Muscle function and running activity in mouse models of hereditary muscle dystrophy: impact of double knockout for dystrophin and the transcription factor MyoD.

INTRODUCTION: Mice that lack both the transcription factor MyoD and dystrophin display a more pronounced myopathic phenotype when compared with mdx mice. No data on skeletal muscle function and the impact of exercise training are available. METHODS: Six-month-old wild-type, mdx, myoD(-/-), mdx:myoD(+/-), and mdx:myoD(-/-) mice were randomly assigned to either 4 weeks of voluntary running or sedentary behavior. The mdx:myoD(-/-) mice were not able to exercise at all and were kept sedentary. RESULTS: The soleus muscle of sedentary 7-month-old mdx:myoD(-/-) mice showed a significantly lower force development compared with all other mice. Voluntary running beginning at the age of 6 months led to lower force development of soleus muscle in the mdx animals. CONCLUSIONS: mdx:myoD(-/-) is not a suitable model to study exercise-induced effects on dystrophic muscles. Voluntary exercise in adult mdx mice seems to have detrimental effects on the function of soleus muscle.

Pulse Wave Velocity Predicts Response to Renal Denervation in Isolated Systolic Hypertension.

BACKGROUND: Renal sympathetic denervation seems to be less effective as a treatment for hypertension in patients with isolated systolic hypertension, a condition associated with elevated central arterial stiffness. Because isolated systolic hypertension can also be caused by wave reflection or increased cardiac output, a more differentiated approach might improve patient preselection for renal sympathetic denervation. We sought to evaluate the additional predictive value of invasive pulse wave velocity for response to renal sympathetic denervation in patients with combined versus isolated systolic hypertension. METHODS AND RESULTS: Patients scheduled for renal sympathetic denervation underwent additional invasive measurement of pulse wave velocity and pulse pressure before denervation. Blood pressure was assessed via ambulatory measurement at baseline and after 3 months. In total 109 patients (40 patients with isolated systolic hypertension) were included in our analysis. After 3 months, blood pressure reduction was more pronounced among patients with combined hypertension compared with patients with isolated systolic hypertension (systolic 24-hour average 9.3±10.5 versus 5.0±11.5 mm Hg, P=0.046). However, when stratifying patients with isolated systolic hypertension by invasive pulse wave velocity, patients in the lowest tertile of pulse wave velocity had comparable blood pressure reduction (12.1±12.6 mm Hg, P=0.006) despite lower baseline blood pressure than patients with combined hypertension (systolic 24-hour average 154.8±12.5 mm Hg in combined hypertension versus 141.2±8.1, 148.4±10.9, and 150.5±12.7 mm Hg, respectively, by tertiles of pulse wave velocity, P=0.002). CONCLUSIONS: Extended assessment of arterial stiffness can help improve patient preselection for renal sympathetic denervation and identify a subgroup of isolated systolic hypertension patients who benefit from sympathetic modulation.

Endovascular ultrasound for renal sympathetic denervation in patients with therapy-resistant hypertension not responding to radiofrequency renal sympathetic denervation.

AIMS: Recent studies have reported a considerable number of non-responders after renal sympathetic de-nervation (RSD) with radiofrequency technology. Here we report our results of repeat RSD using ultrasound in these patients. METHODS AND RESULTS: A cohort study was performed in patients who underwent ultrasound RSD after non-response to RSD with radiofrequency. Non-response was defined as mean daytime systolic blood pressure ≥140 mmHg and/or a reduction of ≤10 mmHg in ambulatory blood pressure measurement (ABPM) ≥6 months after radiofrequency denervation. ABPM was recorded at baseline, post radiofrequency RSD as well as at three and six months post ultrasound RSD. A total of 24 non-responders underwent retreatment with the ultrasound device at a mean 15.3±8.2 months after radiofrequency RSD. Ultrasound RSD was performed successfully in all patients without severe adverse events. Mean daytime systolic blood pressure changed from 161.7±14.6 mmHg at baseline to 158.5±9.5 mmHg post radiofrequency RSD and to 150.5±10.4 mmHg and 151.6±11.0 mmHg at three and six months, respectively, post ultrasound RSD (p<0.01 with repeated measures analysis of variance). The main results of post hoc testing were as follows: baseline versus post radiofrequency RSD, p=0.83; baseline versus three months post ultrasound RSD, p=0.01; and baseline versus six months post ultrasound RSD, p=0.04. CONCLUSIONS: Ultrasound RSD appears to be safe and an effective therapeutic approach in patients not responding to previous RSD with radiofrequency technology.

Minimally invasive aortic valve replacement: the Leipzig experience.

