Jan P. Loennechen

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 &bgr;-blockers and angiotensin-converting enzyme inhibitors (aged 75.5±11.1 years; left ventricular [LV] ejection fraction 29%; &OV0312;o2peak 13 mL · kg−1 · 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. &OV0312;o2peak 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 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.

Increased contractility and calcium sensitivity in cardiac myocytes isolated from endurance trained rats

OBJECTIVE Regular exercise enhances cardiac function and modulates myocyte growth in healthy individuals. The purpose of the present study was to assess contractile function and expression of selected genes associated with intracellular Ca2+ regulation after intensity controlled aerobic endurance training in the rat. METHODS Female Sprague-Dawley rats were randomly assigned to sedentary control (SED) or treadmill running (TR) 2 h per day, 5 days per week for 2, 4 or 13 weeks. Rats ran 8-min intervals at 85-90% of VO2max separated by 2 min at 50-60%. Myocyte length, intracellular Ca2+ (Fura-2), and intracellular pH (BCECF) were measured in dissociated cells in response to electrical stimulation at a range of stimulation rates. RESULTS The increase in VO2max plateaued after 6-8 weeks, 60% above SED. After 13 weeks, left and right ventricular weights were 39 and 36% higher than in SED. Left ventricular myocytes were 13% longer, whereas width remained unchanged. After 4 weeks training, myocyte contractility was approximately 20% higher in TR. Peak systolic intracellular Ca2+ and time for the decay from systole were 20-35 and 12-17% lower, respectively. These results suggest that increased myofilament Ca2+ sensitivity is the dominant effect responsible for enhanced myocyte contractility in TR. Intracellular pH progressively decreased as stimulation frequency was increased in the SED group. This decrease was markedly attenuated in TR and the intracellular pH was significantly higher in the TR group at a stimulation rate of 5-10 Hz. This effect may contribute to the increased contractility observed at the higher stimulation frequencies in TR. A higher intrinsic myofilament Ca2+ sensitivity was observed in permeabilised myocytes from the TR group under conditions of constant pH and [Ca2+]. Western blot analysis indicated 21 and 46% higher myocardial SERCA-2 and phospholamban, but unaltered Na+/Ca(2+)-exchanger levels. Competitive RT-PCR revealed that TR significantly increased Na+/H(+)-exchanger mRNA. CONCLUSION Intensity controlled interval training increases cardiomyocyte contractility. Higher myofilament Ca(2+)-sensitivity, and enhanced Ca(2+)-handling and pH-regulation are putative mechanisms. Our results suggest that physical exercise induces adaptive hypertrophy in cardiac myocytes with improved contractile function.

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.

Mechanical Dispersion Assessed by Myocardial Strain in Patients After Myocardial Infarction for Risk Prediction of Ventricular Arrhythmia

