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Aims: Synchronized diaphragmatic stimulation (SDS) modulates intrathoracic and intra-abdominal pressures with favourable effects on cardiac function for patients with a reduced left ventricular ejection fraction (LVEF) and heart failure (HFrEF). VisONE-HF is a first-in-patient, observational study assessing the feasibility and 1 year effects of a novel, minimally invasive SDS device., Methods and Results: The SDS system comprises a pulse generator and two laparoscopically delivered, bipolar, active-fixation leads on the inferior diaphragmatic surface. Fifteen symptomatic men with HFrEF and ischaemic heart disease receiving guideline-recommended therapy were enrolled (age 60 [56, 67] years, New York Heart Association class II [53%] /III [47%], LVEF 27 [23, 33] %, QRSd 117 [100, 125] ms, & N terminal pro brain natriuretic peptide [NT-proBNP] 1779 [911, 2,072] pg/mL). Implant success was 100%. Patients were evaluated at 3, 6, and 12 months for device-related or lead-related complications, quality of life (SF-36 QOL), 6 min hall walk distance (6MHWd), and by echocardiography. No implant procedure or SDS-related adverse event occurred, and patients were unaware of diaphragmatic stimulation. By 12 months, left ventricular end-systolic volume decreased (136 [123, 170] mL to 98 [89, 106] mL; P = 0.05), 6MHWd increased (315 [300, 330] m to 340 [315, 368] m; P = 0.004), and SF-36 QOL improved (physical scale 0 [0, 0] to 25 [0, 50], P = 0.006; emotional scale 0 [0, 33] to 33 [33, 67], P = 0.001). Although neither reached statistical significance, LVEF decreased (28 [23, 40]% vs. 34 [29, 38]%; P = ns) and NT-proBNP was lower (1784 [920, 2540] pg/mL vs. 1492 [879, 2028] pg/mL; P = ns)., Conclusions: These data demonstrate the feasibility of laparoscopic implantation and delivery of SDS without raising safety concerns. These encouraging findings should be investigated further in adequately powered randomized trials., (© 2022 VISACARDIA, INC. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: We aimed to assess the long-term effect of a strategy of comprehensive vasodilation versus usual care on health-related quality of life (HRQL) among patients with acute heart failure (AHF)., Methods and Results: Health-related quality of life was prospectively assessed by the generic 3-levelled EQ-5D and the disease-specific Kansas City Cardiomyopathy Questionnaire (KCCQ) among adult AHF patients enrolled in an international, multicentre, randomised, open-label blinded-end-point trial of a strategy that emphasized early intensive and sustained vasodilation using maximally tolerated doses of established oral and transdermal vasodilators according to systolic blood pressure. Changes in EQ-5D and KCCQ from admission to 180 day follow-up were individually compared between the intensive vasodilatation and the usual care group. Among 666 patients eligible for 180 day follow-up, 284 (43%, median age 79 years, 35% women) and 198 (30%, median age 77 years, 35% women) had completed the EQ-5D and KCCQ at baseline and follow-up, respectively. There was a significant improvement in HRQL as quantified by both, EQ-5D and KCCQ, from hospitalization to 180 day follow-up, with no significant differences in the change of HRQL between both treatment strategies. For instance, 39 (26%) versus 33 (25%) patients had an improvement by at least one level in at least two categories in the EQ-5D. Median increase in KCCQ overall summary score (KCCQ-OSS) was 17.6 (IQR 2.0-42.6) in the intervention group versus 18.5 (IQR 3.9-39.3) in the usual care group (P < 0.001 vs. baseline, P = 0.945 between groups)., Conclusions: Among patients with AHF, long-term HRQL quantified by EQ-5D and KCCQ improved substantially, with overall no significant differences between a strategy of comprehensive vasodilation versus usual care., (© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Importance: Short-term infusions of single vasodilators, usually given in a fixed dose, have not improved outcomes in patients with acute heart failure (AHF)., Objective: To evaluate the effect of a strategy that emphasized early intensive and sustained vasodilation using individualized up-titrated doses of established vasodilators in patients with AHF., Design, Setting, and Participants: Randomized, open-label blinded-end-point trial enrolling 788 patients hospitalized for AHF with dyspnea, increased plasma concentrations of natriuretic peptides, systolic blood pressure of at least 100 mm Hg, and plan for treatment in a general ward in 10 tertiary and secondary hospitals in Switzerland, Bulgaria, Germany, Brazil, and Spain. Enrollment began in December 2007 and follow-up was completed in February 2019., Interventions: Patients were randomized 1:1 to a strategy of early intensive and sustained vasodilation throughout the hospitalization (n = 386) or usual care (n = 402). Early intensive and sustained vasodilation was a comprehensive pragmatic approach of maximal and sustained vasodilation combining individualized doses of sublingual and transdermal nitrates, low-dose oral hydralazine for 48 hours, and rapid up-titration of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, or sacubitril-valsartan., Main Outcomes and Measures: The primary end point was a composite of all-cause mortality or rehospitalization for AHF at 180 days., Results: Among 788 patients randomized, 781 (99.1%; median age, 78 years; 36.9% women) completed the trial and were eligible for primary end point analysis. Follow-up at 180 days was completed for 779 patients (99.7%). The primary end point, a composite of all-cause mortality or rehospitalization for AHF at 180 days, occurred in 117 patients (30.6%) in the intervention group (including 55 deaths [14.4%]) and in 111 patients (27.8%) in the usual care group (including 61 deaths [15.3%]) (absolute difference for the primary end point, 2.8% [95% CI, -3.7% to 9.3%]; adjusted hazard ratio, 1.07 [95% CI, 0.83-1.39]; P = .59). The most common clinically significant adverse events with early intensive and sustained vasodilation vs usual care were hypokalemia (23% vs 25%), worsening renal function (21% vs 20%), headache (26% vs 10%), dizziness (15% vs 10%), and hypotension (8% vs 2%)., Conclusions and Relevance: Among patients with AHF, a strategy of early intensive and sustained vasodilation, compared with usual care, did not significantly improve a composite outcome of all-cause mortality and AHF rehospitalization at 180 days., Trial Registration: ClinicalTrials.gov Identifier: NCT00512759.

