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RATIONALE: Whether pulmonary hypertension at high altitude limits exercise capacity remains uncertain. OBJECTIVES: To gain further insight into the pathophysiology of hypoxia induced pulmonary hypertension and the resulting reduction in exercise capacity, we investigated if the reduction in hypoxic pulmonary vasoconstrictive response with corticosteroids or phosphodiesterase-5 inhibition improves exercise capacity. METHODS: A cardiopulmonary exercise test and echocardiography to estimate systolic pulmonary artery pressure were performed in 23 subjects with previous history of high altitude pulmonary edema, known to be associated with enhanced hypoxic vasoconstriction. Subjects were randomized to dexamethasone 8 mg twice a day, tadalafil 10 mg twice a day, or placebo (double-blinded), starting the day before ascent. MEASUREMENTS AND MAIN RESULTS: Measurements were performed at low and high (i.e., 4,559 m) altitude. Altitude exposure decreased maximum oxygen uptake and oxygen saturation, increased pulmonary artery pressure, and altered oxygen uptake kinetics. Compared with placebo, dexamethasone improved maximum oxygen uptake (% predicted 74 +/- 13%; tadalafil 63 +/- 13%, placebo 61 +/- 11%; P < 0.05), oxygen kinetics (mean response time 41 +/- 13 s; tadalafil 46 +/- 6 s, placebo 45 +/- 10 s; P < 0.05), and reduced the ventilatory equivalent for CO(2) (42 +/- 4; tadalafil 49 +/- 4, placebo 50 +/- 5; P < 0.01). Peak oxygen saturation did not differ significantly between the three groups (dexamethasone 66 +/- 7%, placebo 62 +/- 7%, tadalafil 69 +/- 5%; P = 0.08). During echocardiography at low-intensity exercise (40% of peak power), dexamethasone compared with placebo resulted in lower pulmonary artery pressure (47 +/- 9 mm Hg; tadalafil 57 +/- 11 mm Hg, placebo 68 +/- 23 mm Hg; P = 0.05) and higher oxygen saturation (74 +/- 7%; tadalafil 67 +/- 3%, placebo 61 +/- 20; P < 0.02). CONCLUSIONS: Corticosteroids, but not phosphodiesterase-5 inhibition, partially prevented the limitation of exercise capacity in subjects with intense hypoxic pulmonary vasoconstriction at high altitude. [ABSTRACT FROM AUTHOR]

Background: The prognostic value of the change in heart rate from the supine to upright position (∆HR) in patients with chronic heart failure (HF) is unknown., Methods and Results: ∆HR was measured in patients enrolled in the Trial of Intensified Medical Therapy in Elderly Patients with Congestive Heart Failure (TIME-CHF) who were in sinus rhythm and had no pacemaker throughout the trial (n=321). The impact of ∆HR on 18-month outcome (HF hospitalization-free survival) was assessed. In addition, the prognostic effect of changes in ∆HR between baseline and month 6 on outcomes in the following 12 months was determined. A lower ∆HR was associated with a higher risk of death or HF hospitalization (hazard ratio 1.79 [95% confidence interval {95% CI} 1.19-2.75] if ∆HR ≤3 beats/min [bpm], P=0.004). In the multivariate analysis, lower ∆HR remained an independent predictor of death or HF hospitalization (hazard ratio 1.75 [95% CI, 1.18-2.61] if ∆HR ≤3 bpm, P=0.004) along with ischemic HF etiology, lower estimated glomerular filtration rate, presence and extent of rales, and no baseline β-blocker use. In patients without event during the first 6 months, the change in ∆HR from baseline to month 6 predicted death or HF hospitalization during the following 12 months (hazard ratio=2.13 [95% CI 1.12-5.00] if rise in ∆HR <2 bpm; P=0.027)., Conclusions: ∆HR as a simple bedside test is an independent prognostic predictor in patients with chronic HF. ∆HR is modifiable, and changes in ∆HR also provide prognostic information, which raises the possibility that ∆HR may help to guide treatment., Clinical Trial Registration Information: URL: www.isrctn.org. Unique identifier: ISRCTN43596477., (© 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

