Migraine and risk of atrial fibrillation: A 9-year follow-up based on the Trøndelag Health Study.

BACKGROUND: Data from some population-based studies have indicated an increased risk of atrial fibrillation (AF) among patients with migraine, particularly among individuals with migraine with aura. The present study aimed to assess the association between primary headache disorders and AF. METHODS: In a population-based 9-year follow-up design, we evaluated the questionnaire-based headache diagnosis, migraine and tension-type headache (TTH) included, collected in the Trøndelag Health Study (HUNT3) conducted in 2006-2008, and the subsequent risk of AF in the period until December 2015. The population at risk consisted of 39,340 individuals ≥20 years without AF at HUNT3 baseline who answered headache questionnaire during HUNT3. The prospective association was evaluated by multivariable Cox proportional hazard models with 95% confidence intervals (CIs). RESULTS: Among the 39,340 participants, 1524 (3.8%) developed AF during the 9-year follow up, whereof 91% of these were ≥55 years. In the multivariable analyses, adjusting for known confounders, we did not find any association between migraine or TTH and risk of AF. The adjusted hazard ratios (HRs) were respectively 0.84 (95% CI = 0.64-1.11) for migraine, 1.16 (95% CI = 0.86-1.27) for TTH and 1.04 (95% CI = 0.86-1.27) for unclassified headache. However, in sensitivity analyses of individuals aged ≥55 years, a lower risk of AF was found for migraine (HR = 0.53; 95% CI = 0.39-0.73). CONCLUSIONS: In this large population-based study, no increased risk of AF was found among individuals with migraine or TTH at baseline. Indeed, among individuals aged ≥55 years, migraine was associated with a lower risk for AF.

Effect of exercise training for five years on all cause mortality in older adults-the Generation 100 study: randomised controlled trial.

OBJECTIVE: To evaluate the effect of five years of supervised exercise training compared with recommendations for physical activity on mortality in older adults (70-77 years). DESIGN: Randomised controlled trial. SETTING: General population of older adults in Trondheim, Norway. PARTICIPANTS: 1567 of 6966 individuals born between 1936 and 1942. INTERVENTION: Participants were randomised to two sessions weekly of high intensity interval training at about 90% of peak heart rate (HIIT, n=400), moderate intensity continuous training at about 70% of peak heart rate (MICT, n=387), or to follow the national guidelines for physical activity (n=780; control group); all for five years. MAIN OUTCOME MEASURE: All cause mortality. An exploratory hypothesis was that HIIT lowers mortality more than MICT. RESULTS: Mean age of the 1567 participants (790 women) was 72.8 (SD 2.1) years. Overall, 87.5% of participants reported to have overall good health, with 80% reporting medium or high physical activity levels at baseline. All cause mortality did not differ between the control group and combined MICT and HIIT group. When MICT and HIIT were analysed separately, with the control group as reference (observed mortality of 4.7%), an absolute risk reduction of 1.7 percentage points was observed after HIIT (hazard ratio 0.63, 95% confidence interval 0.33 to 1.20) and an absolute increased risk of 1.2 percentage points after MICT (1.24, 0.73 to 2.10). When HIIT was compared with MICT as reference group an absolute risk reduction of 2.9 percentage points was observed (0.51, 0.25 to 1.02) for all cause mortality. Control participants chose to perform more of their physical activity as HIIT than the physical activity undertaken by participants in the MICT group. This meant that the controls achieved an exercise dose at an intensity between the MICT and HIIT groups. CONCLUSION: This study suggests that combined MICT and HIIT has no effect on all cause mortality compared with recommended physical activity levels. However, we observed a lower all cause mortality trend after HIIT compared with controls and MICT. TRIAL REGISTRATION: ClinicalTrials.gov NCT01666340.

Physical activity, cardiorespiratory fitness, and cardiovascular outcomes in individuals with atrial fibrillation: the HUNT study.