Background: Patients with atrial fibrillation (AF) have an increased risk for the development of heart failure (HF). In this study, we aimed to detect predictors of HF hospitalizations in an unselected AF population., Methods: The Basel Atrial Fibrillation Cohort Study is an ongoing observational multicenter cohort study in Switzerland. For this analysis, 1193 patients with documented AF underwent clinical examination, venous blood sampling and resting 12-lead ECG at baseline. Questionnaires about lifestyle and medical history were obtained in person at baseline and during yearly follow-up phone calls. HF hospitalizations were validated by two independent physicians. Cox regression analyses were performed using a forward selection strategy., Results: Overall, 29.8% of all patients were female and mean age was 69 ±12 years. Mean follow-up time was 3.7 ±1.5 years. Hospitalization for HF occurred in 110 patients, corresponding to an incidence of 2.5 events per 100 person years of follow-up. Independent predictors for HF were body mass index (HR 1.40 [95%CI 1.17; 1.66], p = 0.0002), chronic kidney disease (2.27 [1.49; 3.45], p = 0.0001), diabetes mellitus (2.13 [1.41; 3.24], p = 0.0004), QTc interval (1.25 [1.04; 1.49], p = 0.02), brain natriuretic peptide (2.19 [1.73; 2.77], p<0.0001), diastolic blood pressure (0.79 [0.65; 0.96], p = 0.02), history of pulmonary vein isolation or electrical cardioversion (0.54 [0.36; 0.80], p = 0.003) and serum chloride (0.82 [0.70; 0.96], p = 0.02)., Conclusions: In this unselected AF population, several traditional cardiovascular risk factors and arrhythmia interventions predicted HF hospitalizations, providing potential opportunities for the implementation of strategies to reduce HF among AF patients.

Background: Data on temporal trends of heart failure (HF) in acute coronary syndrome (ACS) are scarce., Hypothesis: Improved treatment options may have led to lower case-fatality rates (CFRs) during the last years in ACS complicated by HF., Methods: Patients of the nationwide Acute Myocardial Infarction in Switzerland (AMIS)-Plus ACS registry were analyzed from 2000 to 2014., Results: Of 36 366 ACS patients, 3376 (9.3%) had acute or chronic HF, 2111 (5.8%) de novo acute HF (AHF), 964 (2.7%) chronic HF (CHF), and 301 (0.8%) acute decompensated CHF (ADCHF). In-hospital CFRs were highest in patients with ADCHF (32.6%) and de novo AHF (29.7%), followed by patients with CHF (12.9%) and without HF (3.2%, P < 0.001). Although in-hospital CFRs gradually decreased in CHF patients (14.3% to 4.5%, P = 0.003) and patients without HF (3.5% to 2.2%, P < 0.001), they remained high in patients with ADCHF (36.4% to 40.0%, P = 0.45) and de novo AHF (50.0% to 29.4%, P = 0.37). Although there was an increase in specific ACS therapies in the cohort over time, ACS patients with HF received significantly less pharmacological and interventional ACS therapies than patients without HF. There was no significant change in HF medication rates except less frequent use of β-blockers and diuretics in de novo AHF patients in recent years., Conclusions: HF is present in 1 out of 10 patients presenting with ACS and is associated with high in-hospital CFRs, particularly in acute HF. Although advances in ACS therapy improved in-hospital CFRs in patients with no HF or CHF, CFRs remained unchanged and high in patients with acute HF and ACS over the last decade., (© 2017 Wiley Periodicals, Inc.)