Aims: NT-proBNP-guided therapy results in intensification of medical heart failure (HF) therapy and is suggested to improve outcome. However, it is feared that an intensified, NT-proBNP-guided therapy carries a risk of adverse effects. Therefore, the safety and tolerability of NT-proBNP-guided therapy in the Trial of Intensified vs standard Medical therapy in Elderly patients with Congestive Heart Failure (TIME-CHF) was assessed., Methods and Results: A total of 495 chronic HF patients, aged ≥60, with an LVEF ≤45%, NYHA class ≥II, randomized to NT-proBNP-guided or symptom-guided therapy and ≥1 month follow-up were included in the present safety analysis. All adverse events (AEs) were recorded during the 18-month trial period. A total of 5212 AEs were noted, 433 of them serious. NT-proBNP-guided therapy led to a higher up-titration of HF medication and was well tolerated, with a dropout rate (12% vs. 11%, P = 1.0) and AE profile [number of AEs/patient-year 4.7 (2.8-9.4) vs. 5.4 (2.7-11.4), P = 0.69; number of severe AEs/patient-year 0.7 (0-2.7) vs. 1.3 (0-3.9), P = 0.21] similar to that of symptom-guided therapy, although most subjects in both treatment groups (96% vs. 95%, P = 0.55) experienced at least one AE. Age and number of co-morbidities were associated with AEs and interacted with the safety profile of NT-proBNP-guided therapy: positive effects were more frequent in younger and less co-morbid patients whereas potential negative effects-although small and related to non-severe AEs only-were only seen in the older and more co-morbid patients., Conclusions: NT-proBNP-guided therapy is safe in elderly and highly co-morbid HF patients. Trial registration ISRCTN43596477.

Aims: Diabetic cardiomyopathy, characterized by left ventricular (LV) dysfunction and LV hypertrophy independent of myocardial ischaemia and hypertension, could contribute to the increased life-time risk of congestive heart failure seen in patients with diabetes. We assessed prospectively the prevalence, effectiveness of screening methods [brain natriuretic peptide (BNP) and C-reactive protein in combination with clinical parameters], and outcome of pre-clinical diabetic cardiomyopathy., Methods and Results: We studied 100 adults (mean age 57.4 +/- 10.2 years, 44% females) with diabetes and no previous evidence of structural heart disease. By echocardiography, diabetic cardiomyopathy was present in 48% of patients. Screening with combinations of clinical parameters (gender, systolic blood pressure, and body mass index), but not BNP, resulted in high negative predictive values for diabetic cardiomyopathy. During a mean follow-up of 48.5 +/- 9.0 months, in the groups with and without diabetic cardiomyopathy, 12.5 vs. 3.9% (P < 0.2) patients died or experienced cardiovascular events and 37.5 vs. 9.6% (P < 0.002) had a deterioration in NYHA functional class. Overall event-free survival was 54 vs. 87% (P = 0.001) in the groups with and without diabetic cardiomyopathy, respectively. Brain natriuretic peptide was an independent predictor of events [odds ratio 3.5 (1.1-10.9), P = 0.02]., Conclusion: Pre-clinical diabetic cardiomyopathy is common. Screening with combinations of simple clinical parameters, but not BNP, can be useful to identify those patients needing further evaluation. Patients with pre-clinical diabetic cardiomyopathy are at increased risk for functional deterioration and possibly cardiovascular events during follow-up. Brain natriuretic peptide was shown to be an independent predictor of future events.

An exaggerated increase in pulmonary arterial pressure is the hallmark of high-altitude pulmonary edema (HAPE) and is associated with endothelial dysfunction of the pulmonary vasculature. Whether the myocardial circulation is affected as well is not known. The aim of this study was, therefore, to investigate whether myocardial blood flow reserve (MBFr) is altered in mountaineers developing HAPE. Healthy mountaineers taking part in a trial of prophylactic treatment of HAPE were examined at low (490 m) and high altitude (4,559 m). MBFr was derived from low mechanical index contrast echocardiography, performed at rest and during submaximal exercise. Among 24 subjects evaluated for MBFr, 9 were HAPE-susceptible individuals on prophylactic treatment with dexamethasone or tadalafil, 6 were HAPE-susceptible individuals on placebo, and 9 persons without HAPE susceptibility served as controls. At low altitude, MBFr did not differ between groups. At high altitude, MBFr increased significantly in HAPE-susceptible individuals on treatment (from 2.2 +/- 0.8 at low to 2.9 +/- 1.0 at high altitude, P = 0.04) and in control persons (from 1.9 +/- 0.8 to 2.8 +/- 1.0, P = 0.02), but not in HAPE-susceptible individuals on placebo (2.5 +/- 0.3 and 2.0 +/- 1.3 at low and high altitude, respectively, P > 0.1). The response to high altitude was significantly different between the two groups (P = 0.01). There was a significant inverse relation between the increase in the pressure gradient across the tricuspid valve and the change in myocardial blood flow reserve. HAPE-susceptible individuals not taking prophylactic treatment exhibit a reduced MBFr compared with either treated HAPE-susceptible individuals or healthy controls at high altitude.