AIMS: Atrial fibrillation (AF) confers higher risk of mortality and morbidity, but the long-term impact of physical activity (PA) and cardiorespiratory fitness (CRF) on outcomes in AF patients is unknown. We, therefore, examined the prospective associations of PA and estimated CRF (eCRF) with all-cause mortality, cardiovascular disease (CVD) mortality, morbidity and stroke in individuals with AF. METHODS AND RESULTS: We followed 1117 AF patients from the HUNT3 study in 2006-08 until first occurrence of the outcomes or end of follow-up in November 2015. We used Cox proportional hazard regression to examine the prospective associations of self-reported PA and eCRF with the outcomes. Atrial fibrillation patients meeting PA guidelines had lower risk of all-cause [hazard ratio (HR) 0.55, 95% confidence interval (CI) 0.41-0.75] and CVD mortality (HR 0.54, 95% CI 0.34-0.86) compared with inactive patients. The respective HRs for CVD morbidity and stroke were 0.78 (95% CI 0.58-1.04) and 0.70 (95% CI 0.42-1.15). Each 1-metabolic equivalent task (MET) higher eCRF was associated with a lower risk of all-cause (HR 0.88, 95% CI 0.81-0.95), CVD mortality (HR 0.85, 95% CI 0.76-0.95), and morbidity (HR 0.88, 95% CI 0.82-0.95). CONCLUSION: Higher PA and CRF are associated with lower long-term risk of CVD and all-cause mortality in individuals with AF. The findings support a role for regular PA and improved CRF in AF patients, in order to combat the elevated risk for mortality and morbidity.

Symptoms of anxiety and depression and risk of atrial fibrillation-The HUNT study.

BACKGROUND: Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia. Anxiety and depression may activate the autonomic nervous system which is likely to play an important role in the etiology of AF. However, little is known about the association between symptoms of anxiety and depression and risk of AF. OBJECTIVE: This study aimed to assess the association between symptoms of anxiety and depression and risk of AF. METHODS: In a population-based study, 37,402 adult residents were followed for incident AF from 2006 to 2008 until 2015. Participants were classified according to data on anxiety and depression symptoms. Cox proportional regression models were used to adjust for common AF risk factors. RESULTS: During a median follow-up of 8.1 years, 1433 (3.8%) participants developed AF. In comparisons with no anxiety symptoms, the multivariable-adjusted hazard ratios (HRs) were 1.1 (95% CI: 0.9-1.5) for mild to moderate anxiety symptoms and 1.0 (95% CI: 0.8-1.4) for severe anxiety symptoms. In comparisons with no depression symptoms, the multivariable-adjusted HRs were 1.5 (95% CI: 1.2-1.8) for mild to moderate depression symptoms and 0.9 (95% CI: 0.6-1.3) for severe depression symptoms. Recurrent anxiety/depression symptoms were not associated with increased AF risk. CONCLUSIONS: In this large, population-based study, we found no evidence of an association between symptoms of anxiety or severe depression and AF risk, even for recurrent anxiety or depression symptoms. An unexpected association of symptoms of mild to moderate depression with increased AF risk requires confirmation in other studies. Our findings add to the sparse literature on symptoms of anxiety and depression and risk of AF.

Estimated Cardiorespiratory Fitness and Risk of Atrial Fibrillation: The Nord-Trøndelag Health Study.

