The adult heart responds to increased workload with physiologic hypertrophy, cardiac stem cell activation, and new myocyte formation.

Aims: It is a dogma of cardiovascular pathophysiology that the increased cardiac mass in response to increased workload is produced by the hypertrophy of the pre-existing myocytes. The role, if any, of adult-resident endogenous cardiac stem/progenitor cells (eCSCs) and new cardiomyocyte formation in physiological cardiac remodelling remains unexplored.

Methods And Results: In response to regular, intensity-controlled exercise training, adult rats respond with hypertrophy of the pre-existing myocytes.

Influence of age, sex, and aerobic capacity on forearm and skin blood flow and vascular conductance.

This study investigated the influence of age, sex, and aerobic capacity on resting and peak forearm and cutaneous blood flow (FBF, CBF). We recruited 93 female and 129 male subjects (age range 16-76 years). FBF and CBF were assessed by plethysmography and laser-Doppler flowmetry, respectively.

The effect of 48 weeks of aerobic exercise training on cutaneous vasodilator function in post-menopausal females.

Skin blood flow (SkBF) and endothelial-dependent vasodilatation decline with ageing and can be reversed with exercise training. We tested whether 48 weeks of training could improve SkBF and endothelial function in post-menopausal females; 20 post-menopausal subjects completed the study. SkBF was measured by laser-Doppler flowmetry (LDF).

Proteomic investigation of changes in human vastus lateralis muscle in response to interval-exercise training.

No previous study has used proteomics to investigate the effects of exercise training on human skeletal muscle. Five recreationally active men completed a 6-wk training programme involving three sessions per week, utilising six 1-min bouts at maximum oxygen uptake (V O(2)max) interspersed with 4 min at 50% V O(2)max. Vastus lateralis was biopsied at standardised times before and after the training intervention.

A prospective longitudinal evaluation of the benefits of epicardial lead placement for cardiac resynchronization therapy.

Aims: Cardiac resynchronization therapy (CRT) is a recognized treatment for appropriate patients. However, placement of the transvenous left ventricular lead is unsuccessful in 5-10% of patients and a further 20% fail to respond. For these groups, epicardial left ventricular lead placement is one alternative.

Maximizing patient benefit from cardiac resynchronization therapy with the addition of structured exercise training: a randomized controlled study.

Objectives: We evaluated the benefits of additional exercise training after cardiac resynchronization therapy (CRT).

Background: Cardiac resynchronization therapy results in improved morbidity and mortality in appropriate patients. We hypothesized that a structured exercise training program in addition to CRT would maximize the improvements in exercise capacity, symptoms, and quality of life (QOL).

Reduced cardiac functional reserve and quality of life in adults with GH deficiency.

Introduction: Patients with severe GH deficiency (GHD) suffer with a reduced quality of life in addition to diverse changes in cardiac size and performance. So far, the cardiac reserve ability to maintain the circulation during peak exercise has not been measured. We tested the hypothesis that patients with severe GHD have reduced cardiac reserve function compared with healthy controls and that this could explain, in part, their reduced quality of life.

Cardiac functional reserve is diminished in growth hormone-deficient adults.

Various studies have shown that patients with severe growth hormone deficiency (GHD) have diverse changes in left ventricular (LV) size or performance but so far there is no direct indication of cardiac reserve ability to maintain the circulation during peak exercise. We tested the hypothesis that patients with severe GHD have reduced cardiac reserve function compared with healthy controls. Eighteen patients with severe GHD were studied and compared with 18 age-, sex-, and body mass index (BMI)-matched healthy controls.

A study of presbycardia, with gender differences favoring ageing women.

Background: The impact of ageing on the human cardiovascular system has been the subject of several studies in recent years, but with insufficient emphasis on defining sex-specific differences. To rectify this, gender-specific differences in structure and function in the human cardiovascular system were studied in a European population during natural ageing.

Methods: Cardiac power output (CPO) was measured and integrated with changes in left ventricular (LV) mass, diastolic, systolic and limb blood flow, blood pressure and exercise capacity in 93 health-screened men and 122 women, aged 20 to 75 years.

