Endocrine, Metabolic & Immune Disorders-Drug Targets (Formerly Current Drug Targets - Immune, Endocrine & Metabolic Disorders) - Volume 13, Issue 1, 2013

The association between subclinical thyroid dysfunction and cardiovascular outcomes has been recently clarified with the publication of three individual participant data (IPD) analyses from the Thyroid Studies Collaboration. We identified original cohort studies with a systematic review and pooled individual data from over 70'000 participants to obtain a more precise estimate of the risks of cardiovascular outcomes associated with subclinical thyroid dysfunction. Subclinical hypothyroidism and subclinical hyperthyroidism, defined as normal thyroxine (FT4) levels with increased or decreased Thyroid-Stimulating Hormones (TSH or thyrotropin) respectively, are associated with increased risk of cardiovascular outcomes compared to euthyroid state, particularly in those with a more pronounced thyroid dysfunction. Specifically, subclinical hypothyroidism is associated with an increased risk of coronary heart disease (CHD) events, CHD mortality and heart failure (HF) events in individuals with higher TSH levels, particularly in those with TSH levels ≥10.0 mIU/L. Conversely, subclinical hyperthyroidism is associated with an increased risk of total mortality, CHD mortality, HF and atrial fibrillation, particularly in those with suppressed TSH levels <0.10 mIU/L. Pending ongoing randomized controlled trials, these observational findings allow identifying potential TSH thresholds for thyroid medication initiation based on risk of clinical outcomes, although clinical decision based solely on observational data need caution. The impact of thyroid replacement among the elderly with subclinical hypothyroidism is currently studied in a multicenter international randomized controlled trial (Thyroid Hormone Replacement for Subclinical Hypothyroidism Trial, TRUST trial).

Context: Although the negative impact of subclinical hypothyroidism (sHT) in terms of cardiovascular risk in young adults is mostly acknowledged it remains to be established in the elderly, especially in the oldest old. Evidence Acquisition: We searched Medline for reports published with the following search words: hypothyroidism, sHT, ageing, elderly, L-thyroxin, thyroid, guidelines, treatment, quality of life, cardiovascular risk, heart failure (HF), ischemic heart disease (IHD), endothelial dysfunction. The search was restricted to reports published in English since 1980, but some reports published before 1980 were also incorporated. We supplemented the search with records from personal files and references of relevant articles and textbooks. Parameters analyzed included epidemiology of sHT and thyroid failure the effect of thyroid hormone on ageing process and cardiovascular function as well as the potential benefits of L-thyroxin therapy on quality of life, HF progression and events. Evidence Synthesis: TSH levels increase with age, even in older patients without thyroid disease, in whom higher TSH value might favor longevity; better quality of life and lower IHD mortality in the oldest old population has been reported yet. However, at odds with the relationship between sHT and IHD risk and mortality, which shows a clear age dependent feature, vanishing in the last decades of life, the detrimental effect of sHT on HF progression and events remains evident also in older patients, although no data are available in the oldest old population. Conclusions: The lack of specific randomized trials enrolling either old or very old subjects, aimed at evaluate the efficacy of hormonal replacement on overall survival and cardiovascular risk reduction along with the negative effects of possible over-treatment, makes the decision to treat older people a still unresolved clinical challenge. Moreover, the possibility that restoring euthyroidism may be harmful in the elderly should be always taken into account.

Thyroid hormones have relevant activity at cardiac and vascular level, by influencing heart rate, myocardial excitability as well as inotropic and lusitropic status, systemic vascular resistance and blood pressure. Moreover, they interact with neuro-hormonal systems such as sympathetic nervous system and renin-angiotensin-aldosterone system thus also indirectly influencing cardiovascular function. Due to these effects, both hypothyroidism and hyperthyroidism, either in their overt or subclinical forms, can have an unfavourable impact in the setting of cardiovascular diseases. The aim of this review is to focus on the prognostic consequences of thyroid disorders in heart failure patients. Moreover, the therapeutical approach and the possible beneficial effects of restoring euthyroidism are reviewed.

Diabetes and chronic heart failure are interrelated conditions with major medical and economic impact that have to be treated as a distinct entity. Several pathological mechanisms have been investigated and proposed to explain the structural and functional changes associated with diabetic cardiomyopathy. These mechanisms are likely to act synergically and may potentiate one the other. This review outlines recent advances in the pathophysiological mechanisms implicated in the development and progression of diabetic cardiomyopathy and in current therapeutic strategies.

