Objective To assess prevalence, incidence, prognosis and progression of degenerative valvular aortic stenosis (AS). Setting The Tromsø Study and the University Hospital of North Norway. Design Population based prospective study. Population Over a 14 year span we performed three repeated echocardiographic examinations (1994, 2001 and 2008) of a random sample of initially 3273 participants. Data from the only hospital serving this population were included. Results There were 164 subjects with AS. Prevalence consistently increased with age, average values being 0.2% in the 50-59 year cohort, 1.3% in the 60-69 year cohort, 3.9% in the 70-79 year cohort and 9.8% in the 80-89 year cohort. The incidence rate in the study was 4.9‰/year. The mean annual increase in mean transvalvular pressure gradient was 3.2 mm Hg. The increase was lower in mild AS than in more severe disease, disclosing a non-linear development of the gradient, but with large individual variations. Mortality was not significantly increased in the asymptomatic AS-group (HR=1.28), nor in those who received aortic valve replacement (n=34, HR=0.93), compared with the general population.

Reduced cardiac contractility during heart failure (HF) is linked to impaired Ca2+ release from Ryanodine Receptors (RyRs). We investigated whether this deficit can be traced to nanoscale RyR reorganization. Using super-resolution imaging, we observed dispersion of RyR clusters in cardiomyocytes from post-infarction HF rats, resulting in more numerous, smaller clusters. Functional groupings of RyR clusters which produce Ca2+ sparks (Ca2+ release units, CRUs) also became less solid. An increased fraction of small CRUs in HF was linked to augmented ‘silent’ Ca2+ leak, not visible as sparks. Larger multi-cluster CRUs common in HF also exhibited low fidelity spark generation. When successfully triggered, sparks in failing cells displayed slow kinetics as Ca2+ spread across dispersed CRUs. During the action potential, these slow sparks protracted and desynchronized the overall Ca2+ transient. Thus, nanoscale RyR reorganization during HF augments Ca2+ leak and slows Ca2+ release kinetics, leading to weakened contraction in this disease.

The observed changes in SERCA2 activity after increasing and decreasing serine(16) PLB phosphorylation in cardiomyocytes from sham and failing hearts, suggest that the observed reduction in serine(16) PLB phosphorylation is one major factor determining the reduced SERCA2 activity in heart failure after MI.

Abstract-A decreased exercise tolerance is a common symptom in patients with congestive heart failure (CHF). This decrease has been suggested to be partly due to altered skeletal muscle function. Therefore, we have studied contractile function and cytoplasmic free Ca 2ϩ concentration ([Ca 2ϩ ] i , measured with the fluorescent dye indo 1) in isolated muscles from rats in which CHF was induced by ligation of the left coronary artery. The results show no major changes of the contractile function and [Ca 2ϩ ] i handling in unfatigued intact fast-twitch fibers isolated from flexor digitorum brevis muscles of CHF rats, but these fibers were markedly more susceptible to damage during microdissection. Furthermore, CHF fibers displayed a marked increase of baseline [Ca 2ϩ ] i during fatigue. Isolated slow-twitch soleus muscles of CHF rats displayed slower twitch contraction and tetanic relaxation than did muscles from sham-operated rats; the slowing of relaxation became more pronounced during fatigue in CHF muscles. Immunoblot analyses of sarcoplasmic reticulum proteins and sarcolemma Na ϩ ,K ϩ -ATPase showed no difference in flexor digitorum brevis muscles of sham-operated versus CHF rats. In conclusion, functional impairments can be observed in limb muscle isolated from rats with CHF. These impairments seem to mainly involve structures surrounding the muscle cells and sarcoplasmic reticulum Ca Key Words: heart failure Ⅲ skeletal muscle Ⅲ fatigue Ⅲ intracellular Ca 2ϩ handling D ecreased fatigue resistance and skeletal muscle weakness are important symptoms in humans with congestive heart failure (CHF). The reason for the decreased fatigue resistance is not clear. Often, there is no clear correlation between the degree of heart dysfunction and the decrease in exercise tolerance. 1 This suggests that there could be functional impairments within the skeletal muscles that are due to, for instance, alterations in the local environment with restricted local blood flow. 2 In addition, numerous studies have been focused on possible abnormalities in skeletal muscle cells, and significant changes have been found both at the mRNA and protein levels. Generally observed changes in skeletal muscle cells in CHF include a shift of myosin heavy chain distribution toward more fast-type myosin heavy chain, 3-5 altered expression of sarcoplasmic reticulum (SR) Ca 2ϩ -ATPase (SERCA), 6,7 and in later stages, decrements in mitochondrial enzymes and muscle cell atrophy. 8 Functional studies of limb muscle function in CHF are more sparse. One study on bundles of muscle fibers from the fast-twitch extensor digitorum longus (EDL) muscles of rats showed marked dysfunction in CHF with Ϸ50% reductions in tetanic Ca 2ϩ and force and markedly accelerated fatigue development, which was not due to muscle cell atrophy. 9 There seems to be a discrepancy between these very dramatic functional changes and the relatively subtle changes of muscle protein levels observed in muscles from CHF subjects. In accordance, a more recent study showed more mode...

