Amos Katz

Relaxin for the treatment of patients with acute heart failure (Pre-RELAX-AHF): a multicentre, randomised, placebo-controlled, parallel-group, dose-finding phase IIb study

BACKGROUND Most patients admitted for acute heart failure have normal or increase blood pressure. Relaxin is a natural human peptide that affects multiple vascular control pathways, suggesting potential mechanisms of benefit for such patients. We assessed the dose response of relaxins effect on symptom relief, other clinical outcomes, and safety. METHODS In a placebo-controlled, parallel-group, dose-ranging study, 234 patients with acute heart failure, dyspnoea, congestion on chest radiograph, and increased brain natriuretic peptide (BNP) or N-terminal prohormone of BNP, mild-to-moderate renal insufficiency, and systolic blood pressure greater than 125 mm Hg were recruited from 54 sites in eight countries and enrolled within 16 h of presentation. Patients were randomly assigned, in a double-blind manner via a telephone-based interactive voice response system, to standard care plus 48-h intravenous infusion of placebo (n=62) or relaxin 10 microg/kg (n=40), 30 microg/kg (n=43), 100 microg/kg (n=39), or 250 microg/kg (n=50) per day. Several clinical endpoints were explored to assess whether intravenous relaxin should be pursued in larger studies of acute heart failure, to identify an optimum dose, and to help to assess endpoint selection and power calculations. Analysis was by modified intention to treat. This study is registered with ClinicalTrials.gov, number NCT00520806. FINDINGS In the modified intention-to-treat population, 61 patients were assessed in the placebo group, 40 in the relaxin 10 microg/kg per day group, 42 in the relaxin 30 microg/kg per day group, 37 in the relaxin 100 microg/kg per day group, and 49 in the relaxin 250 microg/kg per day group. Dyspnoea improved with relaxin 30 microg/kg compared with placebo, as assessed by Likert scale (17 of 42 patients [40%] moderately or markedly improved at 6 h, 12 h, and 24 h vs 14 of 61 [23%]; p=0.044) and visual analogue scale through day 14 (8214 mm x h [SD 8712] vs 4622 mm x h [9003]; p=0.053). Length of stay was 10.2 days (SD 6.1) for relaxin-treated patients versus 12.0 days (7.3) for those given placebo, and days alive out of hospital were 47.9 (10.1) versus 44.2 (14.2). Cardiovascular death or readmission due to heart or renal failure at day 60 was reduced with relaxin (2.6% [95% CI 0.4-16.8] vs 17.2% [9.6-29.6]; p=0.053). The number of serious adverse events was similar between groups. INTERPRETATION When given to patients with acute heart failure and normal-to-increased blood pressure, relaxin was associated with favourable relief of dyspnoea and other clinical outcomes, with acceptable safety.

The weighted diagnostic distortion (WDD) measure for ECG signal compression

In this paper, a new distortion measure for electrocardiogram (ECG) signal compression, called weighted diagnostic distortion (WDD) is introduced. The WDD measure is designed for comparing the distortion between original ECG signal and reconstructed ECG signal (after compression). The WDD is based on PQRST complex diagnostic features (such as P wave duration, QT interval, T shape, ST elevation) of the original ECG signal and the reconstructed one. Unlike other conventional distortion measures [e.g. percentage root mean square (rms) difference, or PRD], the WDD contains direct diagnostic information and thus is more meaningful and useful. Four compression algorithms were implemented (AZTEC, SAPA2, LTP, ASEC) in order to evaluate the WDD. A mean opinion score (MOS) test was applied to test the quality of the reconstructed signals and to compare the quality measure (MOS/sub error/) with the proposed WDD measure and the popular PRD measure. The evaluators in the WIGS test were three independent expert cardiologists, who studied the reconstructed ECG signals in a blind and a semiblind tests. The correlation between the proposed WDD measure and the MOS test measure (MOS/sub error/) was found superior to the correlation between the popular PRD measure and the MOS/sub error/.

Implant-based multiparameter telemonitoring of patients with heart failure (IN-TIME): a randomised controlled trial