PURPOSE: To investigate the association between estimated cardiorespiratory fitness (eCRF) and risk of atrial fibrillation (AF), and examine how long-term changes in eCRF affects the AF risk. METHODS: This prospective cohort study includes data of 39,844 men and women from the HUNT2 (August 15, 1995 to June 18, 1997) and the HUNT3 study (October 3, 2006 to June 25, 2008). The follow-up period was from HUNT3 until AF diagnosis or November 30, 2015. The AF diagnoses were retrieved from hospital registers and validated by medical doctors. A nonexercise test based on age, waist circumference, resting heart rate and self-reported physical activity was used to estimate CRF. Cox regression was performed to assess the association between eCRF and AF. RESULTS: The mean age was 50.6 ± 14.6 yr for men and 50.2 ± 15.2 yr for women. Mean follow-up time was 8.1 yr. One thousand fifty-seven cases of AF were documented. For men, the highest risk reduction of AF was 31% in the fourth quintile of eCRF when compared with the first quintile (hazard ratio [HR], 0.69; 95% confidence interval [CI], 0.53-0.89). For women, the highest risk reduction was 47% in the fifth quintile when compared with the first quintile (HR, 0.53; 95% CI, 0.38-0.74). One metabolic equivalent increase in eCRF over a 10-yr period was associated with 7% lower risk of AF (HR, 0.93; 95% CI, 0.86-1.00). Participants with improved eCRF had 44% lower AF risk compared with those with decreased eCRF (HR, 0.56; 95% CI, 0.36-0.87). CONCLUSIONS: The eCRF was inversely associated with AF, and participants with improved eCRF over a 10-yr period had less risk of AF. These findings support the hypothesis that fitness may prevent AF.

Weight and weight change and risk of atrial fibrillation: the HUNT study.

AIMS: Although obesity has been associated with risk of atrial fibrillation (AF), the associations of long-term obesity, recent obesity, and weight change with AF risk throughout adulthood are uncertain. METHODS AND RESULTS: An ambispective cohort study was conducted which included 15 214 individuals. The cohort was created from 2006 to 2008 (the baseline) and was followed for incident AF until 2015. Weight and height were directly measured at baseline. Data on previous weight and height were retrieved retrospectively from measurements conducted 10, 20, and 40 years prior to baseline. Average body mass index (BMI) over time and weight change was calculated. During follow-up, 1149 participants developed AF. The multivariable-adjusted hazard ratios were 1.2 (95% confidence interval 1.0-1.4) for average BMI 25.0-29.9 kg/m2 and 1.6 (1.2-2.0) for average BMI ≥30 kg/m2 when compared with normal weight. The association of average BMI with AF risk was only slightly attenuated after adjustment for most recent BMI. In contrast, current BMI was not strongly associated with the risk of AF after adjustment for average BMI earlier in life. Compared with stable BMI, both loss and gain in BMI were associated with increased AF risk. After adjustment for most recent BMI, the association of BMI gain with AF risk was largely unchanged, while the association of BMI loss with AF risk was weakened. CONCLUSION: Long-term obesity and BMI change are associated with AF risk. Obesity earlier in life and weight gain over time exert cumulative effects on AF development even after accounting for most recent BMI.

Metabolically Healthy Obesity and Risk for Atrial Fibrillation: The HUNT Study.

OBJECTIVE: Atrial fibrillation (AF) is the most common arrhythmia and has been described as a global epidemic. Although AF is associated with both obesity and its metabolic consequences, little is known about the association between metabolically healthy obesity and AF. METHODS: In a population-based study, 47,870 adults were followed for incident AF from 2006 to 2008 until 2015. Participants were classified according to BMI and metabolic status (using waist circumference, triglycerides, high-density lipoprotein cholesterol, blood pressure, and glucose) at baseline. RESULTS: During a median follow-up of 8.1 years, 1,758 participants developed AF. Compared with metabolically healthy individuals with BMI < 25 kg/m2 , the multivariable-adjusted hazard ratios for metabolically healthy and unhealthy obesity were 1.6 (95% CI: 1.2 to 2.1) and 1.6 (95% CI: 1.3 to 1.9), respectively. AF risk increased according to the severity of obesity. CONCLUSIONS: Metabolically healthy and unhealthy obesity increased AF risk to a similar extent. Severity of obesity was positively associated with AF risk regardless of metabolic status.

Physical activity modifies the risk of atrial fibrillation in obese individuals: The HUNT3 study.

