Novel concept to guide systolic heart failure medication by repeated biomarker testing-results from TIME-CHF in context of predictive, preventive, and personalized medicine.

BACKGROUND: It is uncertain whether repeated measurements of a multi-target biomarker panel may help to personalize medical heart failure (HF) therapy to improve outcome in chronic HF. METHODS: This analysis included 499 patients from the Trial of Intensified versus standard Medical therapy in Elderly patients with Congestive Heart Failure (TIME-CHF), aged ≥ 60 years, LVEF ≤ 45%, and NYHA ≥ II, who had repeated clinical visits within 19 months follow-up. The interaction between repeated measurements of biomarkers and treatment effects of loop diuretics, spironolactone, ß-blockers, and renin-angiotensin system (RAS) inhibitors on risk of HF hospitalization or death was investigated in a hypothesis-generating analysis. Generalized estimating equation (GEE) models were used to account for the correlation between recurrences of events in a patient. RESULTS: One hundred patients (20%) had just one event (HF hospitalization or death) and 87 (17.4%) had at least two events. Loop diuretic up-titration had a beneficial effect for patients with high interleukin-6 (IL6) or high high-sensitivity C-reactive protein (hsCRP) (interaction, P = 0.013 and P = 0.001), whereas the opposite was the case with low hsCRP (interaction, P = 0.013). Higher dosage of loop diuretics was associated with poor outcome in patients with high blood urea nitrogen (BUN) or prealbumin (interaction, P = 0.006 and P = 0.001), but not in those with low levels of these biomarkers. Spironolactone up-titration was associated with lower risk of HF hospitalization or death in patients with high cystatin C (CysC) (interaction, P = 0.021). ß-Blockers up-titration might have a beneficial effect in patients with low soluble fms-like tyrosine kinase-1 (sFlt) (interaction, P = 0.021). No treatment biomarker interactions were found for RAS inhibition. CONCLUSION: The data of this post hoc analysis suggest that decision-making using repeated biomarker measurements may be very promising in bringing treatment of heart failure to a new level in the context of predictive, preventive, and personalized medicine. Clearly, prospective testing is needed before this novel concept can be adopted. CLINICAL TRIAL REGISTRATION: isrctn.org, identifier: ISRCTN43596477.

Dual-comb modelocked laser.

In this paper we present the first semiconductor disk laser (SDL) emitting simultaneously two collinearly overlapping cross-polarized gigahertz modelocked pulse trains with different pulse repetition rates. Using only a simple photo detector and a microwave spectrum analyzer directly down-converts the frequency comb difference from the optical to the microwave frequency domain. With this setup, the relative carrier-envelope-offset (CEO) frequency can be accessed directly without an f-to2f interferometer. A very compact design is obtained using the modelocked integrated external-cavity surface emitting laser (MIXSEL) which is part of the family of optically pumped SDLs and similar to a vertical external cavity surface emitting laser (VECSEL) but with both gain and saturable absorber integrated into the same semiconductor wafer (i.e. MIXSEL chip). We then simply added an additional intracavity birefringent crystal inside the linear straight cavity between the output coupler and the MIXSEL chip which splits the cavity beam into two collinear but spatially separated cross-polarized beams on the MIXSEL chip. This results in two modelocked collinear and fully overlapping cross-polarized output beams with adjustable pulse repetition frequencies with excellent noise performance. We stabilized both pulse repetition rates of the dual comb MIXSEL.

Novel extracellular matrix biomarkers as predictors of adverse outcome in chronic heart failure: association between biglycan and response to statin therapy in the CORONA trial.

