Robert Willix

Is vitamin D deficiency associated with heart failure? A review of current evidence.

An estimated 1 billion people worldwide have deficient or insufficient levels of vitamin D. Even more alarming is the association of vitamin D deficiency with many types of diseases, particularly heart failure (HF). Hypovitaminosis D has been observed to be highly prevalent in the HF community with rates varying from approximately 80% to 95%. Higher rates of deficiency have been linked to winter months, in patients with protracted decompensated HF, darker skin pigmentation, and higher New York Heart Association (NYHA) classes. In fact, some data suggest vitamin D deficiency may even be an independent predictor of mortality in patients with HF. Traditionally obtained through UV exposure and activated in the liver and then the kidneys, vitamin D is classified as a vitamin but functions as a steroid hormone. The hormone acts through the vitamin D receptor (VDR), which is expressed in vascular smooth muscle cells, renal juxtaglomerular cells, and most interestingly, cardiac myocytes. Studies have shown that the association between vitamin D deficiency and HF often manifests in the structural components of cardiac myocytes and/or through alterations of the neurohormonal cascade. In addition, vitamin D may also act rapidly through intracellular nongenomic receptors that alter cardiac contractility. Unfortunately, prospective vitamin D supplementation trials show mixed results. In rat models, successful correction of deficiency was associated with reductions in ventricular hypertrophy. In humans, however, echocardiographic dimensions did not change significantly. These results bring into questions whether vitamin D is a risk factor for HF, a marker of HF disease severity, or has a true pathologic role. This article provides a thorough review of vitamin D deficiency etiology, prevalence, and possible pathophysiologic role in HF. Furthermore, we carefully review prospective trials on vitamin D therapy in HF. We believe more trials on vitamin D therapy in HF need to be conducted before any conclusions can be drawn.

Review: Testosterone Therapy: Treatment of Metabolic Disturbances in Heart Failure

Heart failure (HF) is a complex progressive multisystem disease state with significant morbidity and mortality, which is not solely defined by pathology of the cardiovascular system but also is influenced by neurohormonal regulatory adjustments, peripheral cytokines, as well as hormonal and musculoskeletal dysfunction. Recent attention to the catabolic state found in patients with chronic heart failure has sparked interest in new potential targets for medical therapy. In particular, as many as 26% to 37% of men affected with HF have been found to be testosterone deficient. The severity of androgen deficiency has been shown to correlate with symptoms, functional class, and prognosis in patients with heart failure. Testosterone supplementation has been an accepted therapy in hypogonadal men with fatigue, muscle wasting, and sexual dysfunction for some time. Patients with severe HF show a similar constellation of symptoms and hypothetically would benefit from androgen replacement. Recent clinical studies have confirmed that functional, biochemical, and cardiopulmonary status in patients with HF have significant improvements when treated with testosterone supplementation. Symptomatic improvements may be obtainable in hypogonadal patients with HF who receive supplemental testosterone. This review seeks to outline the cardiovascular and peripheral effects of testosterone supplementation in patients with chronic HF.

The Potential Effects of IGF-1 and GH on Patients With Chronic Heart Failure:

Heart failure (HF) is an important health concern with almost a quarter million deaths each year despite advances in medical therapy. Improvement of cardiac function has been shown to reduce morbidity and mortality in patients with HF. There has been recent interest in the growth hormone (GH) / insulin-like growth factor (IGF) pathway as a potential therapeutic target for patients with HF. Insulin-like growth factor 1 has been shown to augment cardiac function ex vivo and in animals. It was hypothesized that IGF-1/IGF-binding protein 3 levels might be able to provide prognostic benefits in patients with heart disease. Initial observational studies have shown significant benefits from GH supplementation including improved ejection fraction, increased exercise tolerance, and decreased New York Heart Association functional class. These results, however, were not replicated in randomized, controlled trials. Patients with advanced stages of HF might develop cachexia associated with a state of significant GH resistance. The lack of response to GH supplementation may be secondary to a deficiency in IGF-1, the effector hormone. Hypothetically, this group of patients could benefit from direct IGF-1 supplementation. Combined therapy with GH and IGF-1 is appealing; however, future trials in patients with advanced HF are warranted to prove this concept.

