speech disturbances, a tremor in the hand(s), and disequilibrium, which could contribute to a fall in older populations (Masmoudi 2012; Montastruc 2006).
Vasopressin Receptor Antagonists
Vasopressin, also known as antidiuretic hormone, is produced by the pituitary gland and acts on the kidney to promote water reabsorption and the preservation of blood volume. It also acts on the blood vessels to promote vasoconstriction. Vasopressin levels are elevated in heart failure patients. Vasopressin receptor antagonists, which prevent vasopressin signaling, are a promising approach in patients with heart failure (Szabó 2009). Clinical trials that examined the vasopressin receptor agonist tolvaptan (Samsca®) have shown that it may be effective for reducing congestion (fluid retention) specifically in heart failure patients who have low blood electrolytes (Hori 2011; O'Connell 2012).
Stem Cell Therapy
The adult heart maintains at least a minimal level of cellular turnover (the production of new cardiac cells to replace old/damaged ones) throughout life. This is due to the existence of multipotent cardiac stem cells (CSCs) that reside within the adult heart. Stem cells are renewable, unspecialized precursor cells that are capable of replicating and transforming into a number of different cell types; cardiac stem cells are capable of becoming cardiomyocytes (heart muscle cells) or cells of the coronary blood vessels (Anversa 2013). The observation that stem cells are able to regenerate damaged heart tissue (such as from infarction) dates back to 2001, when this was demonstrated in a study on mice and, soon after that, in a human patient (Heusch 2011). An open-label trial using cardiac stem cells in heart failure patients (SCIPIO trial) is underway as of the time of this writing. In preliminary published data on 14 patients who received infusions of CSCs, their left ventricular ejection fraction increased at 4 months after the infusion and a further increase was noted at 12 months, with no changes seen in the control patients (Bolli 2011; Chugh 2012).
Vagus Nerve Stimulation
Each of the two vagus nerves carries signals from the brain to the heart to control the heart rate as part of the parasympathetic nervous system. In chronic heart failure, vagal activity is reduced, increasing the heart rate and correlating with increased mortality (Bibevski 2011; De Ferrari 2011; Sabbah 2011). Vagus nerve stimulation is an approved treatment for depression, epilepsy that does not respond to drug therapy, and it may also be useful in the treatment of chronic heart failure. In a multi-center open-label trial, implantation of an electro-stimulator device around the right vagus nerve and chronic nerve stimulation for 1 year significantly improved quality of life, ejection fraction, and six-minute walk test in 23 NYHA class II/III patients (De Ferrari 2011).
The kidneys have a central function in the control of blood pressure and play an important role in the development of heart failure; most heart failure patients show some form of kidney disease. The kidneys control sodium and water retention, production of the hypertensive hormone angiotensin II, and can respond to other hypertensive hormones released by the brain (vasopressin) and adrenal glands (aldosterone). The activation of the renal sympathetic nerves controls several of these functions. Renal denervation (the surgical disruption of the renal nerves) reduces many of the hypertensive activities of the kidney and has long been known to reduce blood pressure and improve survival in patients with hypertension (Sobotka 2012). A new catheter-based device has been developed (Symplicity™ denervation system) that uses low-level radio waves to denervate the renal nerves, thus alleviating the need for riskier surgical procedures. In a small pilot trial of 7 patients with chronic systolic heart failure, renal denervation caused no post-surgical complications during a 6-month follow-up period and demonstrated improvements in exercise capacity (Davies 2013). Two larger controlled prospective trials on renal denervation are underway as of the time of this writing (Sobotka 2012).
Inadequate levels of the sex hormone testosterone can contribute to cardiovascular diseases, including heart failure. However, this connection is overlooked by many mainstream physicians (Kalicinska 2013; Tirabassi 2013). Testosterone is important for the maintenance of skeletal muscles, and a decline in circulating testosterone may exacerbate the exercise intolerance and loss of muscle mass (cachexia) seen in heart failure patents (Volterrani 2012; Aukrust 2009). An estimated 25–30% of men with heart failure have evidence of testosterone deficiency (Malkin 2006; Malkin 2010). In men with NYHA Class I-IV heart failure, circulating testosterone levels have been related to exercise capacity (Jankowska 2009), and normal anabolic hormone levels (total and free testosterone, DHEA sulfate, and insulin-like growth factor) have been associated with better 3-year survival rates compared to those who have deficiencies in one, two, or three of these hormones (Jankowska 2006).
Testosterone replacement therapy (restoring physiological levels) has been demonstrated to improve exercise capacity in males with heart failure who have low circulating testosterone levels (Aaronson 2011; Stout 2012; Toma 2012) with no adverse effects noted. Some evidence suggests testosterone replacement may also benefit women with heart failure. Testosterone therapy was shown to improve exercise capacity (6-minute walk test and muscle performance) and insulin resistance in a study of 36 women with stable heart failure (Iellamo 2010).
Individuals with heart failure should consider testing their testosterone levels using an inexpensive blood test. If levels are found to be suboptimal, working with a healthcare provider to initiate testosterone replacement therapy may relieve some heart failure symptoms. More information about testosterone replacement therapy is available in the Male Hormone Restoration and Female Hormone Restoration protocols.