Background Atrial fibrillation is the most common heart rhythm disorder, and high body mass index is a well-established risk factor for atrial fibrillation. The objective of this study was to examine the associations of physical activity and body mass index and risk of atrial fibrillation, and the modifying role of physical activity on the association between body mass index and atrial fibrillation. Design The design was a prospective cohort study. Methods This study followed 43,602 men and women from the HUNT3 study in 2006-2008 until first atrial fibrillation diagnosis or end of follow-up in 2015. Atrial fibrillation diagnoses were collected from hospital registers and validated by medical doctors. Cox proportional hazard regression analysis was performed to assess the association between physical activity, body mass index and atrial fibrillation. Results During a mean follow-up of 8.1 years (352,770 person-years), 1459 cases of atrial fibrillation were detected (4.1 events per 1000 person-years). Increasing levels of physical activity were associated with gradually lower risk of atrial fibrillation ( p trend 0.069). Overweight and obesity were associated with an 18% (hazard ratio 1.18, 95% confidence interval 1.03-1.35) and 59% (hazard ratio 1.59, 95% confidence interval 1.37-1.84) increased risk of atrial fibrillation, respectively. High levels of physical activity attenuated some of the higher atrial fibrillation risk in obese individuals (hazard ratio 1.53, 95% confidence interval 1.03-2.28 in active and 1.96, 95% confidence interval 1.44-2.67 in inactive) compared to normal weight active individuals. Conclusion Overweight and obesity were associated with increased risk of atrial fibrillation. Physical activity offsets some, but not all, atrial fibrillation risk associated with obesity.

Aerobic Interval Training Prevents Age-Dependent Vulnerability to Atrial Fibrillation in Rodents.

Aims: Increasing age is the most important risk factor for atrial fibrillation (AF). Very high doses of exercise training might increase AF risk, while moderate levels seem to be protective. This study aimed to examine the effects of age on vulnerability to AF and whether long-term aerobic interval training (AIT) could modify these effects. Methods: Nine months old, male Sprague-Dawley rats were randomized to AIT for 16 weeks (old-ex) or to a sedentary control group (old-sed), and compared to young sedentary males (young-sed). After the intervention, animals underwent echocardiography, testing of exercise capacity (VO2max), and electrophysiology with AF induction before ex vivo electrophysiology. Fibrosis quantification, immunohistochemistry and western blotting of atrial tissue were performed. Results: Sustained AF was induced in vivo in 4 of 11 old-sed animals, but none of the old-ex or young-sed rats (p = 0.006). VO2max was lower in old-sed, while old-ex had comparable results to young-sed. Fibrosis was increased in old-sed (p = 0.006), with similar results in old-ex. There was a significantly slower atrial conduction in old-sed (p = 0.038), with an increase in old-ex (p = 0.027). Action potential duration was unaltered in old-sed, but prolonged in old-ex (p = 0.036). There were no differences in amount of atrial connexin 43 between groups, but a lateralization in atrial cardiomyocytes of old-sed, with similar findings in old-ex. Conclusion: AF vulnerability was higher in old-sed animals, associated with increased atrial fibrosis, lateralization of connexin-43, and reduced atrial conduction velocity. AIT reduced the age-associated susceptibility to AF, possibly through increased conduction velocity and prolongation of action potentials.

Validation of self-reported and hospital-diagnosed atrial fibrillation: the HUNT study.

BACKGROUND: Self-reported atrial fibrillation (AF) and diagnoses from hospital registers are often used to identify persons with AF. The objective of this study was to validate self-reported AF and hospital discharge diagnoses of AF among participants in a population-based study. MATERIALS AND METHODS: Among 50,805 persons who participated in the third survey of the HUNT Study (HUNT3), 16,247 participants from three municipalities were included. Individuals who reported cardiovascular disease, renal disease, or hypertension in the main questionnaire received a cardiovascular-specific questionnaire. An affirmative answer to a question on physician-diagnosed AF in this second questionnaire defined self-reported AF diagnoses in the study. In addition, AF diagnoses were retrieved from hospital and primary care (PC) registers. All AF diagnoses were verified by review of hospital and PC medical records. RESULTS: A total of 502 HUNT3 participants had a diagnosis of AF verified in hospital or PC records. Of these, 249 reported their AF diagnosis in the HUNT3 questionnaires and 370 had an AF diagnosis in hospital discharge registers before participation in HUNT3. The sensitivity of self-reported AF in HUNT3 was 49.6%, specificity 99.2%, positive predictive value (PPV) 66.2%, and negative predictive value (NPV) 98.4%. The sensitivity of a hospital discharge diagnosis of AF was 73.7%, specificity 99.7%, PPV 88.5%, and NPV 99.2%. CONCLUSION: Use of questionnaires alone to identify cases of AF has low sensitivity. Extraction of diagnoses from health care registers enhances the sensitivity substantially and should be applied when estimates of incidence and prevalence of AF are studied.