BACKGROUND An increasing number of patients with heart failure receive implantable cardioverter-defibrillators (ICDs) or cardiac resynchronisation defibrillators (CRT-Ds) with telemonitoring function. Early detection of worsening heart failure, or upstream factors predisposing to worsening heart failure, by implant-based telemonitoring might enable pre-emptive intervention and improve outcomes, but the evidence is weak. We investigated this possibility in IN-TIME, a clinical trial. METHODS We did this randomised, controlled trial at 36 tertiary clinical centres and hospitals in Australia, Europe, and Israel. We enrolled patients with chronic heart failure, NYHA class II-III symptoms, ejection fraction of no more than 35%, optimal drug treatment, no permanent atrial fibrillation, and a recent dual-chamber ICD or CRT-D implantation. After a 1 month run-in phase, patients were randomly assigned (1:1) to either automatic, daily, implant-based, multiparameter telemonitoring in addition to standard care or standard care without telemonitoring. Investigators were not masked to treatment allocation. Patients were masked to allocation unless they were contacted because of telemonitoring findings. Follow-up was 1 year. The primary outcome measure was a composite clinical score combining all-cause death, overnight hospital admission for heart failure, change in NYHA class, and change in patient global self-assessment, for the intention-to-treat population. The trial is registered with ClinicalTrials.gov, number NCT00538356. FINDINGS We enrolled 716 patients, of whom 664 were randomly assigned (333 to telemonitoring, 331 to control). Mean age was 65·5 years and mean ejection fraction was 26%. 285 (43%) of patients had NYHA functional class II and 378 (57%) had NYHA class III. Most patients received CRT-Ds (390; 58·7%). At 1 year, 63 (18·9%) of 333 patients in the telemonitoring group versus 90 (27·2%) of 331 in the control group (p=0·013) had worsened composite score (odds ratio 0·63, 95% CI 0·43-0·90). Ten versus 27 patients died during follow-up. INTERPRETATION Automatic, daily, implant-based, multiparameter telemonitoring can significantly improve clinical outcomes for patients with heart failure. Such telemonitoring is feasible and should be used in clinical practice. FUNDING Biotronik SE & Co. KG.

ECG signal compression using analysis by synthesis coding

An electrocardiogram (ECG) compression algorithm, called analysis by synthesis ECG compressor (ASEC), is introduced. The ASEC algorithm is based on analysis by synthesis coding, and consists of a beat codebook, long and short-term predictors, and an adaptive residual quantizer. The compression algorithm uses a defined distortion measure in order to efficiently encode every heartbeat, with minimum bit rate, while maintaining a predetermined distortion level. The compression algorithm was implemented and tested with both the percentage rms difference (PRD) measure and the recently introduced weighted diagnostic distortion (WDD) measure. The compression algorithm has been evaluated with the MIT-BIH Arrhythmia Database. A mean compression rate of approximately 100 bits/s (compression ratio of about 30:1) has been achieved with a good reconstructed signal quality (WDD below 4% and PRD below 8%). The ASEC was compared with several well-known ECG compression algorithms and was found to be superior at all tested bit rates. A mean opinion score (MOS) test was also applied. The testers were three independent expert cardiologists. As In the quantitative test, the proposed compression algorithm was found to be superior to the other tested compression algorithms.

Evaluation of ranolazine in patients with type 2 diabetes mellitus and chronic stable angina: results from the TERISA randomized clinical trial (Type 2 Diabetes Evaluation of Ranolazine in Subjects With Chronic Stable Angina).

OBJECTIVES This study sought to examine the efficacy of ranolazine versus placebo on weekly angina frequency and sublingual nitroglycerin use in subjects with type 2 diabetes mellitus, coronary artery disease (CAD), and chronic stable angina who remain symptomatic despite treatment with up to 2 antianginal agents. BACKGROUND Patients with diabetes have more extensive CAD than those without diabetes, and a high burden of angina. Ranolazine is not only effective in treating angina but also may improve glycemic control, thus providing several potential benefits in this high-risk group. We conducted a randomized trial to test the antianginal benefit of ranolazine in patients with diabetes and stable angina. METHODS TERISA (Type 2 Diabetes Evaluation of Ranolazine in Subjects With Chronic Stable Angina) was an international, randomized, double-blind trial of ranolazine versus placebo in patients with diabetes, CAD, and stable angina treated with 1 to 2 antianginals. After a single-blind, 4-week placebo run-in, patients were randomized to 8 weeks of double-blind ranolazine (target dose 1000 mg bid) or placebo. Anginal episodes and nitroglycerin use were recorded with daily entry into a novel electronic diary. Primary outcome was the average weekly number of anginal episodes over the last 6 weeks of the study. RESULTS A total of 949 patients were randomized across 104 centers in 14 countries. Mean age was 64 years, 61% were men, mean diabetes duration was 7.5 years, and mean baseline HbA1c was 7.3%. Electronic diary data capture was 98% in both groups. Weekly angina frequency was significantly lower with ranolazine versus placebo (3.8 [95% confidence interval (CI): 3.6 to 4.1] episodes vs. 4.3 [95% CI: 4.0 to 4.5] episodes, p = 0.008), as was the weekly sublingual nitroglycerin use (1.7 [95% CI: 1.6 to 1.9] doses vs. 2.1 [95% CI: 1.9 to 2.3] doses, p = 0.003). There was no difference in the incidence of serious adverse events between groups. CONCLUSIONS Among patients with diabetes and chronic angina despite treatment with up to 2 agents, ranolazine reduced angina and sublingual nitroglycerin use and was well tolerated. (Type 2 Diabetes Evaluation of Ranolazine in Subjects With Chronic Stable Angina [TERISA]; NCT01425359).