BACKGROUND: The extracellular matrix (ECM) plays an important role in left ventricular remodeling and progression of heart failure (HF). Biglycan and mimecan are ECM proteins that are abundantly expressed in cardiac tissue but have not been evaluated as prognostic markers in HF. We investigated their interaction with statin treatment and association with adverse outcome in chronic HF. METHODS AND RESULTS: The association between serum levels of biglycan and mimecan and the primary end point (cardiovascular [CV] death, nonfatal myocardial infarction, nonfatal stroke), all-cause mortality, CV death, the composite of all-cause mortality/hospitalization for worsening of HF, and the coronary end point was evaluated in 1,390 patients >60 years of age with ischemic systolic HF in the Controlled Rosuvastatin Multinational Trial in HF (CORONA) population, randomly assigned to 10 mg rosuvastatin or placebo. Serum biglycan and mimecan added no prognostic information beyond conventional risk factors, including N-terminal pro-B-type natriuretic peptide. However, statin treatment improved all outcomes except CV death in patients with low biglycan levels (ie, lower tertile), even after full multivariable adjustment. CONCLUSIONS: Although circulating levels of mimecan and biglycan were of limited predictive value in patients with chronic HF, circulating biglycan could be a useful marker for targeting statin therapy in patients with HF.

Predictive value of endostatin in chronic heart failure patients with poor kidney function.

OBJECTIVES: Increased circulating endostatin levels have been demonstrated in progressive cardiovascular (CV) and renal disorders. We investigated the predictive value of endostatin in patients with chronic heart failure (HF) and the association between endostatin and renal function. METHODS: The interaction between serum endostatin, estimated glomerular filtration rate (eGFR) and predefined endpoints, including the primary endpoint (CV death, nonfatal myocardial infarction, nonfatal stroke; n = 397), all-cause mortality (n = 410), CV death (n = 335) or the coronary endpoint (n = 317), was evaluated in 1,390 patients >60 years of age with ischemic systolic HF in the Controlled Rosuvastatin Multinational Trial in HF (CORONA) population, who were randomly assigned to 10 mg rosuvastatin or placebo. RESULTS: In the population as a whole, endostatin added no predictive information after full multivariable adjustment including eGFR and N-terminal pro-brain natriuretic peptide. Serum endostatin was strongly correlated with eGFR (r = 0.59, p < 0.001). After full multivariable adjustment, an association between high serum endostatin and increased risk of all-cause mortality and decreased risk of the primary and coronary endpoints was seen in HF patients with impaired and preserved renal function, respectively. CONCLUSIONS: Endostatin added no predictive information regarding the adverse outcome in patients with chronic systolic HF of ischemic etiology. An increased risk of all-cause mortality was seen in patients with decreased renal function.

Gigahertz self-referenceable frequency comb from a semiconductor disk laser.

We present a 1.75-GHz self-referenceable frequency comb from a vertical external-cavity surface-emitting laser (VECSEL) passively modelocked with a semiconductor saturable absorber mirror (SESAM). The VECSEL delivers 231-fs pulses with an average power of 100 mW and is optimized for stable and reliable operation. The optical spectrum was centered around 1038 nm and nearly transform-limited with a full width half maximum (FWHM) bandwidth of 5.5 nm. The pulses were first amplified to an average power of 5.5 W using a backward-pumped Yb-doped double-clad large mode area (LMA) fiber and then compressed to 85 fs with 2.2 W of average power with a passive LMA fiber and transmission gratings. Subsequently, we launched the pulses into a highly nonlinear photonic crystal fiber (PCF) and generated a coherent octave-spanning supercontinuum (SC). We then detected the carrier-envelope offset (CEO) frequency (f(CEO)) beat note using a standard f-to-2f-interferometer. The f(CEO) exhibits a signal-to-noise ratio of 17 dB in a 100-kHz resolution bandwidth and a FWHM of ≈10 MHz. To our knowledge, this is the first report on the detection of the f(CEO) from a semiconductor laser, opening the door to fully stabilized compact frequency combs based on modelocked semiconductor disk lasers.

Pulse repetition rate scaling from 5 to 100 GHz with a high-power semiconductor disk laser.

