Novel and Emerging Therapies for Heart Failure
Stem Cell Therapy
Stem cell therapy for cardiac regeneration is an emerging and continuously evolving field. Stem cells are renewable, unspecialized precursor cells that can transform into specialized cell types.144-146 Acute myocardial infarction, chronic ischemic heart failure, cardiomyopathy, and left ventricle dysfunction are all associated with a loss of cardiomyocytes (cardiac muscle cells) that was previously considered irreversible. Adult cardiomyocytes have a limited capacity for self-repair; however, research suggests stem cells could offer a novel approach to replacing or repairing damaged cells and tissues.147,148 Multiple preclinical studies suggest stem cells may help reduce inflammatory response and cardiac fibrosis, and also help with the recovery of damaged cardiac tissue, yet much remains to be discovered and clarified.149
Several clinical studies have been conducted with stem cells as a potential treatment for heart failure and other cardiac-related conditions. Several reviews and meta-analyses indicate that stem cell treatments appear to benefit heart failure patients, with those treated experiencing lower mortality rates and fewer cardiac events.147,150,151 However, the authors of these articles recommend interpreting the results with caution, as many of the studies were of lower quality and had minimal benefits. Other clinical trials have shown no benefit from stem cell treatments.152,153
Some scientists pointed out that different methods of processing stem cells may have led to the contradictory clinical outcomes.154 The initial hype surrounding stem cell therapy also likely led to clinical testing before the science was fully appreciated and understood, leading to inconsistent results.148,155 Some studies that led to the early excitement have since been discovered to be faulty, and several were retracted.155 As such, the science behind whether stem cells may benefit heart failure patients is still not clear and will require more reproducible, well-designed studies.
The use of stem cells as a therapy for heart failure is an interesting and potentially important area; however, more high-quality studies (clinical and preclinical) are needed before its usefulness can be determined and implemented as a standard treatment.
Testosterone is a male hormone that helps regulate bone density, fat distribution, muscle strength, red blood cell production, sperm production, and sex drive. Inadequate levels of testosterone can contribute to cardiovascular diseases, including heart failure. However, this connection is overlooked by many mainstream physicians.156,157 A decline in circulating testosterone may exacerbate exercise intolerance and muscle mass loss (cachexia) seen in heart failure patients.158,159
An estimated 25% of men with heart failure have evidence of testosterone deficiency.160 A recent study involving 167 Chinese men with chronic heart failure measured their testosterone levels and followed them for at least three years. Patients in the low testosterone group had worse cardiac function and higher mortality and hospital readmission rates.161 A review of eight published studies indicated testosterone replacement therapy can enhance exercise capacity and muscle strength, but not ejection fraction, blood pressure, and other markers of cardiac health. More quality research is needed to understand the association between testosterone levels and clinical outcomes in heart failure patients.162 Another study randomized 39 men with heart failure and testosterone deficiency to an exercise training, intramuscular testosterone injection, or training and testosterone group. The combination group showed the most improved muscle nerve activity, muscle wasting, and functional capacity.163
Some evidence suggests testosterone replacement may also benefit women with heart failure. Testosterone therapy was shown to improve exercise capacity (six-minute walk test and muscle performance) and insulin resistance in a study of 36 women with stable heart failure.164 Testosterone therapy may be useful in cardiovascular events such as heart failure, angina, and ischemia.165
Individuals with heart failure should consider testing their testosterone levels using an inexpensive blood test. If levels are suboptimal, testosterone replacement therapy may relieve some heart failure symptoms. More randomized, controlled clinical trials are required to clarify testosterone’s role in cardiac health. More information about testosterone replacement therapy is available in the Male Hormone Restoration and Female Hormone Restoration protocols.
Vagus Nerve Stimulation
Each of two vagus nerves carries signals from the brain to the heart to control heart rate as part of the parasympathetic nervous system. In chronic heart failure, vagal activity is reduced, increasing heart rate and mortality.166-168 Vagus nerve stimulation is an approved treatment for depression and epilepsy that does not respond to drug therapy, and 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 one year significantly improved quality of life, ejection fraction, and a six-minute walk test in 23 NYHA class II/III patients.167
The INOVATE-HF (Increase of Vagal Tone in Heart Failure) trial was a multinational, randomized, controlled trial that examined 707 people with heart failure and reduced ejection fraction. The study found that vagus nerve stimulation improved 6-minute walk distance, NYHA functional classification, and quality of life scores, but did not improve risk of death or a cardiac event.169 Further research is warranted to better understand optimal delivery of this therapy, and if specific patient subgroups are more likely to benefit from this therapy.
As heart failure develops, perturbations in energy metabolism in the heart compromise its function. The failing heart muscle cells are unable to derive energy from fatty acids, the primary energy source for the healthy heart. Therefore, declining cardiac function in heart failure is compounded by inefficient fatty acid utilization.170,171
The drug trimetazidine (TMZ) has garnered interest because it has been shown to help overcome impaired cardiac fatty acid metabolism. TMZ boosts glucose utilization in the heart, lessening the reliance on fatty acids for energy.309,310 Animal research suggests TMZ may also help mitigate cardiac fibrosis, which contributes to heart failure progression.311 Some clinical evidence suggests TMZ, along with conventional therapies, improves symptoms, cardiac function, and prognosis in some patients with heart failure.172,312 However, much of this evidence comes from small studies that lack rigorous design and execution, so should be viewed as preliminary until larger, well-designed trials evaluate the effects of TMZ in people with heart failure.