Epidemiological studies have recently shown that obesity, and abdominal obesity in particular, is an independent risk factor for the development of heart failure (HF). Higher cardiac oxidative stress is the early stage of heart dysfunction due to obesity, and it is the result of insulin resistance, altered fatty acid and glucose metabolism, and impaired mitochondrial biogenesis. Extense myocyte hypertrophy and myocardial fibrosis are early microscopic changes in patients with HF, whereas circumferential strain during the left ventricular (LV) systole, LV increase in both chamber size and wall thickness (LV hypertrophy), and LV dilatation are the early macroscopic and functional alterations in obese developing heart failure. LV hypertrophy leads to diastolic dysfunction and subendocardial ischemia in obesity, and pericardial fat has been shown to be significantly associated with LV diastolic dysfunction. Evolving abnormalities of diastolic dysfunction may include progressive hypertrophy and systolic dysfunction, and various degrees of eccentric and/or concentric LV hypertrophy may be present with time. Once HF is established, overweight and obese have a better prognosis than do their lean counterparts with the same level of cardiovascular disease, and this phenomenon is called “obesity paradox”. It is mainly due to lower muscle protein degradation, brain natriuretic peptide circulating levels and cardio-respiratory fitness than normal weight patients with HF.

Skeletal muscle abnormalities and loss are frequently present in patients with mild or moderate cardiac heart failure (CHF) and may contribute to fatigue and dyspnea. These muscle abnormalities may be associated with age related body composition changes, such as sarcopenia. Muscle damage has also been observed in subjects with cardiac cahexia, a serious CHF complication, associated with poor prognosis independently of functional disease severity, age, and measures of exercise capacity and cardiac function. Loss of muscle mass is a feature of cachexia, whereas most sarcopenic subjects are not cachectic. Individuals with no weight loss, no anorexia, and no measurable systemic inflammatory response may be sarcopenic. Patients with severe CHF show multiple marked histological abnormalities of skeletal muscle, such as muscle fiber atrophy. These abnormalities are different in sarcopenia and cachexia. The majority of mechanisms involved in sarcopenia play a role even in the determination of cachexia and they are amplified in cachexia where they may induce both muscle damage as well as other abnormalities, such as fat and weight loss, through activation of lypolisis or anorexia. To distinguish cachexia and sarcopenia in CHF patients, even if not easy, should be clinically relevant, because no specific treatment is available for cachectic patients whereas treatment options are possible for sarcopenia.

Cardiac hypertrophy/remodeling manifests as a critical condition which may likely predispose to the risk of fatal heart failure and multiple organ dysfunction if not efficiently addressed, as a result of irreversible neuroendocrine, autonomic and immune system imbalances. Undeniably, the over-excitation of sympathetic and/or the breakdown of central parasympathetic tone play a significant role to be the basis of the persistent immune activation in chronic heart failure (CHF) which, to a certain extent, is primed by inflammatory reactions in the Central Nervous System. Moreover, till today, the clinical management of CHF seeks the identification of molecularly targeted drugs in comparison to those considered so far. This review focuses on the possible neuroimmune-mediated pathways involved in CHF and throws light on the current therapeutic strategies.

The classic model of Chronic Heart Failure (CHF) is rooted in the overexpression of neurohormonal molecules. To complement this paradigm, increasing evidence indicates that a variety of hormones may be down-regulated in CHF patients. The list includes growth hormone (GH) and its tissue effector insulin-like growth factor-1 (IGF-1). The GH/IGF-1 axis regulates cardiac growth, stimulates myocardial contractility, and influences the vascular system. The relationship between the GH/IGF-1 axis and the cardiovascular system has been extensively demonstrated in numerous studies in animals models and confirmed by the cardiac derangements secondary to both GH excess and deficiency in humans. Impaired activity of the GH/IGF-1 axis in CHF has been described by several independent groups and includes a wide array of abnormalities, including low IGF-1 levels, GH deficiency (GHD), and GH resistance that may be related to the severity of heart disease. According to several observations, these derangements are associated with poor clinical status and outcome. Since the first study of GH therapy in CHF in 1996, several placebo-controlled trials have been conducted with conflicting results. These discordant findings are likely explained by the degree of CHF-associated GH/IGF-1 impairment that may impact on individual responsiveness to GH administration. Biological actions of GH and IGF-1, cardiovascular implication of GH deficiency and GH excess, relation between somatotrophic axis and CHF are discussed. Results from trials of GH therapy, emerging therapeutic strategies, safety issues, and lack in evidence are also reported.