The high-power semiconductor laser studied here is a modelocked integrated external-cavity surface emitting laser (MIXSEL), which combines the gain of vertical-external-cavity surface-emitting lasers (VECSELs) with the saturable absorber of a semiconductor saturable absorber mirror (SESAM) in a single semiconductor layer stack. The MIXSEL concept allows for stable and self-starting fundamental passive modelocking in a simple straight cavity and the average power scaling is based on the semiconductor disk laser concept. Previously record-high average output power from an optically pumped MIXSEL was demonstrated, however the long pulse duration of 17 ps prevented higher pulse repetition rates and many interesting applications such as supercontinuum generation and broadband frequency comb generation. With a novel MIXSEL structure, the first femtosecond operation was then demonstrated just recently. Here we show that such a MIXSEL can also support pulse repetition rate scaling from ≈5 GHz to >100 GHz with excellent beam quality and high average output power, by mechanically changing the cavity length of the linear straight cavity and the output coupler. Up to a pulse repetition rate of 15 GHz we obtained average output power >1 W and pulse durations <4 ps. Furthermore we have been able to demonstrate the highest pulse repetition rate from any fundamentally modelocked semiconductor disk laser with 101.2 GHz at an average output power of 127 mW and a pulse duration of 570 fs.

Avosentan is protective in hypertensive nephropathy at doses not causing fluid retention.

Multiple studies indicate that endothelin antagonism may have a protective effect for chronic kidney disease. Despite that, clinical studies using avosentan have been halted due to adverse effects including fluid overload. Therefore, we aimed at investigating whether avosentan may have protective effects against hypertensive nephropathy at doses below those inducing fluid-retention. We used double transgenic rats (dTGR), overexpressing both the human renin and angiotensinogen gene, which develop malignant hypertension. Effects of avosentan alone or in combination with low-dose of valsartan (angiotensin AT1 receptor antagonist) on end-organ damage were studied. Avosentan induced a decrease of diuresis (18.3%) with a consequent decrease in hematocrit (8.3%) only at the highest dose investigated (100mg/kg). Treatment with the combination of avosentan and valsartan (10 and 0.1mg/kg, once daily by gavage, respectively) decreased albuminuria to a greater extent than each compound given alone (avosentan: 19.6mg/24h; valsartan: 12.9mg/24h; avosentan+valsartan: 1.7mg/24h, data are median values). Histological severity score also showed a drastic reduction of kidney damage. Furthermore, avosentan alone or in combination therapy dramatically decreased mortality compared to the 100% in untreated animals. These data support a therapeutic effect of avosentan at doses below those inducing fluid overload.

Femtosecond pulses from a modelocked integrated external-cavity surface emitting laser (MIXSEL).

Novel surface-emitting optically pumped semiconductor lasers have demonstrated >1 W modelocked and >100 W continuous wave (cw) average output power. The modelocked integrated external-cavity surface emitting laser (MIXSEL) combines the gain of vertical-external-cavity surface-emitting lasers (VECSELs) with the saturable absorber of a semiconductor saturable absorber mirror (SESAM) in one single semiconductor structure. This unique concept allows for stable and self-starting passive modelocking in a simple straight cavity. With quantum-dot based absorbers, record-high average output power was demonstrated previously, however the pulse duration was limited to 17 ps so far. Here, we present the first femtosecond MIXSEL emitting pulses with a duration as short as 620 fs at 4.8 GHz repetition rate and 101 mW average output power. The novel MIXSEL structure relies on a single low temperature grown quantum-well saturable absorber with a low saturation fluence and fast recovery dynamics. A detailed characterization of the key modelocking parameters of the absorber and the challenges for absorber integration into the MIXSEL structure are discussed.

Brushing without brushing?--a review of the efficacy of powered toothbrushes in noncontact biofilm removal.