A meta-analysis of three randomized clinical trials involving 326 heart failure patients found that TMZ, when provided as an add-on therapy, offered a protective effect, reduced all-cause mortality, and increased survival rates.173 Another meta-analysis of 19 randomized controlled trials involving nearly 1,000 chronic heart failure patients found TMZ treatment improved clinical symptoms and cardiac function and reduced cardiac hospitalizations and serum levels of BNP and C-reactive protein.174
In a comprehensive analysis of studies including 884 subjects with chronic heart failure, TMZ reduced hospitalization for cardiac causes by 57%. Moreover, TMZ was associated with improved left ventricular ejection fraction, exercise capacity, left ventricular end-diastolic diameter, and NYHA functional classification.175
In another review of published studies including data on 955 heart failure patients, TMZ was associated with improved left ventricular ejection fraction, left ventricular end-systolic volume, NYHA classification, and exercise capacity. Most impressively, TMZ use was associated with a 71% reduction in all-cause mortality and 58% reduction in cardiovascular events.176
However, a randomized double-blind study in 60 patients with stable, nonischemic heart failure found 35 mg of TMZ twice daily did not result in significant changes to left ventricular ejection fraction, exercise capacity, oxygen uptake, or quality of life.177 Another randomized controlled trial published in February 2019 found TMZ failed to improve exercise capacity among patients with hypertrophic cardiomyopathy whose mean age was 50 years.313 A randomized trial conducted in Bangladesh during 2015–2016 found that glyceryl trinitrate outperformed TMZ in improving NYHA classification at six and 12 weeks in patients with ischemic cardiomyopathy.314 Some evidence suggests diabetics with heart failure may benefit from TMZ, but not all studies have confirmed the benefits for this group.315
Despite over 40 years of published studies,178 TMZ has not received FDA approval. Marketed as Vastarel MR in Europe, scientific research shows TMZ has the capability to protect vulnerable, oxygen-deprived heart muscle. However, concerns about lack of long-term data on heart attack and cardiac mortality make regulatory approval difficult.
The authors of a literature review of TMZ and heart failure concluded the following315:
“… we cannot recommend using trimetazidine in [CHF patients] as a result of the significant limitations connected with these studies—meta-analyses based on unpowered studies and the retrospective character of [a key study]. A well designed, randomized clinical study, placebo-controlled, with well selected endpoints, appropriate patient group, and follow-up duration is still needed to possibly recommend the use of trimetazidine in HF patients… There are still no answers to key questions as to the role of this drug in selected cardiovascular conditions as well as whether this drug can reduce mortality in any group of patients with cardiovascular disease.”
TMZ can cause side effects such as Parkinsonism (ie, slowed or stiff movements, speech disturbances, hand tremors, and disequilibrium), which could contribute to a fall in older populations.179,180 A 2019 population-based study found TMZ use was a significant predictor of new-onset Parkinsonism symptoms. The researchers called for close monitoring of patients prescribed TMZ for emergence of Parkinsonism symptoms.316 Another study found that while TMZ often produces Parkinsonism, drug withdrawal generally results in resolution of symptoms in patients with mild, symmetrical Parkinsonism.317
Some trials are underway,318 and recent review articles319,320 suggest there is interest in continuing to explore the potential benefits of TMZ. Future trials will help clarify what role TMZ has to play in the management of heart failure and related conditions.
Other Potential Therapies
Gene therapy holds some promise for treating heart failure. Efforts are underway to enhance heart muscle sensitivity to calcium via the SERCA2a gene, a protein that pumps calcium into cardiac muscle cells. Other calcium-handling proteins may be candidates for future gene therapy work. Antagomirs are a class of drug that block microRNA, which play a role in gene expression and protein synthesis. Preliminary research suggests antagomirs improve cardiac function.10
Another potential therapy involves CD31 agonist peptides. CD31, a transmembrane glycoprotein present on endothelial cells and white blood cells, may play a protective role in heart failure. In a recent randomized study, mice with both preserved and reduced ejection fractions received either 2.5 mg/kg of CD31 or placebo by subcutaneous infusion. Daily treatment with CD31 improved ejection fraction and left ventricle filling pressure. In mice with a preserved ejection fraction, it prevented diastolic left ventricle dysfunction. Researchers concluded CD31 improved heart function and may be useful in treating heart failure.181 Ultrafiltration therapy can be used for fluid reduction in patients with refractory heart failure (ie, those with advanced heart failure who experience symptoms while at rest) that are not responsive to other medical therapies, such as diuretics. Ultrafiltration removes sodium and water from the blood across a semipermeable membrane and a pressure gradient to make plasma water. It improves congestion, cardiac output, and lowers right atrial and pulmonary pressures.182
In early 2019 the FDA approved a device to treat patients with chronic, moderate-to-severe heart failure who remain symptomatic despite receiving optimal medical therapy, and who lack other treatment options.303 The Optimizer Smart System has been shown in clinical trials to improve walking distance, decrease symptoms, improve quality of life, and improve cardiovascular outcomes.304-306 This device may also decrease mortality in these patients.304,307
The Optimizer device is implanted in a minimally-invasive procedure under local anaesthesia,308 and has been associated with a low rate of complications.304 A trial published in 2019 found that, in patients with left ventricular ejection fraction between 25% and 45%, hospitalizations decreased by 75% compared to before implantation of the device. In this group of patients, three-year survival did not differ from that predicted by an established model; however, among those with a left ventricular ejection fraction of 35‒45%, three-year survival was significantly better than that predicted by the same model.305