Aerobic Interval Training Reduces the Burden of Atrial Fibrillation in the Short Term: A Randomized Trial.

BACKGROUND: Exercise training is an effective treatment for important atrial fibrillation (AF) comorbidities. However, a high level of endurance exercise is associated with an increased AF prevalence. We assessed the effects of aerobic interval training (AIT) on time in AF, AF symptoms, cardiovascular health, and quality of life in AF patients. METHODS AND RESULTS: Fifty-one patients with nonpermanent AF were randomized to AIT (n=26) consisting of four 4-minute intervals at 85% to 95% of peak heart rate 3 times a week for 12 weeks or to a control group (n=25) continuing their regular exercise habits. An implanted loop recorder measured time in AF continuously from 4 weeks before to 4 weeks after the intervention period. Cardiac function, peak oxygen uptake (o2peak), lipid status, quality of life, and AF symptoms were evaluated before and after the 12-week intervention period. Mean time in AF increased from 10.4% to 14.6% in the control group and was reduced from 8.1% to 4.8% in the exercise group (P=0.001 between groups). AF symptom frequency (P=0.006) and AF symptom severity (P=0.009) were reduced after AIT. AIT improved o2peak, left atrial and ventricular ejection fraction, quality-of-life measures of general health and vitality, and lipid values compared with the control group. There was a trend toward fewer cardioversions and hospital admissions after AIT. CONCLUSIONS: AIT for 12 weeks reduces the time in AF in patients with nonpermanent AF. This is followed by a significant improvement in AF symptoms, o2peak, left atrial and ventricular function, lipid levels, and QoL. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01325675.

[A young woman with cardiac arrest]. / Ung kvinne med hjertestans.

A 20-year-old woman presented with dyspnoea in the Emergency department and subsequently suffered a cardiac arrest. The initial rhythm was PEA (pulseless electrical activity). She had intermittent return of spontaneous circulation. Transthoracic echocardiography showed a dilated hypokinetic right ventricle and a collapsed left ventricle. The tentative diagnosis was pulmonary embolism, but she remained hemodynamically unstable despite thrombolysis. 90 min after the collapse she was put on cardiopulmonary bypass and surgical embolectomy was performed. Large masses of thrombotic material were collected from central parts of the right and left pulmonary artery. Therapeutic hypothermia was applied for 24 hours postoperatively. The remaining hospital stay was uneventful and ten days after the presentation she was transferred to her local hospital. At this point she was without neurological sequelae. The patient had used oral contraceptives (ethinyl estradiol/ drospirenone).

Both aerobic endurance and strength training programmes improve cardiovascular health in obese adults.