OBJECTIVES: The aim of the present review was to analyze the impact of the hydrodynamic effects created by powered toothbrushes on biofilm removal in vitro. MATERIALS AND METHODS: A MEDLINE search was performed for publications published by 20 May 2012; this search was complemented by a manual search. The study selection, data preparation, and validity assessment were conducted by two reviewers. RESULTS: Sixteen studies were included. The studies differed with respect to the methods of biofilm formation and brushing protocols. Eighteen different powered toothbrush models were evaluated. Toothbrushes with side-to-side action demonstrated biofilm removal without direct bristle contact to biofilms ranging from 38 to 99%. Most studies found biofilm removal exceeding 50%. Biofilm reduction using multidimensional toothbrushes was significantly lower than by those with the side-to-side mode. Detachment forces due to hydrodynamic phenomena, passing air-liquid interfaces, and acoustic energy transfer were suggested to cause reduction of the biofilm. CONCLUSION: Noncontact biofilm reduction was obtained by the hydrodynamic effects of some powered toothbrushes in vitro. CLINICAL RELEVANCE: Powered toothbrushes may have the potential to simplify self-performed oral hygiene. However, additional beneficial effects of higher amounts of noncontact biofilm removal in vitro have not been shown clinically, yet.

Antidiuretic effects of the endothelin receptor antagonist avosentan.

Several clinical studies have investigated the potential benefits of endothelin receptor antagonism in chronic pathologies such as diabetic kidney disease. However, fluid retention and edema have been identified as major side effects of endothelin receptor antagonists. In the present study we hypothesized that avosentan which was described as a predominant ET(A) receptor antagonist would produce fluid retention at high concentrations where non-specific blockade of ET(B) receptors may occur. Incremental doses of the predominant ET(A) receptor antagonist SPP301 (0.003; 0.03; 3 mg/kg) were administered intravenously to anesthetized Sprague-Dawley rats undergoing saline diuresis. Diuresis, glomerular filtration rate, and blood pressure (BP) were monitored. SPP301 decreased urine output (5.6; 34.8; 58.8% decrease from vehicle) and fractional excretion of water (5.7; 31.7; 56.4% decrease from vehicle) in a concentration-dependent manner. Glomerular filtration rate was unchanged while BP was reduced by 10 mmHg only by the highest dose of SPP301. Administration of the ET(B) selective receptor antagonist BQ-788 (3 mg/kg) following SPP301 3 mg/kg did not further decrease urine output or water excretion and was without effect on glomerular filtration rate. These data indicate that increasing concentrations of SPP301 may also block ET(B) receptors and cause antidiuresis. This effect could explain why fluid retention and edema occur during treatment with predominant ET(A) receptor blockers.

B2-kinin receptor plays a key role in B1-, angiotensin converting enzyme inhibitor-, and vascular endothelial growth factor-stimulated in vitro angiogenesis in the hypoxic mouse heart.

AIMS: Angiotensin converting enzyme (ACE) inhibition reduces heart disease and vascular stiffness in hypertension and leads to kinin accumulation. In this study, we analysed the role and importance of two kinin receptor subtypes in angiogenesis during ACE inhibition in an in vitro model of angiogenesis of the mouse heart. METHODS AND RESULTS: First, we analysed the angiogenic properties of bradykinin and enalapril on wild-type C57Bl/6 and B2 receptor(-/-) mouse heart under normoxia (21% O(2)) and hypoxia (1% O(2)) in vitro and the contribution of B1 and B2 kinin receptors to this effect. Bradykinin induced dose-dependent endothelial sprout formation in vitro in adult mouse heart only under hypoxia (1.7 fold, n = 6, P < 0.05). The B2 receptor mediated sprouting that was induced by bradykinin and vascular endothelial growth factor (VEGF(164); n = 6, P < 0.05), but did not mediate sprouting that was induced by growth factors bFGF or PDGF-BB. Enalapril induced sprouting through both the B1 and B2 kinin receptors, but it required the presence of the B2 receptor in both scenarios and was dependent on BK synthesis. B1-receptor agonists induced sprout formation via the B1 receptor (2.5 fold, n = 6, P < 0.05), but it required the presence of the B2 receptor for them to do so. Both B2-receptor and B1-receptor agonist-induced angiogenesis required nitric oxide biosynthesis. CONCLUSION: The kinin B2 receptor plays a crucial role in angiogenesis that is induced by different vasoactive molecules, namely bradykinin, ACE inhibitors, B1-stimulating kinin metabolites, and VEGF164 in an in vitro model of angiogenesis of mouse heart under hypoxia. Therapeutic treatment of hypertensive patients by using ACE inhibitors may potentially benefit the ischaemic heart through inducing B2-dependent heart neovascularization.