Cardiac stem cell-based myocardial regeneration: towards a translational approach.

The adult mammalian heart, including humans, harbors bone fide cardiac stem cells (CSCs) distributed throughout the atria and ventricles. Their discovery almost four years ago initiated a brand new field of cardiac regenerative biology that has profoundly changed the outlook of developmental and adult cardiac biology/physiology and the potential for treating cardiac failure. Indeed, despite its initial hesitance, the research community has now accepted that the heart has an endogenous myocardial regenerative potential owed to CSCs, which challenges the previous accepted notion of the adult heart as a post-mitotic organ.

Acute beta-adrenergic overload produces myocyte damage through calcium leakage from the ryanodine receptor 2 but spares cardiac stem cells.

A hyperadrenergic state is a seminal aspect of chronic heart failure. Also, "Takotsubo stress cardiomyopathy," is associated with increased plasma catecholamine levels. The mechanisms of myocyte damage secondary to excess catecholamine exposure as well as the consequence of this neurohumoral burst on cardiac stem cells (CSCs) are unknown.

Anabolic effects of a non-myotoxic dose of the beta2-adrenergic receptor agonist clenbuterol on rat plantaris muscle.

Previous investigations of the effects of clenbuterol have used suprapharmacological doses that induce myocyte death, alter muscle phenotype, and do not approximate the proposed therapeutic dose for humans. Recently, we reported that smaller doses of clenbuterol induce muscle growth without causing myocyte death. In the present study we used histochemical and proteomic techniques to investigate the molecular effects of this dose.

Relative myotoxic and haemodynamic effects of the beta-agonists fenoterol and clenbuterol measured in conscious unrestrained rats.

The beta(2)-adrenoceptor (beta(2)-AR) agonists clenbuterol and fenoterol have similar beneficial effects in animal models of heart failure. However, large doses of clenbuterol can induce cardiomyocyte death, and it is not known which of these agents has the most favourable therapeutic profile. We have investigated the cardiotoxicity of clenbuterol and fenoterol alongside that of isoprenaline, and compared their haemodynamic effects.

Dose-dependent separation of the hypertrophic and myotoxic effects of the beta(2)-adrenergic receptor agonist clenbuterol in rat striated muscles.

Muscle growth in response to large doses (milligrams per kilogram) of beta(2)-adrenergic receptor agonists has been reported consistently. However, such doses may also induce myocyte death in the heart and skeletal muscles and hence may not be safe doses for humans. We report the hypertrophic and myotoxic effects of different doses of clenbuterol.

Relative toxicity of cardiotonic agents: some induce more cardiac and skeletal myocyte apoptosis and necrosis in vivo than others.

We sought to determine the relative myotoxicity of a sample of cardiotonic (catecholaminergic and PDE Inhibitory) agents currently available for clinical use. Male Wistar rats (292 +/- 24 g) were administered single subcutaneous injections of 20 mmol kg(-1) of each agent. Myocyte apoptosis (caspase-3 and annexin-V) and necrosis (anti-myosin antibody) were detected immunohistochemically on cryosections of the heart and soleus muscle.

Ageing and activity: their effects on the functional reserve capacities of the heart and vascular smooth and skeletal muscles.

During perinatal life striated muscles grow through the acquisition of more contractile cells (myocytes or fibres) followed by their postnatal enlargement (i.e. hypertrophy).

Dose-dependent apoptotic and necrotic myocyte death induced by the beta2-adrenergic receptor agonist, clenbuterol.

We have investigated the dose- and time-dependency of myocyte apoptosis and necrosis induced by the beta2-adrenergic receptor agonist, clenbuterol, with the aim of determining whether myocyte apoptosis and necrosis are two separate processes or a continuum of events. Male Wistar rats were administered subcutaneous injections of clenbuterol, and immunohistochemistry was used to detect myocyte-specific apoptosis and necrosis. Myocyte apoptosis peaked 4 h after, and necrosis 12 h after, clenbuterol administration.

Angiotensin II induces apoptosis in vivo in skeletal, as well as cardiac, muscle of the rat.