A simple bedside test of 1-minute heart rate variability during deep breathing as a prognostic index after myocardial infarction☆☆☆

BACKGROUND We evaluate a simple, bedside test that measures 1-minute heart rate variability in deep breathing as a predictor of death after myocardial infarction. METHODS Bedside heart rate variability was assessed in 185 consecutive patients 5.1 +/- 2.5 days after a first myocardial infarction. Patients were instructed to take 6 deep respirations in 1 minute while changes in heart rate were measured and calculated by an electrocardiographic recorder. An abnormal test result was defined as a difference of less than 10 beats/min between the shortest and longest heart rate interval. RESULTS Heart rate variability <10 beats/min was found in 65 patients (35%) and was significantly lower (P <.05) in women, patients >60 years of age, patients with diabetes, patients with congestive heart failure, and patients taking angiotensin-converting enzyme inhibitors. Mean follow-up period was 16 months. Ten patients died during follow-up: 9 of cardiac causes and 1 of stroke. Nine of these 10 patients had heart rate variability <10 beats/min (P =.004). The sensitivity and specificity of this test for cardiovascular mortality is 90.0% and 68.0%, respectively. The negative predictive value is 99.2% and the relative risk is 16.6. Heart rate variability <10 beats/min remained a significant predictor of death after adjusting for clinical, demographic, and left ventricular function with an odds ratio of 1.38 (95% confidence interval, 1.13-1.63). CONCLUSIONS This simple, brief bedside deep breathing test of heart rate variability in patients after myocardial infarction appears to be a good predictor for all-cause mortality and sudden death. It may be used as a clinical test for risk stratification after myocardial infarction.

Measurements of cardiac output by impedance cardiography in pacemaker patients at rest: Effects of various atrioventricular delays

OBJECTIVES The purpose of this study was to evaluate the ability of impedance cardiography to determine the change in cardiac output caused by modifications in the atrioventricular (AV) delay in DDD (dual-chamber) pacing mode while pacing the atrium and ventricle at different programmed rates. BACKGROUND Impedance cardiography permits continuous noninvasive monitoring of hemodynamic variables on a beat to beat basis. METHODS Eleven patients with a DDD pacemaker were evaluated by impedance cardiography. Stroke volume, cardiac output and total peripheral resistance were assessed in the supine rest position during both DDD and ventricular (VVI) pacing. Hemodynamic variables were measured during DDD pacing at rates ranging from 60 to 110 beats/min in 10-beats/min increments with programmed AV delay varying from 50 to 250 ms in 50-ms increments. When the pacemaker was reprogrammed to the VVI pacing mode, these measurements were repeated at the same pacing rates. RESULTS Cardiac output measurements during programmed conditions were found to be highly reproducible. The mean coefficient of variation was 3% during DDD pacing; it was 6% in the VVI pacing mode. A large decrease in cardiac output (approximately 30%) was found when a pacemaker was reprogrammed from the DDD to the VVI pacing mode. At DDD pacing rates between 70 to 110 beats/min, the highest cardiac output occurred at an average AV delay of < 120 ms from atrial stimulus to ventricular stimulus. At an average AV delay of > or = 200 ms, the cardiac output in the DDD and VVI pacing modes was similar. CONCLUSIONS 1) Impedance cardiography allows highly reproducible noninvasive assessments of cardiac output in pacemaker patients; 2) inappropriate programming of the AV interval in patients with atrial and ventricular pacing can decrease cardiac output significantly, and the extent of the decrease is similar to or less than that observed in ventricular pacing; 3) hemodynamic measurements obtained with impedance cardiography can facilitate optimal programming of pacemaker variables.