Regular exercise training is recognized as a powerful tool to improve work capacity, endothelial function and the cardiovascular risk profile in obesity, but it is unknown which of high-intensity aerobic exercise, moderate-intensity aerobic exercise or strength training is the optimal mode of exercise. In the present study, a total of 40 subjects were randomized to high-intensity interval aerobic training, continuous moderate-intensity aerobic training or maximal strength training programmes for 12 weeks, three times/week. The high-intensity group performed aerobic interval walking/running at 85-95% of maximal heart rate, whereas the moderate-intensity group exercised continuously at 60-70% of maximal heart rate; protocols were isocaloric. The strength training group performed 'high-intensity' leg press, abdominal and back strength training. Maximal oxygen uptake and endothelial function improved in all groups; the greatest improvement was observed after high-intensity training, and an equal improvement was observed after moderate-intensity aerobic training and strength training. High-intensity aerobic training and strength training were associated with increased PGC-1alpha (peroxisome-proliferator-activated receptor gamma co-activator 1alpha) levels and improved Ca(2+) transport in the skeletal muscle, whereas only strength training improved antioxidant status. Both strength training and moderate-intensity aerobic training decreased oxidized LDL (low-density lipoprotein) levels. Only aerobic training decreased body weight and diastolic blood pressure. In conclusion, high-intensity aerobic interval training was better than moderate-intensity aerobic training in improving aerobic work capacity and endothelial function. An important contribution towards improved aerobic work capacity, endothelial function and cardiovascular health originates from strength training, which may serve as a substitute when whole-body aerobic exercise is contra-indicated or difficult to perform.

Superior cardiovascular effect of aerobic interval training versus moderate continuous training in heart failure patients: a randomized study.

BACKGROUND: Exercise training reduces the symptoms of chronic heart failure. Which exercise intensity yields maximal beneficial adaptations is controversial. Furthermore, the incidence of chronic heart failure increases with advanced age; it has been reported that 88% and 49% of patients with a first diagnosis of chronic heart failure are >65 and >80 years old, respectively. Despite this, most previous studies have excluded patients with an age >70 years. Our objective was to compare training programs with moderate versus high exercise intensity with regard to variables associated with cardiovascular function and prognosis in patients with postinfarction heart failure. METHODS AND RESULTS: Twenty-seven patients with stable postinfarction heart failure who were undergoing optimal medical treatment, including beta-blockers and angiotensin-converting enzyme inhibitors (aged 75.5+/-11.1 years; left ventricular [LV] ejection fraction 29%; VO2peak 13 mL x kg(-1) x min(-1)) were randomized to either moderate continuous training (70% of highest measured heart rate, ie, peak heart rate) or aerobic interval training (95% of peak heart rate) 3 times per week for 12 weeks or to a control group that received standard advice regarding physical activity. VO2peak increased more with aerobic interval training than moderate continuous training (46% versus 14%, P<0.001) and was associated with reverse LV remodeling. LV end-diastolic and end-systolic volumes declined with aerobic interval training only, by 18% and 25%, respectively; LV ejection fraction increased 35%, and pro-brain natriuretic peptide decreased 40%. Improvement in brachial artery flow-mediated dilation (endothelial function) was greater with aerobic interval training, and mitochondrial function in lateral vastus muscle increased with aerobic interval training only. The MacNew global score for quality of life in cardiovascular disease increased in both exercise groups. No changes occurred in the control group. CONCLUSIONS: Exercise intensity was an important factor for reversing LV remodeling and improving aerobic capacity, endothelial function, and quality of life in patients with postinfarction heart failure. These findings may have important implications for exercise training in rehabilitation programs and future studies.

Long-term serotonin effects in the rat are prevented by terguride.

Long-term hyperserotoninemia induces heart valve disease in rats, and cases of cardiac valvulopathies have been reported in patients using ergolines, possibly through activation of the 5-hydroxytryptamine(2B) (5HT(2B)) receptor. The ergoline terguride (transdihydrolisuride) is a 5HT(2B/2C) receptor antagonist. Using a rat model, we have investigated whether terguride could prevent serotonin-induced changes in general and heart disease specifically. During 4 months, twelve Sprague-Dawley rats were given daily subcutaneous serotonin injections; twelve rats received a combination of serotonin injections and terguride by gavage, whereas ten rats were untreated controls. Using echocardiography, rats with aortic insufficiency were found in all 3 groups, while pulmonary insufficiency was only found in two rats injected with serotonin alone. Animals given serotonin alone had significantly higher heart weights compared to the controls (p=0.029) and rats given terguride (p=0.034). Rats injected with serotonin alone developed macroscopic skin changes at the injection sites, histologically identified as orthokeratosis and acanthosis. Terguride completely prevented these changes (p=0.0001, p=0.0003). Liver weights were higher in the animals given serotonin alone compared to controls (p=0.014) and terguride treated animals (p=0.009). Stomach weights were higher in animals given serotonin alone compared to rats given terguride (p=0.012). In the mesenchymal cell-line MC3T3-E1, terguride almost completely inhibited serotonin-induced proliferation (p<0.01). Serotonin increases heart, liver and stomach weights, possibly through enhanced proliferation. Terguride inhibits these effects. We propose that terguride may have beneficial effects in the treatment of diseases such as carcinoid syndrome, where serotonin plays an important pathogenic role.