Dimethyl fumarate, a small molecule drug for psoriasis, inhibits Nuclear Factor-kappaB and reduces myocardial infarct size in rats.

Persistent Nuclear Factor-kappaB (NF-kappaB) activation is hypothesized to contribute to myocardial injuries following ischemia-reperfusion. Because inhibition or control of NF-kappaB signaling in the heart probably confers cardioprotection, we determined the potency of the NF-kappaB inhibitor dimethyl fumarate (DMF) in cardiovascular cells, and determined whether administration of DMF translates into beneficial effects in an animal model of myocardial infarction. In rat heart endothelial cells (RHEC), we analysed inhibitory effects of DMF on NF-kappaB using shift assay and immunohistofluorescence. In in vivo experiments, male Sprague Dawley rats undergoing left coronary artery occlusion for 45 min received either DMF (10 mg/kg body weight) or vehicle 90 min before ischemia as well as immediately before ischemia. After 120 min of reperfusion, the hearts were stained with phthalocyanine blue dye and triphenyltetrazolium chloride. Additionally, acute hemodynamic and electrophysiologic effects of DMF were determined in dose-response experiments in isolated perfused rat hearts. DMF inhibited TNF-alpha-induced nuclear entry of NF-kappaB in RHEC. In in vivo experiments, myocardial infarct size was significantly smaller in rats that had received DMF (20.7%+/-9.7% in % of risk area; n=17) than in control rats (28.2%+/-6.2%; n=15). Dose-response experiments in isolated perfused rat hearts excluded acute hemodynamic or electrophysiologic effects as mechanisms for the effects of DMF. DMF inhibits nuclear entry of NF-kappaB in RHEC and reduces myocardial infarct size after ischemia and reperfusion in rats in vivo. There was no indication that the beneficial effects of DMF were due to acute hemodynamic or electrophysiologic influences.

Mutation of the circadian clock gene Per2 alters vascular endothelial function.

BACKGROUND: The circadian clock regulates biological processes including cardiovascular function and metabolism. In the present study, we investigated the role of the circadian clock gene Period2 (Per2) in endothelial function in a mouse model. METHODS AND RESULTS: Compared with the wild-type littermates, mice with Per2 mutation exhibited impaired endothelium-dependent relaxations to acetylcholine in aortic rings suspended in organ chambers. During transition from the inactive to active phase, this response was further increased in the wild-type mice but further decreased in the Per2 mutants. The endothelial dysfunction in the Per2 mutants was also observed with ionomycin, which was improved by the cyclooxygenase inhibitor indomethacin. No changes in the expression of endothelial acetylcholine-M3 receptor or endothelial nitric oxide synthase protein but increased cyclooxygenase-1 (not cyclooxygenase-2) protein levels were observed in the aortas of the Per2 mutants. Compared with Per2 mutants, a greater endothelium-dependent relaxation to ATP was observed in the wild-type mice, which was reduced by indomethacin. In quiescent aortic rings, ATP caused greater endothelium-dependent contractions in the Per2 mutants than in the wild-type mice, contractions that were abolished by indomethacin. The endothelial dysfunction in the Per2 mutant mice is not associated with hypertension or dyslipidemia. CONCLUSIONS: Mutation in the Per2 gene in mice is associated with aortic endothelial dysfunction involving decreased production of NO and vasodilatory prostaglandin(s) and increased release of cyclooxygenase-1-derived vasoconstrictor(s). The results suggest an important role of the Per2 gene in maintenance of normal cardiovascular functions.

Bradykinin is a mediator, but unlikely a trigger, of antiarrhythmic effects of ischemic preconditioning.