Testosterone deficiency syndrome (TDS) induces several negative effects that generally involve different organs such as testis, bone, skeletal muscle, and heart, leading to reduction in testis function, causing osteoporosis, strongly reducing muscle mass, decreasing exercise capacity and strength and facilitating heart failure. Approximately 25% of patients affected by chronic heart failure (CHF) is characterized by plasma Testosterone (T) levels below normal ranges also related to disease progression. In addition, reduction of circulating testosterone levels may contribute to some specific features of CHF, such as abnormal energy handling, weakness, dyspnoea and cachexia in particular. According to some recent evidence it has emerged that testosterone replacement therapy (TRT) may improve muscle strength and functional pulmonary capacity in CHF men with TDS. This review will place emphasis on the pathophysiological role of testosterone deficiency in CHF men as well as the effects of the testosterone replacement therapy.

Heart failure (HF) is a clinical syndrome featuring cardiac pump failure along with signs and symptoms arising from salt and water retention mediated by activated renin-angiotensin-aldosterone system (RAAS). In addition to this cardiorenal perspective, HF is accompanied by a systemic illness, especially in advanced stages characterized by oxidative stress in various tissues, causing damage to soft tissue and bone. Secondary hyperparathyroidism (SHPT) which is also considered to contribute this systemic illness is therefore prominent in advanced HF. SHPT in HF occurs as a result of RAAS activation, prominent hyperaldosteronism, loop diuretic usage and decreased calcitriol level, all of which results in calcium excretion. We review the evidence that high parathyroid hormone (PTH) is associated with advanced HF, as well as evidence that it's associated with HF with preserved ejection fraction (HFPEF).

n-3 polyunsaturated fatty acids (PUFA) have been proposed as potential treatments for human heart failure. The cardioprotective effects of n-3 PUFA are supported by extensive cell culture, animal and human studies. Animal studies with n-3 PUFA have shown marked improvements in many independent risk factors for heart failure, including obesity, type II diabetes, insulin resistance, hypertension and inflammation. However, the evidence from observational studies, randomised controlled trials and meta-analyses that these benefits on risk factors lead to improvements in the symptoms of heart failure in patients is much less convincing. Further, most studies have used marine n-3 PUFA; the role of the plant-derived PUFA, α-linolenic acid (ALA), is even less clear. This discontinuity of scientific evidence from animal to human studies suggests that future studies should focus on defining the optimal dosage range and the efficacy of n-3 PUFA compared to standard treatments using standardised study designs. Further studies on ALA would seem justified.

In South Africa, rapid urbanisation and epidemiological transition have left the black urban population vulnerable to diseases of lifestyle such as diabetes, high blood pressure, obesity and heart disease, as well as chronic heart failure. This is in part due to the fact that changes in dietary patterns during urbanisation play an important role in the increase of risk factors of these diseases. The South African population is made up of many different ethnic and cultural groups, each with its own way of eating and food choices. The black African population is one such an ethnic group, with its own distinct eating patterns and food choices. The diets of people living in rural areas tend to still be higher in carbohydrates, lower in fat, lower in sugar and higher in fibre, corresponding to the more traditional way of eating. With urbanisation their diet has changed to a more westernised diet with the resultant decrease in carbohydrates and fibre and an increased fat, processed food and salt consumption. Factors that might contribute to this change in dietary patterns include lack of awareness and knowledge around nutritional recommendations for persons suffering from chronic heart failure, urbanisation, socio-economic circumstances, food insecurity and level of education. Nutritional recommendations and intervention programs for the prevention and management of CHF focusing on food that is culturally sensitive and affordable should be implemented.

Nowadays, erectile dysfunction (ED) is considered an increasingly important clinical condition in men with heart failure (HF) which may influence the therapeutic approach to these patients. Since there is cogent evidence that ED is a “sentinel marker” of acute cardiovascular events especially in men younger than 65 years or in those affected by type 2 diabetes mellitus, it deserves an early diagnosis and an appropriate treatment. In NYHA III-IV class HF patients, sexual activity could lead to acute cardiovascular events and this should be taken into account when approaching ED patients. Moreover, it is well known that some classes of drugs, normally employed in the treatment of HF patients (e.g.thiazide diuretics, spironolactone and β-blockers), might worsen or even contribute to ED development. On the other hand, growing evidence suggests that PDE 5 inhibitors (vardenafil, tadalafil and sildenafil) seem to better satisfy the needs of NYHA HF I- II class men suffering from ED. In fact, they show few side effects, while improving both cardiopulmonary parameters and quality of life. Therefore, the aim of this review is to sum up the most recent evidence regarding the management of ED in men suffering from HF.