Moderate vs. high exercise intensity: differential effects on aerobic fitness, cardiomyocyte contractility, and endothelial function.

OBJECTIVE: Current guidelines are controversial regarding exercise intensity in cardiovascular prevention and rehabilitation. Although high-intensity training induces larger increases in fitness and maximal oxygen uptake (VO(2max)), moderate intensity is often recommended as equally effective. Controlled preclinical studies and randomized clinical trials are required to determine whether regular exercise at moderate versus high intensity is more beneficial. We therefore assessed relative effectiveness of 10-week HIGH versus moderate (MOD) exercise intensity on integrative and cellular functions. METHODS: Sprague-Dawley rats performed treadmill running intervals at either 85%-90% (HIGH) or 65%-70% (MOD) of VO2max 1 h per day, 5 days per week. Weekly VO2max-testing adjusted exercise intensity. RESULTS: HIGH and MOD increased VO2max by 71% and 28%, respectively. This was paralleled by intensity-dependent cardiomyocyte hypertrophy, 14% and 5% in HIGH and MOD, respectively. Cardiomyocyte function (fractional shortening) increased by 45% and 23%, contraction rate decreased by 43% and 39%, and relaxation rate decreased by 20% and 10%, in HIGH and MOD, respectively. Ca2+ transient time-courses paralleled contraction/relaxation, whereas Ca2+ sensitivity increased 40% and 30% in HIGH and MOD, respectively. Carotid artery endothelial function improved similarly with both intensities. EC50 for acetylcholine-induced relaxation decreased 4.3-fold in HIGH (p < 0.05) and 2.8-fold in MOD (p < 0.20) as compared to sedentary; difference HIGH versus MOD 1.5-fold (p = 0.72). Multiple regression identified rate of systolic Ca2+ increase and diastolic myocyte relengthening as main variables associated with VO2max. Cell hypertrophy, contractility and vasorelaxation also correlated significantly with VO2max. CONCLUSIONS: The present study demonstrates that cardiovascular adaptations to training are intensity-dependent. A close correlation between VO2max, cardiomyocyte dimensions and contractile capacity suggests significantly higher benefit with high intensity, whereas endothelial function appears equivalent at moderate levels. Thus, exercise intensity emerges as an important variable in future preclinical and clinical investigations.

Long-term serotonin administration induces heart valve disease in rats.

BACKGROUND: The purpose of this study was to investigate whether rats dosed with serotonin develop changes similar to those seen in human carcinoid heart disease. METHODS AND RESULTS: Ten Sprague-Dawley rats were given serotonin injections subcutaneously once daily for 3 months; controls were given saline. A long-lasting hyperserotoninemia with a >10-fold increase in both platelet-poor plasma and dialysate from the femoral muscles appeared. The animals developed clinical signs such as flushing and loose stools. After 3 months, 6 of 10 rats given serotonin had pathological echocardiographs. Two animals had a combination of aortic and pulmonary valve insufficiency, 1 had isolated aortic valve insufficiency, and 3 had isolated pulmonary valve insufficiency. Histopathological examination revealed shortened and thickened aortic cusps and carcinoidlike plaques characterized by a collection of myofibroblasts within an extracellular matrix of collagen ground substance. Immunostaining for Ki-67 demonstrated an increased number of proliferating subendocardial cells. In the control group, no pathological changes were seen. With the use of reverse-transcription polymerase chain reaction, normal rat aortic cusps were shown to express mRNA for serotonin receptors 5-HT1A, 5-HT2A, and 5-HT2B and the serotonin transporter 5-HTT. CONCLUSIONS: For the first time, long-term serotonin administration was performed in rats. Morphological and echocardiographic changes similar to those seen in human carcinoid heart disease developed. This study demonstrates that serotonin most likely is involved in the pathogenesis of carcinoid heart disease.