OBJECTIVE: Brief reversible ischemic episodes (ischemic preconditioning, IPC) protect the heart against arrhythmias during a subsequent prolonged low-flow ischemia. We have recently shown that this protection involves release of bradykinin, activation of bradykinin B2 receptors followed by opening of sarcolemmal, but not mitochondrial ATP-sensitive K+ channels. The goal of this study was to clarify a trigger and/or mediator role of bradykinin in the antiarrhythmic effects of IPC during low-flow ischemia. METHODS: Isolated perfused rat hearts underwent 60 minutes of low-flow ischemia induced by reducing perfusion pressure followed by 60 minutes of reperfusion. Preconditioning was induced by 2 x 5 minutes episodes of zero-flow ischemia. In yet other groups, preconditioned or non-preconditioned hearts were treated either with bradykinin (10 nmol/L) or with HOE 140 (bradykinin B2 receptor antagonist, 100 nmol/L). RESULTS: IPC reduced the number of ventricular premature beats, as well as the incidence of ventricular tachycardia and of ventricular fibrillation during low-flow ischemia. In addition, this protection was abolished by HOE 140 given during low-flow ischemia. Pharmacological preconditioning using short bradykinin perfusion instead of IPC did not show antiarrhythmic effects. However, bradykinin administered during low-flow ischemia and reperfusion reduced the number of ventricular premature beats and the incidence of ventricular tachycardia and of ventricular fibrillation during low-flow ischemia. CONCLUSION: Bradykinin is a mediator, but unlikely a trigger, of antiarrhythmic effects of IPC during low-flow ischemia.

Interval versus continuous high-intensity exercise in chronic obstructive pulmonary disease: a randomized trial.

BACKGROUND: Guidelines recommend high-intensity continuous exercise to reduce peripheral muscle dysfunction in patients with chronic obstructive pulmonary disease but acknowledge that interval exercise might be an equally effective alternative that is better tolerated by patients. OBJECTIVE: To assess whether interval exercise is no less effective than high-intensity continuous exercise and whether it is tolerated better by patients with severe chronic obstructive pulmonary disease. DESIGN: Randomized, noninferiority trial. SETTING: Publicly funded rehabilitation hospital in Switzerland. PATIENTS: 98 patients with severe chronic obstructive pulmonary disease, with or without recent exacerbations. INTERVENTION: 12 to 15 supervised interval or high-intensity continuous exercise sessions (over 3 weeks) followed by exercise at home. MEASUREMENTS: Health-related quality of life determined by using the Chronic Respiratory Questionnaire (CRQ) (scores from 1 [most severe impairment] to 7 [no impairment]) after 5 weeks and number of unintended breaks during supervised exercise. RESULTS: Both groups experienced large improvements in health-related quality of life (increase of CRQ total scores of 1.00 [SD, 0.98] for the interval exercise group and 1.02 [SD, 1.05] for the continuous exercise group). Adjusted between-group differences between the interval exercise group and the continuous exercise group (-0.05 [95% CI, -0.42 to -0.32] for CRQ and 1.1 meters [CI, -25.4 to 27.6 meters] for 6-minute walking distance) were within the a priori defined boundaries of noninferiority (0.5 for CRQ and 45 meters for 6-minute walking distance). Twenty-one (47.9%) patients using interval exercise and 11 (24.0%) patients using continuous exercise were able to adhere to the protocol (difference, 23.9 percentage points [CI, 5.0 to 42.8 percentage points]; P = 0.014). The median number of unintended breaks lasting 1 minute or more was 2 (interquartile range, 0 to 16) for patients in the interval exercise group and 11 (interquartile range, 2 to 26) for patients in the continuous exercise group (P = 0.023). LIMITATIONS: The study focused on initiation of exercise and not on outpatient or home-based maintenance of exercise. CONCLUSIONS: Clinicians and patients can choose either of the 2 exercise plans to initiate physical exercise. International Standard Randomized Controlled Trial number: SRCTN11611768.

Interval exercise versus continuous exercise in patients with moderate to severe chronic obstructive pulmonary disease--study protocol for a randomised controlled trial [ISRCTN11611768].

