Exercise Reveals Proline Dehydrogenase as a Potential Target in Heart Failure.

The benefits of physical activity in cardiovascular diseases have long been appreciated. However, the molecular mechanisms that trigger and sustain the cardiac benefits of exercise are poorly understood, and it is anticipated that unveiling these mechanisms will identify novel therapeutic targets. In search of these mechanisms we took advantage of unbiased RNA-sequencing (RNA-seq) technology to discover cardiac gene targets whose expression is disrupted in heart failure (HF) and rescued by exercise in a rat model. Upon exhaustive validation in a separate rat cohort (qPCR) and human datasets, we shortlisted 16 targets for a cell-based screening, aiming to evaluate whether targeted disruption of these genes with silencing RNA would affect the abundance of a CVD biomarker (BNP, B-type natriuretic peptide) in human cardiomyocytes. Overall, these experiments showed that Proline Dehydrogenase (PRODH) expression is reduced in human failing hearts, rescued by exercise in a rat model of HF, and its targeted knockdown increases BNP expression in human cardiomyocytes. On the other hand, overexpression of PRODH increases the abundance of metabolism-related gene transcripts, and PRODH appears to be crucial to sustain normal mitochondrial function and maintenance of ATP levels in human cardiomyocytes in a hypoxic environment, as well as for redox homeostasis in both normoxic and hypoxic conditions. Altogether our findings show that PRODH is a novel molecular target of exercise in failing hearts and highlight its role in cardiomyocyte physiology, thereby proposing PRODH as a potential experimental target for gene therapy in HF.

Role of KATP Channels in Beneficial Effects of Exercise in Ischemic Heart Failure.

PURPOSE: Exercise training reduces pathological remodeling and improves cardiac function in ischemic heart failure; however, causal mechanisms underlying the cardiac benefits of exercise are poorly understood. Because opening of adenosine triphosphate (ATP)-sensitive K ⁺(KATP) channels protects the heart during myocardial stress, we hypothesized that such a mechanism is responsible for some of the cardiac benefits induced by exercise in postinfarction chronic heart failure (CHF). METHODS: Left ventricular myocytes were isolated from three groups of rats: Sham, CHF Tr (4 wk after myocardial infarction, rats underwent 8 wk of aerobic interval training 5 d·wk⁻¹) and CHF Sed (rats sedentary for 12 wk after infarction). Cardiomyocyte survival after oxidative stress exposure (200 µM H2O2) and calcium handling (cells loaded with Fura-2 AM and electrically paced at 1 Hz) were assessed in the presence of KATP channel inhibitor glibenclamide. Expression of KATP subunits (SUR2A and Kir6.2) was evaluated using immunoblotting. RESULTS: Exercise improved cardiac function in CHF Tr animals. Cardiomyocytes from CHF Sed rats were more susceptible to oxidative stress-induced cell death than CHF Tr and Sham cardiomyocytes, with glibenclamide completely abolishing the protective effect of exercise. Glibenclamide did not affect cardiomyocyte survival in Sham or CHF Sed rats. In addition, exercise increased the systolic Ca²âº transient amplitude and improved diastolic Ca²âº removal in CHF Tr cardiomyocytes (compared with CHF Sed); both were significantly attenuated by glibenclamide. Exercise resulted in increased expression of KATP channel subunits in CHF Tr hearts, with more pronounced and significant effect on SUR2A. CONCLUSIONS: Our data suggest that KATP channel upregulation induced by chronic exercise likely mediates some of exercise-induced beneficial effects on cardiac function in postischemic heart failure.

Aerobic interval training attenuates remodelling and mitochondrial dysfunction in the post-infarction failing rat heart.