Intensity-controlled treadmill running in mice: cardiac and skeletal muscle hypertrophy.

Whereas novel pathways of pathological heart enlargement have been unveiled by thoracic aorta constriction in genetically modified mice, the molecular mechanisms of adaptive cardiac hypertrophy remain virtually unexplored and call for an effective and well-characterized model of physiological mechanical loading. Experimental procedures of maximal oxygen consumption (VO(2 max)) and intensity-controlled treadmill running were established in 40 female and 36 male C57BL/6J mice. An inclination-dependent VO(2 max) with 0.98 test-retest correlation was found at 25 degrees treadmill grade. Running for 2 h/day, 5 days/wk, in intervals of 8 min at 85-90% of VO(2 max) and 2 min at 50% (adjusted to weekly VO(2 max) testing) increased VO(2 max) to a plateau 49% above sedentary females and 29% in males. Running economy improved in both sexes, and echocardiography indicated significantly increased left ventricle posterior wall thickness. Ventricular weights increased by 19-29 and 12-17% in females and males, respectively, whereas cardiomyocyte dimensions increased by 20-32, and 17-23% in females and males, respectively; skeletal muscle mass increased by 12-18%. Thus the model mimics human responses to exercise and can be used in future studies of molecular mechanisms underlying these adaptations.

Aerobic exercise reduces cardiomyocyte hypertrophy and increases contractility, Ca2+ sensitivity and SERCA-2 in rat after myocardial infarction.

OBJECTIVE: Although it is generally accepted that endurance training improves cardiac function after myocardial infarction the sub-cellular mechanisms are uncertain. The present study reports the effects of aerobic endurance training on myocardial mass, myocyte dimensions, contractile function, Ca2+ handling, and myofilament responsiveness to Ca2+ in cardiomyocytes from healthy and failing rat hearts. METHODS: Adult female Sprague-Dawley rats ran on a treadmill 1.5 h/day, 5 days a week for 8 weeks. Exercise intervals alternated between 8 min at 85-90% of V(O(2max)) and 2 min at 50-60%. Training started 4 weeks after ligation of the left coronary artery (TR-INF, n=11) or sham operation (TR-SHAM, n=6). Sedentary animals (SED-SHAM, n=6; SED-INF, n=13) were controls. RESULTS: After 6 weeks V(O(2max)) in TR-INF and TR-SHAM leveled off 65% above sedentary controls. In TR-SHAM, left and right ventricle weights were approximately 25% higher than in SED-SHAM, myocytes were approximately 13% longer; width remained unchanged. At physiological stimulation frequencies, relative myocyte shortening was markedly higher whereas peak systolic [Ca2+] and t(1/2) of Ca2+ transient decay were 10-20% lower, indicating higher Ca2+ sensitivity in cardiomyocytes from trained rats, compared to respective controls. In TR-INF the left and right ventricular weights, and myocyte length and width were 15, 23, 12, and 20% less than in SED-INF. Endurance training significantly increased the myocardial SR Ca2+ pump (SERCA-2) and sarcolemmal Na+-Ca2+-exchanger (NCX) protein levels to the extent that TR-INF did not differ from SED-SHAM. CONCLUSION: This is the first study to show that aerobic endurance training attenuates the ventricular and cellular hypertrophy in failing hearts. Furthermore, training consistently restores contractile function, intracellular Ca2+ handling, and Ca2+-sensitivity in cardiomyocytes from rats with myocardial infarction.