OBJECTIVES The aim of this study was to investigate whether myocardial strain echocardiography can predict ventricular arrhythmias in patients after myocardial infarction (MI). BACKGROUND Left ventricular (LV) ejection fraction (EF) is insufficient for selecting patients for implantable cardioverter-defibrillator (ICD) therapy after MI. Electrical dispersion in infarcted myocardium facilitates malignant arrhythmia. Myocardial strain by echocardiography can quantify detailed regional and global myocardial function and timing. We hypothesized that electrical abnormalities in patients after MI will lead to LV mechanical dispersion, which can be measured as regional heterogeneity of contraction by myocardial strain. METHODS We prospectively included 85 post-MI patients, 44 meeting primary and 41 meeting secondary ICD prevention criteria. After 2.3 years (range 0.6 to 5.5 years) of follow-up, 47 patients had no and 38 patients had 1 or more recorded arrhythmias requiring appropriate ICD therapy. Longitudinal strain was measured by speckle tracking echocardiography. The SD of time to maximum myocardial shortening in a 16-segment LV model was calculated as a parameter of mechanical dispersion. Global strain was calculated as average strain in a 16-segment LV model. RESULTS The EF did not differ between ICD patients with and without arrhythmias occurring during follow-up (34 +/- 11% vs. 35 +/- 9%, p = 0.70). Mechanical dispersion was greater in ICD patients with recorded ventricular arrhythmias compared with those without (85 +/- 29 ms vs. 56 +/- 13 ms, p < 0.001). By Cox regression, mechanical dispersion was a strong and independent predictor of arrhythmias requiring ICD therapy (hazard ratio: 1.25 per 10-ms increase, 95% confidence interval: 1.1 to 1.4, p < 0.001). In patients with an EF >35%, global strain showed better LV function in those without recorded arrhythmias (-14.0% +/- 4.0% vs. -12.0 +/- 3.0%, p = 0.05), whereas the EF did not differ (44 +/- 8% vs. 41 +/- 5%, p = 0.23). CONCLUSIONS Mechanical dispersion was more pronounced in post-MI patients with recurrent arrhythmias. Global strain was a marker of arrhythmias in post-MI patients with relatively preserved ventricular function. These novel parameters assessed by myocardial strain may add important information about susceptibility for ventricular arrhythmias after MI.

High prevalence of exercise-induced arrhythmias in catecholaminergic polymorphic ventricular tachycardia mutation-positive family members diagnosed by cascade genetic screening

AIM Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited cardiac disease predisposing to life-threatening arrhythmias. We aimed to determine the prevalence of arrhythmias and efficacy of beta-blocker treatment in mutation-positive family members diagnosed by cascade genetic screening. METHODS AND RESULTS Relatives of six unrelated CPVT patients were tested for the relevant mutation in the ryanodine receptor-2 gene. Mutation carriers underwent an exercise test at inclusion time and 3 months after the initiation of beta-blocker therapy in the highest tolerable dose. The occurrence of ventricular premature beats, couplets, and non-sustained ventricular arrhythmias (nsVT) were recorded in addition to the heart rate at which they occurred. Thirty family members were mutation carriers and were followed for 22 (13-288) months. Previous undiagnosed CPVT-related symptoms were reported by eight subjects. Exercise test induced ventricular arrhythmias in 23 of the 30 mutation carriers. On beta-blocker treatment, exercise-induced arrhythmias occurred at a lower heart rate (117 +/- 17 vs. 135 +/- 34 beats/min, P = 0.02) but at similar workload (P = 0.78). Beta-blocker treatment suppressed the occurrence of exercise-induced nsVT in three of the four patients, while less severe arrhythmias were unchanged. One patient died during follow-up. CONCLUSION Exercise test revealed a high prevalence of arrhythmias in CPVT mutation carriers diagnosed by cascade genetic screening. beta-Blocker therapy appeared to suppress the most severe exercise-induced arrhythmias, while less severe arrhythmias occurred at a lower heart rate.

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.

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.

Pathological and physiological hypertrophies are regulated by distinct gene programs.

Background This study aims to investigate changes that occur during progression and establishment of physiological and pathological cardiac hypertrophy, by microarray technology and functional annotations. Design and methods Myocardial infarction leading to heart failure was induced in rats, with animals killed 1, 3, 7, 14, 42, and 92 days after coronary artery ligation. A second group was subjected to daily treadmill exercise and killed 1, 4, 24, and 48h after a single exercise bout, or after 28 or 56 days of exercise training. Results Physiological hypertrophy was associated with less transcriptional alternation than pathological hypertrophy, indicating that posttranscriptional and translational regulation may be more important. The main difference between the two types of hypertrophy was that myocardial infarction was associated with downregulation of genes related to fatty acid metabolism, whereas no such change occurred after exercise training. Thus, fatty acid metabolism may distinguish adverse maladaptive hypertrophy from beneficial adaptive hypertrophy. Conclusion This study points to specific genes and gene classes related to biological processes that may be important in these well-characterized rat models of physiological and pathological cardiac hypertrophy.

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.