BACKGROUND: Minimally invasive techniques are progressively challenging traditional approaches in cardiothoracic surgery. Minimally invasive aortic valve replacement (AVR) has become a routine procedure at our institution. METHODS: We retrospectively analyzed all patients undergoing minimally invasive isolated AVR between January 2003 and March 2014, at our institution. Mean follow-up was 4.7±4.3 years (range: 0-18 years) and was 99.8% complete. RESULTS: There were 1,714 patients who received an isolated minimally invasive AVR. The mean (± SD) patient age was 65±12.8 years, ejection fraction 60%±12% and log EuroSCORE 5.3%±5.1%. Mean cross-clamp time was 58±18 minutes and mean cardiopulmonary bypass (CPB) time was 82.9±26.7 minutes. Thirty-day survival was 97.8%±0.4%, and 69.4%±1.7% at 10-years. The multivariate analysis revealed age at surgery [P=0.016; odds ratio (OR), 1.1], length of surgery time (P=0.002; OR, 1.01), female gender (P=0.023; OR, 3.54), preoperative myocardial infarction (MI) (P=0.006; OR, 7.87), preoperative stroke (P=0.001; OR, 13.76) and preoperative liver failure (P=0.015; OR, 10.28) as independent risk factors for mortality. Cox-regression analysis revealed the following predictors for long term mortality: age over 75 years (P<0.001; OR, 3.5), preoperative dialysis (P<0.01; OR, 2.14), ejection fraction less than 30% (P=0.003; OR, 3.28) and urgent or emergency operation (P<0.001; OR, 2.3). CONCLUSIONS: Minimally invasive AVR can be performed safely and effectively with very few perioperative complications. The early and long-term outcomes in these patients are acceptable.

Childhood obesity: impact on cardiac geometry and function.

OBJECTIVES: The aim of our study was to assess geometric and functional changes of the heart in obese compared with nonobese children and adolescents. BACKGROUND: Obesity in children and adolescents has increased over the past decades and is considered a strong risk factor for future cardiovascular morbidity and mortality. Obesity has been associated with myocardial structural alterations that may influence cardiac mechanics. METHODS: We prospectively recruited 61 obese (13.5 ± 2.7 years of age, 46% male sex, SD score body mass index, 2.52 ± 0.60) and 40 nonobese (14.1 ± 2.8 years of age, 50% male sex, SD score body mass index, -0.33 ± 0.83) consecutive, nonselected Caucasian children and adolescents. A standardized 2-dimensional (2D) echocardiography and 2D speckle-tracking analysis was performed in all children. Furthermore, blood chemistry including lipid and glucose metabolism was assessed in all children. RESULTS: Compared with nonobese children, blood pressure, low-density lipoprotein cholesterol, and parameters of glucose metabolism were significantly increased in obese children, whereas high-density lipoprotein cholesterol was significantly lower. Compared with nonobese children, obese children were characterized by enlarged left- and right-sided cardiac chambers, thicker left ventricular walls, and, consequently, increased left ventricular mass. Despite a comparable left ventricular ejection fraction, decreased tissue Doppler-derived peak systolic velocity and regional basoseptal strain were found in obese children compared with nonobese children. Beyond that, 2D speckle tracking-derived longitudinal (-18.2 ± 2.0 vs. -20.5 ± 2.3, p < 0.001) and circumferential (-17.0 ± 2.7 vs. -19.5 ± 2.9, p < 0.001) strain of the left ventricle was reduced in obese children compared with nonobese children. Diastolic function was also impaired in obese compared with nonobese children. Both longitudinal strain and circumferential strain were independently associated with obesity. CONCLUSIONS: The results of this study demonstrate that childhood obesity is associated with significant changes in myocardial geometry and function, indicating an early onset of potentially unfavorable alterations in the myocardium.

Exercise training prevents TNF-α induced loss of force in the diaphragm of mice.

RATIONALE: Inflammatory cytokines like tumor necrosis factor alpha (TNF-α) are elevated in congestive heart failure and are known to induce the production of reactive oxygen species as well as to deteriorate respiratory muscle function. OBJECTIVES: Given the antioxidative effects of exercise training, the aim of the present study was to investigate if exercise training is capable of preventing a TNF-α induced loss of diaphragmatic force in mice and, if so, to elucidate the potential underlying mechanisms. METHODS: Prior to intraperitoneal injection of TNF-α or saline, C57Bl6 mice were assigned to four weeks of exercise training or sedentary behavior. Diaphragmatic force and power generation were determined in vitro. Expression/activity of radical scavenger enzymes, enzymes producing reactive oxygen species and marker of oxidative stress were measured in the diaphragm. MAIN RESULTS: In sedentary animals, TNF-α reduced specific force development by 42% concomitant with a 2.6-fold increase in the amount of carbonylated α-actin and creatine kinase. Furthermore, TNF-α led to an increased NAD(P)H oxidase activity in both sedentary and exercised mice whereas xanthine oxidase activity and intramitochondrial ROS production was only enhanced in sedentary animals by TNF-α. Exercise training prevented the TNF-α induced force reduction and led to an enhanced mRNA expression and activity of glutathione peroxidase. Carbonylation of proteins, in particular of α-actin and creatine kinase, was diminished by exercise training. CONCLUSION: TNF-α reduces the force development in the diaphragm of mice. This effect is almost abolished by exercise training. This may be a result of reduced carbonylation of proteins due to the antioxidative properties of exercise training.