AIMS: Following a large myocardial infarction (MI), remaining viable muscle often undergoes pathological remodelling and progresses towards chronic heart failure. Mitochondria may also be affected by this process and, due to their functional importance, likely contribute to the progression of the disease. Aerobic interval training (AIT) has been shown effective in diminishing pathological myocardial transformation, but the effects of AIT on mitochondrial function in hearts undergoing remodelling are not known. METHODS AND RESULTS: Adult female Sprague-Dawley rats were randomized to either 8 weeks of aerobic interval treadmill running (5 days/week), which started 4 weeks after left coronary artery ligation (MI-Trained), or a sedentary group (MI-Sedentary). Echocardiography was performed before and after the 8-week period, at which point the left ventricles (LVs) were also harvested. Twelve weeks after surgery, MI-Sedentary rats had significantly lower LV fractional shortening compared with MI-Trained rats. Complex I-dependent respiration assessed in isolated LV mitochondria was decreased by ∼37% in MI-Sedentary and 17% in MI-Trained animals (group differences P < 0.05), compared with sham-operated animals. This was paralleled with diminished ATP production and increased degree of protein oxidation in MI-Sedentary rats. The enzymatic activity of complex I was also decreased to a greater extent in MI-Sedentary than in MI-Trained animals, with no evidence of its reduced expression. When complex II substrate was used, no differences among the three groups were observed. CONCLUSION: Exercise reduces LV contractile deterioration in post-infarction heart failure and alleviates the extent of mitochondrial dysfunction, which is paralleled with preserved complex I activity.

The influence of varying inspired fractions of O2 and CO2 on the development of involuntary breathing movements during maximal apnoea.

The growing urge to breathe that occurs during breath-holding results in development of involuntary breathing movements (IBMs). The present study determined whether IBMs are initiated at critical levels of hypercapnia and/or hypoxia during maximal apnoea. Arterial blood gasses at the onset of IBM were monitored during maximal voluntary breath-holds. Eleven healthy men performed breath holds after breathing air, hyperoxic-normocapnia, hypoxic-normocapnia, and normoxic-hypercapnia. Pre-breathing of the gas mixtures facilitated the IBM onset, reducing the time-to-onset for ∼46% (hyperoxic condition) and for ∼80% (hypoxic condition) compared to the normoxic air breathing time. A strong correlation (R=0.83, P=0.002) between arterial partial pressure of CO2 (PaCO2) at IBM onset after pre-breathing hyperoxic and hypercapnic gas mixtures was observed, suggesting the existence of a possible IBM PaCO2 threshold level of ∼6.5 ± 0.5 kPa. No clear "threshold" was observed for partial pressure of arterial O2(PaO2). However, we observed that IBM onset was influenced, in part, by an interaction between PaO2 and PaCO2 levels during maximal apnoea. This study demonstrated the complex interaction between arterial blood-gases and the physiological response to maximal breath holding.

First Croatian transvaginal laparoscopically assisted cholecystectomies.

BACKGROUND/AIMS: The aim of this study was to determine the feasibility and technical aspects of a new endoluminal surgical procedure: transvaginal laparoscopically assisted endoscopic cholecystectomy. METHODOLOGY: Three female patients underwent transvaginal laparoscopically assisted endoscopic cholecystectomy (aged 40, 61 and 33 years). Pneumoperitoneum was created through a 5mm supraumbilical incision. Through the posterior fornix of the vagina the second 10mm trocar, laparoscope and 5mm laparoscopic grasper were introduced. The gallbladder was dissected using standard 5mm laparoscopic grasper, hook, electrocoagulation and harmonic shears introduced supraumbilically. The dissected gallbladder was removed in a specimen retrieval bag. RESULTS: Transvaginal laparoscopically assisted endoscopic cholecystectomy was feasible in all patients. No intraoperative or postoperative complications were observed and there was no need for extra-umbilical skin incisions. Total operative time ranged between 60 and 75 minutes. Median length of hospital stay was 1 day. CONCLUSIONS: This was the first clinical application of transvaginal laparoscopically assisted cholecystectomy in Croatia. The initial clinical application of this technique in 3 female patients was feasible, effective and safe when performed by experienced laparoscopic surgeons using standard laparoscopic instruments.

Cardiovascular changes during underwater static and dynamic breath-hold dives in trained divers.