The case of an 80-year-old woman who underwent permanent VDD-pacemaker implantation for recurrent syncope in the presence of second-degree type 2 AV-block is reported. During follow-up, low atrial sensing with AV-synchrony of only 58-73% was noted. Four years after the pacemaker implantation, the patient was hospitalized for non-cardiac reasons and the chest radiograph showed displacement of the atrial dipole into the right ventricular outflow tract (RVOT). It is hypothesized that AV-synchrony was maintained by left atrial sensing due to the anatomic proximity of the RVOT to the left atrial appendage.

Objectives: We aimed to compare the hemodynamic effects of right-atrial-paced (DDD) and right-atrial-sensed (VDD) biventricular paced rhythm on cardiac resynchronization therapy (CRT)., Background: Cardiac resynchronization therapy improves hemodynamics in patients with severe heart failure and left ventricular (LV) dyssynchrony. However, the impact of active right atrial pacing on resynchronization therapy is unknown., Methods: Seventeen CRT patients were studied 10 months (range: 1 to 46 months) after implantation. At baseline, the programmed atrioventricular delay was optimized by timing LV contraction properly at the end of atrial contraction. In both modes the acute hemodynamic effects were assessed by multiple Doppler echocardiographic parameters., Results: Compared to DDD pacing, VDD pacing resulted in much better improvement of intraventricular dyssynchrony assessed by the septal-to-posterior wall motion delay (VDD 106 +/- 83 ms vs. DDD 145 +/- 95 ms; p = 0.001), whereas the interventricular mechanical delay (difference between onset of pulmonary and aortic outflow) did not differ (VDD 20 +/- 21 ms vs. DDD 18 +/- 17 ms; p = NS). Furthermore, VDD pacing significantly prolonged the rate-corrected LV filling period (VDD 458 +/- 123 ms vs. DDD 371 +/- 94 ms; p = 0.0001) and improved the myocardial performance index (VDD 0.60 +/- 0.18 vs. DDD 0.71 +/- 0.23; p < 0.01)., Conclusions: Our findings suggest that avoidance of right atrial pacing results in a higher degree of LV resynchronization, in a substantial prolongation of the LV filling period, and in an improved myocardial performance. Thus, the VDD mode seems to be superior to the DDD mode in CRT patients.

Objective: To assess the feasibility and longterm outcome of cardiac resynchronization therapy (CRT) in patients with impaired left ventricular function (LVEF <35%), left bundle branch block (QRS >120 ms) and dyspnoea NYHA 0 III at a single centre., Methods and Results: Forty-seven patients were referred for implantation of a CRT device. In only 4 patients (9%) the device could not be implanted due to technical problems during the procedure. In the remaining 43 patients (65 +/- 10 years; 7 female) a CRT device was implanted. Follow-up time was 12 +/- 10 months. Twenty-one patients had dilated cardiomyopathy (DCM) and 22 patients had coronary artery disease (CAD). NYHA functional class improved from 3.0 +/- 1.4 to 2.5 +/- 0.7 (p <0.0001), accompanied by an improvement of LVEF [median 20% (range 15-25) vs 32% (range 20-40); p <0.0001]. A significant reduction of hospitalisation time for heart failure was found when the year before and the year after device implantation [18 days (range 5-27) vs 1 day (range 0-3); p <0.0001] were compared. Twelve (28%) patients, 9 with CAD, and 3 with DCM died. Two CAD patients and all patients with DCM who died had a combined CRT device with implantable cardioverter/defibrillator., Conclusion: In patients with severely impaired LVEF and wide QRS due to LBBB, CRT is feasible and safe. It improved dyspnoea and LVEF and reduced hospitalisation stays for heart failure during long-term follow-up.