Background: Renal function, as quantified by the estimated glomerular filtration rate (eGFR), is a predictor of death in acute heart failure (AHF). It is unknown whether one of the clinically-available serum creatinine-based formulas to calculate eGFR is superior to the others for predicting mortality., Methods and Results: We quantified renal function using five different formulas (Cockroft-Gault, MDRD-4, MDRD-6, CKD-EPI in patients<70 years, and BIS-1 in patients≥70 years) in 1104 unselected AHF patients presenting to the emergency department and enrolled in a multicenter study. Two independent cardiologists adjudicated the diagnosis of AHF. The primary endpoint was the accuracy of the five eGFR equations to predict death as quantified by the time-dependent area under the receiver-operating characteristics curve (AUC). The secondary endpoint was the accuracy to predict all-cause readmissions and readmissions due to AHF. In a median follow-up of 374 days (IQR: 221 to 687 days), 445 patients (40.3%) died. eGFR as calculated by all equations was an independent predictor of mortality. The Cockcroft-Gault formula showed the highest prognostic accuracy (AUC 0.70 versus 0.65 for MDRD-4, 0.55 for MDRD-6, and 0.67 for the combined formula CKD-EPI/BIS-1, p<0.05). These findings were confirmed in patients with varying degrees of renal function and in three vulnerable subgroups: women, patients with severe left ventricular dysfunction, and the elderly. The prognostic accuracy for readmission was poor for all equations, with an AUC around 0.5., Conclusions: Calculating eGFR using the Cockcroft-Gault formula assesses the risk of mortality in patients with AHF more accurately than other commonly used formulas., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Objective: Compliance with guidelines is increasingly used to benchmark the quality of hospital care, however, very little is known on patients admitted with acute coronary syndromes (ACS) and treated palliatively. This study aimed to evaluate the baseline characteristics and outcomes of these patients., Design: Prospective cohort study., Setting: Eighty-two Swiss hospitals enrolled patients from 1997 to 2014., Participants: All patients with ACS enrolled in the AMIS Plus registry (n=45,091) were analysed according to three treatment groups: palliative treatment, defined as use of aspirin and analgesics only and no reperfusion; conservative treatment, defined as any treatment including antithrombotics or anticoagulants, heparins, P2Y12 inhibitors, GPIIb/IIIa but no pharmacological or mechanical reperfusion; and reperfusion treatment (thrombolysis and/or percutaneous coronary intervention during initial hospitalisation). The primary outcome measure was in-hospital mortality and the secondary measure was 1-year mortality., Results: Of the patients, 1485 (3.3%) were palliatively treated, 11,119 (24.7%) were conservatively treated and 32,487 (72.0%) underwent reperfusion therapy. In 1997, 6% of all patients were treated palliatively and this continuously decreased to 2% in 2013. Baseline characteristics of palliative patients differed in comparison with conservatively treated and reperfusion patients in age, gender and comorbidities (all p<0.001). These patients had more in-hospital complications such as postadmission onset of cardiogenic shock (15.6% vs 5.2%; p<0.001), stroke (1.8% vs 0.8%; p=0.001) and a higher in-hospital mortality (25.8% vs 5.6%; p<0.001).The subgroup of patients followed 1 year after discharge (n=8316) had a higher rate of reinfarction (9.2% vs 3.4%; p=0.003) and mortality (14.0% vs 3.5%; p<0.001)., Conclusions: Patients with ACS treated palliatively were older, sicker, with more heart failure at admission and very high in-hospital mortality. While refraining from more active therapy may often constitute the most humane and appropriate approach, we think it is important to also evaluate these patients and include them in registries and outcome evaluations., Clinical Trial Number: ClinicalTrials.gov Identifier: NCT01 305 785., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Aims: Device-based pacing-induced diaphragmatic stimulation (PIDS) may have therapeutic potential for chronic heart failure (HF) patients. We studied the effects of PIDS on cardiac function and functional outcomes., Methods and Results: In 24 chronic HF patients with CRT, an additional electrode was attached to the left diaphragm. Randomized into two groups, patients received the following PIDS modes for 3 weeks in a different sequence: (i) PIDS off (control group); (ii) PIDS 0 ms mode (PIDS simultaneously with ventricular CRT pulse); or (iii) PIDS optimized mode (PIDS with optimized delay to ventricular CRT pulse). For PIDS optimization, acoustic cardiography was used. Effects of each PIDS mode on dyspnoea, power during exercise testing, and LVEF were assessed. Dyspnoea improved with the PIDS 0 ms mode (P = 0.057) and the PIDS optimized mode (P = 0.034) as compared with the control group. Maximal power increased from median 100.5 W in the control group to 104.0 W in the PIDS 0 ms mode (P = 0.092) and 109.5 W in the PIDS optimized mode (P = 0.022). Median LVEF was 33.5% in the control group, 33.0% in the PIDS 0 ms mode, and 37.0% in the PIDS optimized mode (P = 0.763 and P = 0.009 as compared with the control group, respectively). PIDS was asymptomatic in all patients., Conclusion: PIDS improves dyspnoea, working capacity, and LVEF in chronic HF patients over a 3 week period in addition to CRT. This pilot study demonstrates proof of principle of an innovative technology which should be confirmed in a larger sample., Trial Registration: NCT00769678., (© 2013 The Authors. European Journal of Heart Failure © 2013 European Society of Cardiology.)