Erectile dysfunction as a complication of heart failure.

Erectile dysfunction (ED) is an increasingly common problem in the aging population and has been associated with chronic heart failure (HF), either as an epiphenomenon or even as an early marker for underlying cardiovascular disease. ED has a significant effect on patients’ quality of life. This chapter reviews ED in patients with HF and prevention and treatment based on current data from the literature. Causes include physiologic changes resulting in decreased cardiac function and exercise capacity, intrinsic vascular and neurohormonal abnormalities, and extrinsic factors such as medication side effects and psychological issues. Physicians should address these issues with patients and begin treatment by optimizing HF management and minimizing medications with ED side effects. Use of phosphodiesterase-5 inhibitors provides significant improvement of ED and quality of life. Further research still is needed regarding long-term effects of ED treatment, investigation of newer medications, and preventive measures in this patient population.

Andropause and the development of cardiovascular disease presentation—more than an epi-phenomenon

Andropause refers to a generalized decline of male hormones, including testosterone and dehydroepiandrosterone in middle-aged and aging men. This decline in hormones has been associated with changes such as depression, loss of libido, sexual dysfunction, and changes in body composition. Aging has been associated with an abundance of concomitant diseases, in particular cardiovascular diseases, and although andropause is correlated to aging, a causal relationship between reduction of androgens and the development of chronic diseases such as atherosclerosis and heart failure has not been convincingly established yet. On the other hand, increasing data has emerged that revealed the effects of low levels of androgens on cardiovascular disease progression. As an example, low levels of testosterone have been linked to a higher incidence of coronary artery disease. Whether hormone replacement therapy that is used for andropausal men to alleviate symptoms of “male menopause” can halt progression of cardiovascular disease, remains controversially discussed, primarily due to the lack of well-designed, randomized controlled trials. At least for symptom improvement, the use of androgen replacement therapy in andropausal men may be clinically indicated, and with the appropriate supervision and follow up may prove to be beneficial with regard to preservation of the integrity of cardiovascular health at higher ages.

Myths and truths of growth hormone and testosterone therapy in heart failure

Heart failure is a chronic clinical syndrome with very poor prognosis. Despite being on optimal medical therapy, many patients still experience debilitating symptoms and poor quality of life. In recent years, there has been a great interest in anabolic hormone replacement therapy – namely, growth hormone and testosterone – as an adjunctive therapy in patients with advanced heart failure. It has been observed that low levels of growth hormone and testosterone have been associated with increased mortality and morbidity in patients with heart failure. Animal studies and clinical trials have shown promising clinical improvement with hormonal supplementation. Growth hormone has been shown to increase ventricular wall mass, decrease wall stress, increase cardiac contractility, and reduce peripheral vascular resistance, all of which might help to enhance cardiac function, resulting in improvement in clinical symptoms. Likewise, testosterone has been shown to improve hemodynamic parameters via reduction in peripheral vascular resistance and increased coronary blood flow through vasodilation, thereby improving functional and symptomatic status. To date, growth hormone and testosterone therapy have shown some positive benefits, albeit with some concerns over adverse effects. However, large randomized controlled trials are still needed to assess the long-term safety and efficacy.

Impact of a physician-supervised exercise-nutrition program with testosterone substitution in partial androgen-deficient middle-aged obese men.