Our previous work has established that angiotensin II is cardiotoxic. Here we sought to investigate whether skeletal muscle is similarly susceptible to damage. Male Wistar rats were either given a single subcutaneous injection of angiotensin II (range 1 microg kg-1 to 10 mg kg-1) or only the vehicle and killed 7 h later, or implanted with preconditioned osmotic pumps dispensing 1 mg kg-1 day-1 angiotensin II and killed 9 or 18 h later.

Aldosterone induces myocyte apoptosis in the heart and skeletal muscles of rats in vivo.

Over activation of the renin-angiotensin-aldosterone system is known to be cardiotoxic but the potential injurious effects on the skeletal musculature have not been investigated. Male Wistar rats were given subcutaneous injections of aldosterone (1 microg-10 mg kg-1) and killed 7 h later, or continuous infusion (1 mg kg-1 d-1) and killed 48 h later. The role of the mineralocorticoid receptor in mediating aldosterone-induced apoptosis in vivo was investigated using spironolactone (200 mg kg-1).

beta2-Adrenergic receptor stimulation in vivo induces apoptosis in the rat heart and soleus muscle.

High doses of the beta2-adrenergic receptor (AR) agonist clenbuterol can induce necrotic myocyte death in the heart and slow-twitch skeletal muscle of the rat. However, it is not known whether this agent can also induce myocyte apoptosis and whether this would occur at a lower dose than previously reported for myocyte necrosis. Male Wistar rats were given single subcutaneous injections of clenbuterol.

Catecholamine-induced apoptosis and necrosis in cardiac and skeletal myocytes of the rat in vivo: the same or separate death pathways?

High levels of catecholamines are myotoxic but the relative amounts of apoptosis and necrosis have not been established in vivo in cardiac and skeletal muscles. Immunohistochemistry was used to detect and quantify myocyte-specific necrosis (myosin antibody in vivo) and apoptosis (caspase-3 antibody in vitro) in the heart and soleus muscles of male Wistar rats that had received single subcutaneous injections of isoprenaline over the range 1 microg to 5 mg [kg body weight (BW)](-1). Peak myocyte apoptosis occurred 3-6 h after, and necrosis 18 h after, a single injection of 5 mg (kg BW)(-1) isoprenaline in vivo.

Cardiomyocyte death and the ageing and failing heart.

Mammalian cardiomyocytes have limited regenerative capacity, such that cell death can result in a net loss of viable contractile elements and a decrease in cardiac functional reserve, both during normal ageing and after insults to the myocardium leading to heart failure. At least four types of cell death have been described, with apoptosis and necrosis being the most extreme phenotypes and most extensively studied. Many of the classical morphological and biochemical features associated with these forms of cell death have been derived from studies conducted in vitro and these may not always faithfully reflect events occurring in vivo.

Characterization of adrenoceptor involvement in skeletal and cardiac myotoxicity Induced by sympathomimetic agents: toward a new bioassay for beta-blockers.

Excessive levels of catecholamines have long been known to be cardiotoxic, but less well known are their toxic effects on skeletal muscle. By using an antimyosin monoclonal antibody and quantitative methods to measure the extent of myocyte necrosis, and by employing modulators of adrenoceptors (ARs), including clenbuterol, bupranolol, propranolol, bisoprolol, atenolol, ICI-118551, phenoxybenzamine, prazosin, and yohimbine, the involvement of ARs in isoproterenol-induced myotoxicity was characterized. In the myocardium, the toxic effects were predominantly mediated via the beta(1)-ARs.

Characterisation of isoprenaline myotoxicity on slow-twitch skeletal versus cardiac muscle.

Background: Elevated catecholamines are known to be cardiotoxic, but their potential injurious effects on skeletal muscles are largely unknown. We have investigated whether isoprenaline induces in vivo myocyte necrosis in rat soleus muscle, and characterised the time-course, dose-response, spatial distribution and adrenoceptor involvement of its myotoxicity, in comparison with effects on cardiomyocytes in the same animals.

Material And Methods: Myocyte necrosis in response to subcutaneous isoprenaline was detected in vivo using a monoclonal anti-myosin antibody.