Limited information exists concerning arterial blood pressure (BP) changes in underwater breath-hold diving. Simulated chamber dives to 50 m of freshwater (mfw) reported very high levels of invasive BP in two divers during static apnea (SA), whereas a recent study using a noninvasive subaquatic sphygmomanometer reported unchanged or mildly increased values at 10 m SA dive. In this study we investigated underwater BP changes during not only SA but, for the first time, dynamic apnea (DA) and shortened (SHT) DA in 16 trained breath-hold divers. Measurements included BP (subaquatic sphygmomanometer), ECG, and pulse oxymetry (arterial oxygen saturation, SpO2, and heart rate). BP was measured during dry conditions, at surface fully immersed (SA), and at 2 mfw (DA and SHT DA), whereas ECG and pulse oxymetry were measured continuously. We have found significantly higher mean arterial pressure (MAP) values in SA (∼40%) vs. SHT DA (∼30%). Postapneic recovery of BP was slightly slower after SHT DA. Significantly higher BP gain (mmHg/duration of apnea in s) was found in SHT DA vs. SA. Furthermore, DA attempts resulted in faster desaturation vs. SA. In conclusion, we have found moderate increases in BP during SA, DA, and SHT DA. These cardiovascular changes during immersed SA and DA are in agreement with those reported for dry SA and DA.

Laparoscopic transabdominal preperitoneal approach for inguinal hernia repair: a five-year experience at a single center.

PURPOSE: Laparoscopic hernia repair has emerged as an effective alternative method for treating inguinal hernias. It has several significant advantages over the tension-free open repair now in use. In this report we summarize our laparoscopic hernia repair results and recommendations. METHODS: The transabdominal preperitoneal (TAPP) procedures for groin hernias performed between January 2003 and January 2008 at a single center were analyzed retrospectively. Individual surgeon performances were compared to determine whether the rates of complications were related to the level of surgeon experience. RESULTS: A total of 312 TAPP procedures were reviewed, and 284 (91%) of the patients were followed retrospectively. There were 266 (85.25%) males and 46 (14.75%) females. The average age was 57.4 years. The mean length of hospital stay was 2.1 days. The mean duration of surgery was 35 min. Six (1.92%) intraoperative and seven (2.24%) postoperative complications were noted. Two recurrences occurred (0.70%). CONCLUSIONS: Laparoscopic TAPP hernia repair has proven to be an efficient method for the treatment of groin hernias at our institution. Most patients can be treated as day-cases, namely they are hospitalized for 1 day, and they demonstrate a low recurrence rate (0.70%). Such low morbidity makes TAPP an attractive method for the routine treatment of groin hernias.

Laparoscopic cholecystectomy in Cantonal Hospital Livno, Bosnia and Herzegovina and University Hospital Center Split, Croatia.

Cholecystectomy is the most frequently performed operation in abdominal surgery. The aim of this study was to compare the operative procedure and outcomes of the laparoscopic cholecystectomy in two hospitals, the University Hospital Center Split and the Regional Hospital in Livno. A total of 97 patients who underwent laparoscopic cholecystectomy for cholelithiasis at University Hospital Center Split and 86 patients from Regional Hospital in Livno, both groups sampled in 2005 were included in this study. Differences in patients' age, gender, operation time, total hospital stay, number of trocarsi ports, antibiotic and parenteral therapy, and complications were analyzed. There were significantly fewer men than women who underwent laparoscopic cholecystectomy in both hospitals. The mean age of the patients undergoing laparoscopic cholecystectomy at University Hospital Center Split was higher than that of the patients at Regional Hospital in Livno. The operation time was shorter at the University Hospital Center Split than that at Regional Hospital in Livno. There was a significant difference, in favor of the University Hospital Center Split, in the number of patients who received postoperative antibiotics and parenteral therapy, with fewer patients who received postoperative therapy in Split. At the Regional Hospital in Livno fewer trocars were used for laparoscopic cholecystectomy. The average hospital stay of patients undergoing laparoscopic procedures at University Hospital Center Split was shorter than that of patients at Regional Hospital in Livno. Two complications occurred in postoperative period at the University Hospital Center Split and one complication was noticed in hospital in Livno. In conclusion, there were no major complications in postoperative period. It is also encouraging to find that there was significant improvement of surgical approach and technique at the hospital in Livno during the period of time analyzed in this study.