BACKGROUND: Physical exercise has become a cornerstone of management of chronic obstructive pulmonary disease (COPD) because it leads to clinically relevant improvements of exercise capacity and health-related quality of life (HRQL). Despite the scarcity of randomised trials directly comparing exercise protocols, current guidelines recommend high intensity continuous exercise for lower extremities as the probably most effective exercise modality. However, for patients admitted to inpatient respiratory rehabilitation programmes, it is often difficult to initiate such an exercise programme because they are severely limited by dyspnoea and leg fatigue and therefore unable to perform continuous exercise at higher intensities and for periods longer than 30 minutes. Interval exercise may be an attractive alternative for these COPD patients because it allows high intensity exercise with recovery periods. The aim of this study is to assess if interval exercise compared to high intensity continuous exercise is not of inferior effectiveness in terms of HRQL and exercise capacity improvements but associated with better exercise tolerance in patients with moderate to severe COPD at the beginning of a respiratory rehabilitation. METHODS/DESIGN: We will assign patients with moderately severe to severe COPD to either continuous exercise or interval exercise using a stratified randomisation. Patients will follow 12-15 exercise sessions during a comprehensive inpatient respiratory rehabilitation. Primary end point for effectiveness is HRQL as measured by the Chronic Respiratory Questionnaire (CRQ) two weeks after the end of rehabilitation and secondary endpoints include additional clinical outcomes such as functional exercise capacity, other HRQL measures, patients' experience of physical exercise as well as physiological measures of the effects of physical exercise such as cardiopulmonary exercise testing. Including expected drop-outs, we will need 52 patients per group to show differences corresponding to the minimal clinically important difference of the CRQ. Outcome assessors and investigators involved in data analysis will be blinded to group assignment until analyses have been carried out. DISCUSSION: Clinicians and the scientific community need evidence on the benefits and tolerance of exercise protocols available in clinical practice. The proposed trial will provide important and needed data on interval and continuous exercise for decision making in clinical practice.

Antiarrhythmic effect of ischemic preconditioning during low-flow ischemia. The role of bradykinin and sarcolemmal versus mitochondrial ATP-sensitive K(+) channels.

Short episodes of ischemia (ischemic preconditioning) protect the heart against ventricular arrhythmias during zero-flow ischemia and reperfusion. However, in clinics, many episodes of ischemia present a residual flow (low-flow ischemia). Here we examined whether ischemic preconditioning protects against ventricular arrhythmias during and after a low-flow ischemia and, if so, by what mechanism(s). Isolated rat hearts were subjected to 60 min of low-flow ischemia (12% residual coronary flow) followed by 60 min of reperfusion. Ischemic preconditioning was induced by two cycles of 5 min of zero-flow ischemia followed by 5 and 15 min of reperfusion, respectively. Arrhythmias were evaluated as numbers of ventricular premature beats (VPBs) as well as incidences of ventricular tachycardia (VT) and ventricular fibrillation (VF) during low-flow ischemia and reperfusion. Ischemic preconditioning significantly reduced the number of VPBs and the incidence of VT and of VF during low-flow ischemia. This antiarrhythmic effect of preconditioning was abolished by HOE 140 (100 nM), a bradykinin B(2) receptor blocker. Similar to preconditioning, exogenous bradykinin (10 nM) reduced the number of VPBs and the incidence of VT and of VF during low-flow ischemia. Furthermore, the antiarrhythmic effects of both ischemic preconditioning and bradykinin were abolished by glibenclamide (1 microM), a non-specific blocker of ATP-sensitive K(+) (K(ATP)) channels. Finally, the antiarrhythmic effects of both ischemic preconditioning and bradykinin were abolished by HMR 1098 (10 microM), a sarcolemmal K(ATP) channel blocker but not by 5-hydroxydecanoate (100 microM), a mitochondrial K(ATP) channel blocker. In conclusion, ischemic preconditioning protects against ventricular arrhythmias induced by low-flow ischemia, and this protection involves activation of bradykinin B(2) receptors and subsequent opening of sarcolemmal but not of mitochondrial K(ATP) channels.