Objective: This study aimed to assess the impact of individual comorbid conditions as well as the weight assignment, predictive properties and discriminating power of the Charlson Comorbidity Index (CCI) on outcome in patients with acute coronary syndrome (ACS)., Methods: A prospective multicentre observational study (AMIS Plus Registry) from 69 Swiss hospitals with 29 620 ACS patients enrolled from 2002 to 2012. The main outcome measures were in-hospital and 1-year follow-up mortality., Results: Of the patients, 27% were female (age 72.1 ± 12.6 years) and 73% were male (64.2 ± 12.9 years). 46.8% had comorbidities and they were less likely to receive guideline-recommended drug therapy and reperfusion. Heart failure (adjusted OR 1.88; 95% CI 1.57 to 2.25), metastatic tumours (OR 2.25; 95% CI 1.60 to 3.19), renal diseases (OR 1.84; 95% CI 1.60 to 2.11) and diabetes (OR 1.35; 95% CI 1.19 to 1.54) were strong predictors of in-hospital mortality. In this population, CCI weighted the history of prior myocardial infarction higher (1 instead of -0.4, 95% CI -1.2 to 0.3 points) but heart failure (1 instead of 3.7, 95% CI 2.6 to 4.7) and renal disease (2 instead of 3.5, 95% CI 2.7 to 4.4) lower than the benchmark, where all comorbidities, age and gender were used as predictors. However, the model with CCI and age has an identical discrimination to this benchmark (areas under the receiver operating characteristic curves were both 0.76)., Conclusions: Comorbidities greatly influenced clinical presentation, therapies received and the outcome of patients admitted with ACS. Heart failure, diabetes, renal disease or metastatic tumours had a major impact on mortality. CCI seems to be an appropriate prognostic indicator for in-hospital and 1-year outcomes in ACS patients. ClinicalTrials.gov Identifier: NCT01305785.

Background: Therapy guided by N-terminal-pro-B-type natriuretic peptide (NT-proBNP) levels may improve outcomes in patients with chronic heart failure (HF), especially in younger patients with reduced left ventricular ejection fraction. It remains unclear whether treatment effects persist after discontinuation of the NT-proBNP-guided treatment strategy., Methods and Results: Trial of Intensified versus standard Medical therapy in Elderly patients with Congestive Heart Failure randomized 499 patients with HF aged≥60 years with left ventricular ejection fraction≤45% to intensified, NT-proBNP-guided versus standard, symptom-guided therapy into prespecified age groups (60-74 and ≥75 years) during 18 months. A total of 329 patients (92%) alive at 18 months agreed to long-term follow-up. HF medication was intensified to a larger extent in the NT-proBNP-guided group. During long-term, NT-proBNP-guided therapy did not improve hospital-free (primary end point: hazard ratio, 0.87; 95% confidence interval, 0.71-1.06; P=0.16) or overall survival (hazard ratio, 0.85; 95% confidence interval, 0.64-1.13; P=0.25) but did improve HF hospitalization-free survival (hazard ratio, 0.70; 95% confidence interval, 0.55-0.90; P=0.005). Patients aged 60 to 74 years had benefit from NT-proBNP-guided therapy on the primary end point and HF hospitalization-free survival, whereas patients aged≥75 years did not (P<0.10 for interaction). In landmark analysis, there was no regression to the mean after cessation of the NT-proBNP-guided strategy. More intensified HF medication at month 12 was associated with better long-term HF hospitalization-free and overall survival., Conclusions: Intensified, NT-proBNP-guided therapy did not improve the primary end point compared with symptom-guided therapy but did improve HF hospitalization-free survival. Within the subgroup of patients aged 60 to 74 years, it improved clinical outcome including the primary end point. These effects did not disappear after cessation of the NT-proBNP-guided strategy on the long-term. This is possibly attributable to a more intensified HF medical therapy in the NT-proBNP-guided group., Clinical Trial Registration: URL: http://www.isrctn.org. Unique identifier: ISRCTN43596477.

Aims: To assess the effects of an NT-proBNP-guided medical management on 18-month outcomes in patients with heart failure (HF) and preserved LVEF ( HFpEF)., Methods and Results: Patients with HFpEF (LVEF >45%; n = 123) and HF with reduced LVEF (HFrEF; LVEF ≤45%; n = 499) with age ≥60 years, NYHA class ≥ II, and elevated NT-proBNP (>400 ng/L or >800 ng/L depending on age) were randomized to medical therapy titrated only to reduce symptoms to NYHA ≤II (symptom-guided) or also to reduce NT-proBNP below the inclusion threshold (NT-proBNP-guided) during a 6-month period. Patients were followed for an additional 12 months. Despite similar treatment escalation, NT-proBNP reduction and symptom relief were less in HFpEF than in HFrEF. Hospitalization-free survival at 18 months was worse in HFpEF than in HFrEF (P = 0.02), while survival and HF hospitalization-free survival did not differ. Among HFpEF patients, NT-proBNP reduction and symptom relief were similar in the symptom-guided (n = 59) and NT-proBNP-guided (n = 64) group despite more aggressive treatment in the NT-proBNP-guided group. In contrast to effects in HFrEF, NT-proBNP-guided management tended to worsen 18-month outcomes in HFpEF, with P-values for the interactions between LVEF stratum and management strategy of 0.2 for hospitalization-free survival, 0.03 for survival, and 0.01 for HF hospitalization-free survival., Conclusions: Outcomes in HFpEF were not better than in HFrEF, and opposite effects of NT-proBNP-guided management were observed in HFpEF compared with HFrEF. These preliminary findings suggest that, in contrast to HFrEF, NT-proBNP-guided therapy may not be beneficial in HFpEF. Trial registration ISRCTN43596477.

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.