Cardiopoietic cell therapy for advanced ischemic heart failure: results at 39 weeks of the prospective, randomized, double blind, sham-controlled CHART-1 clinical trial

Aims Cardiopoietic cells, produced through cardiogenic conditioning of patients’ mesenchymal stem cells, have shown preliminary efficacy. The Congestive Heart Failure Cardiopoietic Regenerative Therapy (CHART-1) trial aimed to validate cardiopoiesis-based biotherapy in a larger heart failure cohort. Methods and results This multinational, randomized, double-blind, sham-controlled study was conducted in 39 hospitals. Patients with symptomatic ischaemic heart failure on guideline-directed therapy (n = 484) were screened; n = 348 underwent bone marrow harvest and mesenchymal stem cell expansion. Those achieving > 24 million mesenchymal stem cells (n = 315) were randomized to cardiopoietic cells delivered endomyocardially with a retention-enhanced catheter (n = 157) or sham procedure (n = 158). Procedures were performed as randomized in 271 patients (n = 120 cardiopoietic cells, n = 151 sham). The primary efficacy endpoint was a Finkelstein–Schoenfeld hierarchical composite (all-cause mortality, worsening heart failure, Minnesota Living with Heart Failure Questionnaire score, 6-min walk distance, left ventricular end-systolic volume, and ejection fraction) at 39 weeks. The primary outcome was neutral (Mann–Whitney estimator 0.54, 95% confidence interval [CI] 0.47–0.61 [value > 0.5 favours cell treatment], P = 0.27). Exploratory analyses suggested a benefit of cell treatment on the primary composite in patients with baseline left ventricular end-diastolic volume 200–370 mL (60% of patients) (Mann–Whitney estimator 0.61, 95% CI 0.52–0.70, P = 0.015). No difference was observed in serious adverse events. One (0.9%) cardiopoietic cell patient and 9 (5.4%) sham patients experienced aborted or sudden cardiac death. Conclusion The primary endpoint was neutral, with safety demonstrated across the cohort. Further evaluation of cardiopoietic cell therapy in patients with elevated end-diastolic volume is warranted.

Initial Experience with a New Algorithm for Automatic Mode Switching from DDDR to DDIR Mode

Implantation of dual chamber devices in patients with paroxysmal atrial tachyarrhythmias who require permanent pacemakers may lead to significant complications due to an inappropriately triggered ventricular response. VVI/VVIR units cause loss of AV synchrony in the presence of sinus activity. A new DDDR device (THERA DR, model 7940), with an automatic mode switching (AMS) algorithm, was evaluated. When the mean atrial rate is > 182 beats/min, atrial tachyarrhythmia is detected, and AMS is activated. Twenty‐three patients (12 males, mean age 71 ± 7 years) underwent implantation of a THERA DDDR device with the AMS algorithm. Seventeen patients had AV block and/ or sick sinus syndrome (SSS) and atrial arrhythmias, and 6 patients (2 with hypertrophic obstructive cardiomyopathy) had SSS and paroxysmal atrial fibrillation (PAF). The follow‐up period was from 1–9 months. During follow‐up, Holter monitoring and treadmill tests were performed. Results: Eighty‐seven episodes of AMS were recorded. Telemetered AMS recordings demonstrated episodes in which the DDDR mode switched to the DDIR mode in the presence of PAF, and reverted to DDDR when sinus rhythm returned. Paroxysmal supraventricuiar arrhythmias with a heart rate < 182 beats/min did not activate tbe mode switch. Conclusions: This early, short‐term clinical experience with a DDDR device capable of AMS from DDDR to DDIR demonstrated appropriate clinical function and response to PAF. These preliminary results suggest that DDDR pacemakers with AMS to DDIR may significantly extend the current indications for dual chamber pacing.

Clinical Evaluation of a New Single Pass Lead VDD Pacing System

Twenty‐five patients with second‐ to third‐degree AV block and normal sinus function (16 males, mean age 60 ± 18; range 15–78 years) underwent implantation of WD pacemakers (THERA VDD, Medtronic, Inc.) with a single pass (SP) lead. Results: During implantation the mean amplitude of the atrial (A) signal was 3.9 ±1.4 mV (range 2.0–7.8 mV). Stable, acceptable A‐signals during implantation were usually observed in the mid‐ or lower part of the right atrium. The lead tip electrical parameters were not compro mised in any patient in order to obtain an acceptable A‐signal. To verify VDD device function, patients underwent pacing system analysis on the second day and again 1, 3, and 6 months after implantation. Acute and chronic electrical measurements in the ventricle were similar to those with regular steroid leads. During follow‐up tests, stable atrial sensing (A ≥ 0.7mV) was found in all but one patient (in whom A was 0.25–0.5 mV and an intermittent loss of atriai sensing occurred). There was no difference between serial measurements of A‐signal amplitudes on the second day or 1, 3, and 6 months after implantation: 1.9 ± 1.3 mV, 1.5 ± 0.6 mV, 1.3 ± 0.8 mV, and 1.5 ± 1.1 mV, respectively. The mean implantation time was 54.0 ± 17 minutes and the mean fluoroscopy time was 3.2 ±1.3 minutes. Conclusions: SP lead VDD pacing is reliable and easy to manage with dependable atriai sensing and ventricular pacing. The significant reduction in atriai postimplantation amplitude is related to the different techniques used for measuring acute and chronic atriai signals.