Background Partial androgen deficiency syndrome in the aging male is associated with signs of aging such as a development of abdominal obesity, sexual dysfunction, increase body fat, weight gain and the development of cardiac disease. Objective We assessed the outcome of a commercially available physician supervised nutrition and exercise program with concomitant testosterone replacement therapy in middle age obese men with partial androgen deficiency in order to reduce cardiac risks factors. Methods Fifty-six self referred men without diabetes mellitus, hypertension, or cardiovascular disease (ages 52.3 ± 7.8 years) were randomly selected from a large cohort. Baseline weight, body fat composition, fasting glucose, hemoglobin A1c and fasting lipid levels, as well as free and total testosterone levels were assessed. All patients were assessed and followed 6–18 months after initiation of the program. The program consisted of a low glycemic load balanced nutrition diet, a recommended structured daily exercise program of 30–60 minutes, as well as once to twice weekly intramuscular testosterone injections (113.0 ± 27.8 mg). Results At follow up, weight was reduced from 233.9 ± 30.0 pounds (lbs) to 221.3 ± 25.1 lbs (P < 0.001), BMI was reduced from 33.2 ± 3.3 kg/m2 to 31.3 ± 2.8 kg/m2 (P < 0.0001). Total body fat was 27.1% ± 5.2% vs. 34.3% ± 5.7% at baseline (P < 0.0001). Fasting glucose was reduced from 95.3 ± 14.4 mg/dL to 87.5 ± 12.6 mg/dL (P < 0.0001). Total cholesterol was reduced from 195.4 ± 33.0 mg/dL to 172.7 ± 35.0 mg/dL (P < 0.005). No clinically significant adverse events were recorded. Conclusions Testosterone replacement therapy in middle aged obese men with partial androgen deficiency appeared safe and might have promoted the effects of a weight reduction diet and daily exercise program as long as an adequate physician supervision and follow up was granted. The combination therapy significantly reduced coronary risk factors such as glucose intolerance and hyperlipidemia.

Growth hormone and testosterone in heart failure therapy

Importance of the field: Heart failure is a progressive disease affecting millions of people worldwide. The disease carries a significantly high morbidity and mortality risk. There are multiple pharmaceutical options to decrease this risk and prolong survival; however, despite optimization of medical management, several patients still await heart transplant, the only definitive cure for heart failure. To slow the progression of disease preventing need for transplantation, improve clinical symptoms, and improve heart failure outcomes, there is a persistent need to discover new therapeutic strategies. Of interest, low growth hormone and testosterone levels have been associated with a worsening degree of heart failure. Many studies have begun to show a clinical improvement in heart failure symptoms when these levels are corrected with hormonal therapy. These findings, although mixed, are promising and indicate that both testosterone and growth hormone therapy should be considered as adjunctive therapy in advanced heart failure patients. Areas covered in this review: This review discusses the physiology of both of these natural hormones, their therapeutic effects in heart failure and data from the published literature on studies using growth hormone or testosterone in patients with chronic heart failure. An extensive search of PubMed was conducted for topics on heart failure, growth hormone, insulin-like growth factor, testosterone, their physiology and pathophysiology, and trials in which they have been used as therapeutic interventions between 1989 and 2009. What the reader will gain: The reader will gain an understanding of the intricate balance of both of these hormones in the disease state of heart failure. In addition, the trials conducted using these hormones in pharmacotherapy for heart failure are discussed along with proposed theories for interstudy variability. Take home message: Testosterone deficiency and growth hormone resistance are positively associated with a poor state of heart failure. Treatment of deficiency improves outcomes in heart failure; however, there is a significant paucity of data with regard to testosterone and heart failure as well as a significant amount of study variability with growth hormone and heart failure.

Update on the safety of testosterone therapy in cardiac disease

Introduction: Testosterone has been used for decades in the treatment of men with hypogonadism and women with low libido. More recently, it has been used in patient populations with cardiac disease and, in particular, in those patients with heart failure. The benefits of testosterone supplementation have been demonstrated in the literature, but there is also concern that testosterone supplementation may not be benign, especially when administered to achieve supraphysiological levels, e.g., to improve athletic performance. Areas covered: This review seeks to address the link between testosterone levels and cardiac disease while discussing the safety concerns of testosterone supplementation in clinical practice. Randomized controlled trials, systematic reviews and meta-analyses that were obtained through a literature search of the Medline database are discussed in this paper. Expert opinion: Ultimately, the definitive role of testosterone in cardiovascular disease remains contentious, but testosterone may have niche roles in certain conditions, such as advanced heart failure and cardiac cachexia. Testosterone has been used safely, and we believe may continue to be used safely, in men with cardiac disease when achieving physiological levels, with adequate monitoring of prostate specific antigen and hematocrit levels during the course of treatment per established clinical guidelines. Testosterone might exert beneficial effects on physical capacity and functioning as well as overall outcomes in patients with chronic heart failure.