Objectives: This study aimed to assess cost-effectiveness of N-terminal pro-B-type natriuretic peptide (NT-proBNP)-guided versus symptom-guided therapy in heart failure (HF) patients ≥60 years old., Background: Cost-effectiveness of NT-proBNP guidance in HF patients is unclear. It may create additional costs with uncertain benefits., Methods: In the TIME-CHF (Trial of Intensified versus Standard Medical Therapy in Elderly Patients with Congestive Heart Failure), patients with left ventricular ejection fraction (LVEF) of ≤45% were randomized to receive intensified NT-proBNP-guided therapy or standard, symptom-guided therapy. For cost-effectiveness analysis, 467 (94%) patients (age 76 ± 7 years, 66% male) were eligible. Incremental cost-effectiveness was calculated as incremental costs per gained life-year and quality-adjusted life-year (QALY) within the 18-month trial period, as defined per protocol., Results: NT-proBNP-guided therapy was dominant (i.e., more effective and less costly) over symptom-guided therapy, saving $2,979 USD (2.5 to 97.5% confidence interval [CI]: $8,758 to $3,265) per patient, with incremental effectiveness of +0.07 life-years and +0.05 QALYs. The probability of NT-proBNP-guided therapy being dominant was 80%, and the probability of saving 1 life-year or QALY at a cost of $50,000 was 97% and 93%, respectively. Exclusion of residence costs resulted in an incremental cost-effectiveness ratio (ICER) of $5,870 per life-year gained. Cost-effectiveness of NT-proBNP-guided therapy was most pronounced in patients <75 years old and in those with <2 significant comorbidities, being dominant in all sensitivity analyses. In the worst-case scenario (excluding residence costs in those with ≥2 comorbidities), the ICER was $11,935 per life-year gained., Conclusions: NT-proBNP-guided therapy has a high probability of being cost effective in HF patients with reduced LVEF, particularly in patients age 60 to 75 years or with less than 2 comorbidities. (Trial of Intensified versus standard Medical therapy in Elderly patients with Congestive Heart Failure [TIME-CHF]; ISRCTN43596477)., (Copyright © 2013 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Diuretic treatment for heart failure may lead to an increased urinary thiamine excretion and in long-term thiamine deficiency, which may further compromise cardiac function. This study evaluated the effect of high dose thiamine supplementation in heart failure patients., Methods: Nine patients with diuretic treatment for symptomatic chronic heart failure and a left ventricular ejection fraction (LVEF) <40% were randomly assigned to receive thiamine (300 mg/day) or placebo for 28 days. After a wash-out of 6 weeks, the patients crossed-over to a second treatment period. The primary outcome was a change in LVEF., Results: Mean age was 56.7 ± 9.2 years (range 44.9-75.4 years). Baseline LVEF was similar for both treatment groups (29.5% in the thiamine group and 29.5% in the placebo group, P = 0.911). After 28 days of thiamine treatment, the LVEF increased to 32.8% which was significantly (P = 0.024) different from the LVEF in the placebo group (28.8%). This corresponds to a treatment effect for LVEF of 3.9% in absolute terms., Conclusions: This study suggests that thiamine supplementation has beneficial effects on cardiac function in patients with diuretic drugs for symptomatic chronic heart failure. Subclinical thiamine deficiency is probably an underestimated issue in these outpatients.

INTRODUCTION. The circadian variation of heart function and heart sounds in patients with and without heart failure (HF) is poorly understood. We hypothesized HF patients would exhibit less circadian variation with worsened cardiac function and sleep apnea. METHODS. We studied 67 HF patients (age 67.4 ± 8.2 years; 42% acute HF) and 63 asymptomatic control subjects with no history of HF (age 61.6 ± 7.7 years). Subjects wore a heart sound/ECG/respiratory monitor. The data were analyzed for sleep apnea, diastolic heart sounds, and systolic time intervals. RESULTS. The HF group had significantly greater prevalence of the third heart sound and prolongation of electro-mechanical activation time, while the control group had an age-related increase in the prevalence of the fourth heart sound. The control group showed more circadian variation in cardiac function. The HF subjects had more sleep apnea and higher occurrence of heart rate non-dipping. CONCLUSIONS. The control subjects demonstrated an increasing incidence of diastolic dysfunction with age, while systolic function was mostly unchanged with aging. Parameters related to systolic function were significantly worse in the HF group with little diurnal variation, indicating a constant stimulation of sympathetic tone in HF and reduction of diurnal regulation.

Introduction: The renin-angiotensin-aldosterone system (RAAS) plays an important role in the pathophysiology of hypertension and heart failure. ACE inhibitors, angiotensin receptor II blockers (AT-II blockers) and aldosterone antagonists have been used to tackle the RAAS in the past but combined ACE and neutral endopeptidase (NEP) inhibitors have been shown to be more potent in reducing blood and especially pulse pressure in patients with hypertension., Areas Covered: Different NEP inhibitors have been tested but omapatrilat is the most widely studied in the setting of hypertension, heart failure and chronic angina. We have undertaken a PubMed search on NEP with a special focus on omapatrilat and its efficacy in hypertension and heart failure. The incidence of angioedema is more frequent in patients taking combined ACE and NEP inhibitors and this has prevented these medications from finding a widespread use. Combinations of NEP inhibitors and AT-II blockers are currently being studied and have been shown to reduce the blood pressure significantly. These medications have so far not been associated with angioedema and have a great potential to be safe and effective alternatives in the near future., Expert Opinion: NEP inhibitors were effective in the treatment of hypertension and heart failure but the relatively high incidence of angioedema stopped their widespread use. New hope has risen with the introduction of combined NEP inhibitors and AT-II blockers and early studies are encouraging.