Heart failure is associated with reduction of exercise capacity that cannot be solely ascribed to reduced maximal oxygen uptake (VdotO2max). Therefore, research has focused on changes in skeletal muscle morphology, metabolism and function. Factors that can cause such changes in skeletal muscle comprise inactivity, malnutrition, constant or repeated episodes of inadequate oxygen delivery and prolonged exposure to altered neurohumoural stimuli. Most of these factors are not specific for the heart failure condition. On the other hand, heart failure is more than one clinical condition. Congestive heart failure (CHF) develops gradually as a result of deteriorating contractility of the viable myocardium, myocardial failure. Is it possible that development of this contractile deficit in the myocardium is paralleled by a corresponding contractile deficit of the skeletal muscles? This question cannot be answered today. Both patient studies and experimental studies support that there is a switch to a faster muscle phenotype and energy metabolism balance is more anaerobic. The muscle atrophy seen in many patients is not so evident in experimental studies. Few investigators have studied contractile function. Both fast twitch and slow twitch muscles seem to become slower, not faster as might be expected, and this is possibly linked to slower intracellular Ca2+ cycling. The neurohumoural stimuli that can cause this change are not known, but recently it has been reported that several cytokines are increased in CHF patients. Thus, the changes seen in skeletal muscles during CHF are partly secondary to inactivity, but the possibility remains that the contractility is altered because of intracellular changes of Ca2+ metabolism that are also seen in the myocardium.

Although increased levels of circulating interleukin (IL)-18 have been demonstrated in patients with cardiovascular diseases, the functional consequences of chronically increased circulating IL-18 with respect to myocardial function have not been defined. Thus we aimed to examine the effects of chronic IL-18 exposure on left ventricular (LV) function in healthy mice. Moreover, to clarify whether IL-18 has direct effects on the cardiomyocyte, we examined effects of IL-18 on cardiomyocytes in vitro. After 7 days of daily intraperitoneal injections of 0.5 microg IL-18 in healthy mice, a 40% (P < 0.05) reduction in the LV maximal positive derivative, a 25% (P < 0.05) reduction in the LV maximal rate of pressure decay, and a 2.8-fold (P < 0.001) increase in the LV end-diastolic pressure were measured, consistent with myocardial dysfunction. Furthermore, we measured a 75% (P < 0.05) reduction in beta-adrenergic responsiveness to isoproterenol. IL-18 induced myocardial hypertrophy, and there was a 2.9-fold increase (P < 0.05) in atrial natriuretic peptide mRNA expression in the LV myocardium. In vitro examinations of isolated adult rat cardiomyocytes being stimulated with IL-18 (0.1 microg/ml) exhibited an increase in peak Ca2+ transients (P < 0.05) and in diastolic Ca2+ concentrations (P < 0.05). In conclusion, this study shows that daily administration of IL-18 in healthy mice causes LV myocardial dysfunction and blunted beta-adrenergic responsiveness to isoproterenol. A direct effect of IL-18 on the cardiomyocyte in vitro was demonstrated, suggesting that IL-18 reduces the responsiveness of the myofilaments to Ca2+. Finally, induction of myocardial hypertrophy by IL-18 indicates a role for this cytokine in myocardial remodeling.

Aims Left ventricular hypertrophy has been shown to be an independent predictor of cardiovascular morbidity. Acknowledging the skewed distribution of left ventricular mass, we wanted to develop criteria for left ventricular hypertrophy based on percentiles of left ventricular mass, and observe the effect on estimates of left ventricular hypertrophy prevalences in different subgroups and on the relationship to cardiovascular risk factors in a general population. Methods and ResultsIn a population-based sample of 3287 subjects aged 25-85 years, left ventricular mass was estimated using M-mode echocardiography. A 'healthy' subgroup was used as a reference sample to define sexspecific left ventricular hypertrophy criteria. Sex-specific 97·5 percentiles for left ventricular mass by height, based on the reference sample, were 145·5 and 125·4 g . m 1 , for men and women, respectively. The prevalences of left ventricular hypertrophy in the total population were 14·9% for men and 9·1% for women. The main independent predictors of left ventricular hypertrophy were male gender, body mass index, systolic blood pressure, valvular heart disease, cardiovascular disease and antihypertensive medication. Body mass index and systolic blood pressure had a strong synergistic association with left ventricular hypertrophy in men, but not in women. ConclusionAn alternative framework for defining left ventricular hypertrophy is provided. Body mass index is the culprit factor for risk of left ventricular hypertrophy. Our study indicates that weight reduction is a relevant measure for treatment and possibly prevention of left ventricular hypertrophy in a substantial part of the general population. (Eur Heart J 1999; 20: 429-438)

To evaluate the effect of intermittent sprint training on sarcoplasmic reticulum (SR) function, nine young men performed a 5 wk high-intensity intermittent bicycle training, and six served as controls. SR function was evaluated from resting vastus lateralis muscle biopsies, before and after the training period. Intermittent sprint performance (ten 8-s all-out periods alternating with 32-s recovery) was enhanced 12% (P < 0.01) after training. The 5-wk sprint training induced a significantly higher (P < 0.05) peak rate of AgNO(3)-stimulated Ca(2+) release from 709 (range 560-877; before) to 774 (596-977) arbitrary units Ca(2+). g protein(-1). min(-1) (after). The relative SR density of functional ryanodine receptors (RyR) remained unchanged after training; there was, however, a 48% (P < 0.05) increase in total number of RyR. No significant differences in Ca(2+) uptake rate and Ca(2+)-ATPase capacity were observed following the training, despite that the relative density of Ca(2+)-ATPase isoforms SERCA1 and SERCA2 had increased 41% and 55%, respectively (P < 0.05). These data suggest that high-intensity training induces an enhanced peak SR Ca(2+) release, due to an enhanced total volume of SR, whereas SR Ca(2+) sequestration function is not altered.