Background: The authors previously described an acoustic cardiographic model that predicted echocardiographic correlates of elevated left ventricular (LV) filling pressure. This study evaluated this bedside acoustic cardiographic model against invasive measurements of LV filling pressure., Methods and Results: Data were prospectively obtained from 68 adults referred for right heart catheterisation. Acoustic cardiographic measurements were obtained during right heart catheterisation. Elevated LV filling pressure was defined as a pulmonary capillary wedge pressure (PCWP) > or =15 mm Hg. Parameters generated from a previous dataset used for the current analysis were measures of LV systolic time, maximum negative area of the P wave, QTc interval and third heart sound (S3) score. Logistic regression was used to calculate area under the curve (AUC). Of the 66 patients included, 39 had elevated PCWP. Estimating the probability of an elevated PCWP from the derived model resulted in an AUC of 0.72 (95% CI 0.60 to 0.85). When the regression model's parameters were held constant but the parameter estimates were allowed to vary, the AUC in the validated model was 0.76 (95% CI 0.64 to 0.88). At a specificity of 90% the positive likelihood ratio (LR+) was 5.0 (1.7 to 15.3) and the negative likelihood ratio was 0.49 (0.34 to 0.71)., Conclusion: These data demonstrate that the four-variable model predicts elevated filling pressure at the bedside with high specificity and an intermediate LR+. With improvements in sensitivity and further prospective validation of this model in a cohort of emergency department patients with undifferentiated dyspnoea this may be a useful bedside diagnostic modality.

Context: It is uncertain whether intensified heart failure therapy guided by N-terminal brain natriuretic peptide (BNP) is superior to symptom-guided therapy., Objective: To compare 18-month outcomes of N-terminal BNP-guided vs symptom-guided heart failure therapy., Design, Setting, and Patients: Randomized controlled multicenter Trial of Intensified vs Standard Medical Therapy in Elderly Patients With Congestive Heart Failure (TIME-CHF) of 499 patients aged 60 years or older with systolic heart failure (ejection fraction < or = 45%), New York Heart Association (NYHA) class of II or greater, prior hospitalization for heart failure within 1 year, and N-terminal BNP level of 2 or more times the upper limit of normal. The study had an 18-month follow-up and it was conducted at 15 outpatient centers in Switzerland and Germany between January 2003 and June 2008., Intervention: Uptitration of guideline-based treatments to reduce symptoms to NYHA class of II or less (symptom-guided therapy) and BNP level of 2 times or less the upper limit of normal and symptoms to NYHA class of II or less (BNP-guided therapy)., Main Outcome Measures: Primary outcomes were 18-month survival free of all-cause hospitalizations and quality of life as assessed by structured validated questionnaires., Results: Heart failure therapy guided by N-terminal BNP and symptom-guided therapy resulted in similar rates of survival free of all-cause hospitalizations (41% vs 40%, respectively; hazard ratio [HR], 0.91 [95% CI, 0.72-1.14]; P = .39). Patients' quality-of-life metrics improved over 18 months of follow-up but these improvements were similar in both the N-terminal BNP-guided and symptom-guided strategies. Compared with the symptom-guided group, survival free of hospitalization for heart failure, a secondary end point, was higher among those in the N-terminal BNP-guided group (72% vs 62%, respectively; HR, 0.68 [95% CI, 0.50-0.92]; P = .01). Heart failure therapy guided by N-terminal BNP improved outcomes in patients aged 60 to 75 years but not in those aged 75 years or older (P < .02 for interaction), Conclusion: Heart failure therapy guided by N-terminal BNP did not improve overall clinical outcomes or quality of life compared with symptom-guided treatment., Trial Registration: isrctn.org Identifier: ISRCTN43596477.

Background: Despite its shortcomings, ejection fraction (EF) is widely used to detect left ventricular systolic dysfunction (LVSD) as has prolonged QRS duration as indirect evidence of LVSD. However, acoustic cardiography provides other parameters for detecting LVSD without these limitations. One parameter, the electromechanical activation time (EMAT), is prolonged in LVSD. We compared the abilities of acoustic cardiography, EF, and QRS duration to detect LVSD., Methods and Results: We studied a sample of 108 patients who underwent elective diagnostic cardiac catheterization. The diagnostic findings included left ventricular filling pressures, angiographic EF, and maximum left ventricular dP/dt. We defined LVSD as a maximum left ventricular dP/dt of <1600 mm Hg/s. At thresholds of 35% and 50% to detect LVSD, the sensitivities of angiographic EF were 39% and 74%; specificities were 89% and 70%, respectively. At QRS duration thresholds of 100 and 120 ms, sensitivities were 63% and 35%; specificities, 63% and 89%, respectively. At thresholds of 100 and 110 ms, EMAT had sensitivities of 53% and 42%, and specificities of 90% and 100%, respectively. EMAT performed better than LV EF or QRS duration in hemodynamic subgroups., Conclusions: Acoustic cardiography is a convenient, automated diagnostic method whose performance for detecting LVSD exceeds both angiographic EF and QRS duration alone.

In patients with left ventricular output failure, the Impella left ventricular assist device increases total cardiac output despite a drop in output provided by the left ventricle itself. We present a patient with cardiogenic shock after myocardial infarction in whom an Impella recover 2.5 was implanted. Correct placement was ensured by fluoroscopy, pressure and current signals displayed on the console of the system, and transthoracic echocardiography. On follow-up, the Impella device was dislocated with the shaft of the device lying on the anterior mitral leaflet causing a functional mitral stenosis evident by an increased transmitral diastolic flow gradient. After removing the device, the patients' haemodynamics improved within minutes. Other than a mild regurgitation, mitral valve was without pathological findings. Although infrequent, this case shows a possible complication of the Impella ventricular assist device and highlights the importance of periodical echocardiographic surveillance, especially in patients who show a poor response to therapy.

This case report describes a weight loss of 146 kg primarily due to diet in a very obese patient with reversal of severe congestive heart failure.

Left-ventricular hypertrophy is the result of cardiac adaptation to global or regional overstress and represents an important cardiovascular risk factor, increasing the risk for development of congestive heart failure and incidence of sudden death. This review describes the pathophysiological and biochemical mechanisms involved in the development of left-ventricular hypertrophy and cardiac fibrosis with particular emphasis on the role of angiotensin II and aldosterone. Central to the cascade of cardiac fibrosis is the increased production or reduced degradation of collagen proteins in fibroblasts. Collagen proteins are proteins needed for the alignment of cellular compartments and the development of forces, contraction and relaxation of the heart. If overexpressed, an important rise of wall stiffness is observed in addition to a reduced capacity to provide oxygen to the cardiac tissue. This latter explains why in areas of histologically hypertrophied heart muscle atrophied muscle cells are observed. The characterization of the second-messenger systems involved in the regulation of cardiac cells as well as the identification of angiotensin-II receptor subtype and angiotensin IV is described. Both of these receptors are present on cardiac fibroblasts and stimulate these to collagen production, which can be inhibited by antagonists or the generation of angiotensin II by ACE inhibitors. In some forms of left-ventricular hypertrophy and in patients with congestive heart failure in addition to elevated angiotensin-II levels, increased aldosterone levels are observed. Aldosterone raises upon stimulation by angiotensin II and upon reduction of angiotensin-II generation subsequent to ACE inhibition through an escape mechanism. The contribution of aldosterone to left-ventricular hypertrophy and cardiac fibrosis can be prevented and reduced by the administration of its antagonist, spironolactone. Further and larger clinical trials are needed and in progress to evaluate if the combination of an ACE inhibitor with spironolactone potentiates the reduction of left-ventricular hypertrophy and if this translates in a reduction of the cardiovascular risk.

All the components of the renin-angiotensin system have been identified in the heart including the angiotensin II receptor subtypes AT1 and AT2. In the normal human heart, there is a decreasing receptor density from the right atrium to the left ventricle. In right atrial membranes prepared from pathological hearts, the percentage of AT1 receptor decreases with the severity of cardiac dysfunction whereas that of AT2 receptor increases. Treatment of hypertrophic rats with AT1 receptor antagonists inhibits cardiac hypertrophy and reverses the increase receptor density, indicating involvement of this Ang II receptor subtype. The role of the AT2 receptor is still largely unknown but it may be involved in cell growth and proliferation. The cloning of both AT1 and AT2 receptors as well as the availability of potent and selective antagonists will help us to understand better the functional role of Angiotensin II in cardiovascular disorders.

The effects of angiotensin converting enzyme inhibition on systemic and coronary hemodynamics and on myocardial lactate metabolism were investigated before and 2 and 6 hours after cilazapril at rest and during supine submaximal exercise in 10 patients with New York Heart Association class II or III chronic congestive heart failure. Angiotensin converting enzyme inhibition, indicated by a significant increase in plasma renin activity, resulted in significant reductions in blood pressure and systemic vascular resistance. Myocardial oxygen demand decreased (resting double product 10.9 +/- 3.7 vs 12.2 +/- 3.8 mm Hg beats/min 10(-3); p less than 0.05), but coronary sinus blood flow remained unchanged and calculated coronary resistance decreased (0.45 vs 0.5 units, rest 6 hours; p less than 0.05) suggesting coronary vasodilatation. Changes in coronary vascular resistance were directly related to changes in systemic vascular resistance (r = 0.75, p less than 0.5). Myocardial lactate extraction increased at rest (47 +/- 60 vs 134 +/- 132 mumol/min; p less than 0.5) and during exercise (27 +/- 54 vs 491 +/- 317 mumol/min; p less than 0.05) both in patients with coronary artery disease (n = 5) and idiopathic dilated cardiomyopathy (n = 5). Resting lactate production was converted to lactate extraction in two patients with coronary artery disease. Neither plasma catecholamine nor atrial natriuretic peptide concentrations changed significantly. The results suggest coronary vasodilation and improved aerobic myocardial metabolism by angiotensin converting enzyme inhibition in patients with congestive heart failure.

The systemic and coronary hemodynamic and neurohumoral effects of nisoldipine, a calcium antagonist drug with high vascular specificity, were investigated in 17 patients with chronic congestive heart failure (CHF). Brachial artery infusions (n = 9) decreased forearm vascular resistance in a dose-dependent manner, attesting to its powerful arterial vasodilator properties. A dose of 3 micrograms/kg intravenously decreased mean blood pressure 16% and systemic vascular resistance 33%, while increasing stroke index 19% and ejection fraction 21% at rest and similarly during exercise. Pulmonary capillary wedge pressure decreased significantly during exercise. Intravenous infusion of nisoldipine increased rest coronary sinus flow 10% (p less than 0.05, n = 7), decreased rest and exercise coronary vascular resistance 28% and 19% (p less than 0.01) and rest myocardial oxygen consumption 14% (p less than 0.05). In 13 patients similar systemic hemodynamic results were found after treatment with oral nisoldipine, 2 X 20 mg for 4 weeks. Stroke index and stroke work index increased long-term more than acutely (31% and 12.4% vs 19% and 4.5% at rest, both p less than 0.05), which may indicate a compensated mild cardiodepressant effect of intravenous nisoldipine. Changes in forearm vascular resistance after intra-arterial administration did not correlate with changes of systemic vascular resistance after intravenous administration, suggesting that factors other than vascular calcium entry blockade importantly influence hemodynamic responses. Elevated control plasmas norepinephrine and renin levels, on average, did not change during chronic therapy but individual changes were compatible with a reduction of sympathetic activity in patients with hemodynamic improvement.(ABSTRACT TRUNCATED AT 250 WORDS)

Mean platelet volume was related to platelet count in patients with myocardial infarction (n = 55) and patients with congestive heart failure (n = 9). 18 patients with acute myocardial infarction were tested at admission and 4-7 days later, together with 13 patients with chronic stable angina and 10 patients with chest pain which was not related to coronary artery disease. In citrated blood a relative reduced frequency of large platelets (greater than 13 fl) occurred in patients with acute myocardial infarction at admission but was not seen during recovery or in patients with chronic stable angina. This suggests consumption of large platelets at time of thrombus formation. No relation was found between plasma catecholamine levels and mean platelet volumes. Effects of serotonine, adrenaline and CGP 28392, a calcium agonist, on platelet volume distributions were determined. Sensitivity of platelets to adrenaline was increased in patients with acute myocardial infarction on admission and reduced 4-7 days later, while in patients with congestive heart failure reactivity to both serotonine and adrenaline were reduced. This indicates a fast down-regulation during the early recovery phase of myocardial infarction and chronically in congestive heart failure.

To define the relation between atrial pressures and the release of atrial natriuretic peptide, we measured plasma concentrations of the peptide in 26 patients with cardiac disease--11 with normal atrial pressures and 15 with elevated atrial pressures (11 of these 15 had elevated pressures in both atria). Mean peptide levels (+/- SEM) in the peripheral venous blood were increased in the 11 patients with cardiac disease and normal atrial pressures, as compared with 60 healthy controls (48 +/- 14 vs. 17 +/- 2 pmol per liter). In the patients with elevated atrial pressures, peptide concentrations were increased twofold in peripheral venous, right atrial, pulmonary arterial, and systemic arterial plasma, as compared with the concentrations in the patients with normal atrial pressures. A step-up in peptide concentration was seen between the venous and right atrial plasma (P less than 0.002) and between the pulmonary and systemic arterial plasma (P less than 0.01), suggesting release of the peptide from the atria. A linear relation was found between right atrial pressure and right atrial peptide concentration (r = 0.835, P less than 0.001) and between pulmonary wedge pressure and the systemic arterial peptide concentration (r = 0.866, P less than 0.001). Right atrial pressure and the peptide concentration both increased with exercise testing in the nine patients evaluated. We conclude that the release of atrial natriuretic peptide is at least partly regulated by right and left atrial pressures. Distinguishing the relative contributions of the two atria and defining the role of peptide release in the pathogenesis of heart failure will require further investigation.

Abstract: Background: The purpose of this pilot study was to determine the utility of acoustic cardiography for the optimization of atrioventricular (AV) and interventricular (VV) delays in cardiac resynchronization therapy (CRT). Methods and Results: We evaluated 14 patients (86% male, mean age 64 ± 9 years, mean time since implant 15 ± 18 months). Subjects were enrolled >10 weeks after CRT implant. Spiroergometry and 2-dimensional/3-dimensional echocardiography were used to assess cardiac performance for “out-of-the-box” settings (baseline settings: AV 120 ms, VV 0 ms) versus optimal settings (determined by acoustic cardiography). Cardiac performance measurements were performed 6 weeks after settings were modified. Optimal AV/VV settings were determined based on the lowest electromechanical activation time (EMAT, the time from the onset of QRS to the mitral valve component of the first heart sound). Statistical analysis was performed using a paired 2-tailed Student''s t-test. In comparison to “out-of-the-box” settings, AV/VV delay optimization with acoustic cardiography improved cardiac performance as indicated by significant changes in work capacity, maximum oxygen uptake, oxygen pulse, ejection fraction, end-systolic volume, and velocity-time integral in left ventricular outflow tract. Conclusions: AV and VV optimization by acoustic cardiography produces significant improvements in objective clinical and hemodynamic parameters in comparison to typical “out-of-the-box” settings. [Copyright &y& Elsevier]