Craig Stolen

Chronic vagal stimulation for the treatment of low ejection fraction heart failure: results of the NEural Cardiac TherApy foR Heart Failure (NECTAR-HF) randomized controlled trial

Aim The neural cardiac therapy for heart failure (NECTAR-HF) was a randomized sham-controlled trial designed to evaluate whether a single dose of vagal nerve stimulation (VNS) would attenuate cardiac remodelling, improve cardiac function and increase exercise capacity in symptomatic heart failure patients with severe left ventricular (LV) systolic dysfunction despite guideline recommended medical therapy. Methods Patients were randomized in a 2 : 1 ratio to receive therapy (VNS ON) or control (VNS OFF) for a 6-month period. The primary endpoint was the change in LV end systolic diameter (LVESD) at 6 months for control vs. therapy, with secondary endpoints of other echocardiography measurements, exercise capacity, quality-of-life assessments, 24-h Holter, and circulating biomarkers. Results Of the 96 implanted patients, 87 had paired datasets for the primary endpoint. Change in LVESD from baseline to 6 months was −0.04 ± 0.25 cm in the therapy group compared with −0.08 ± 0.32 cm in the control group (P = 0.60). Additional echocardiographic parameters of LV end diastolic dimension, LV end systolic volume, left ventricular end diastolic volume, LV ejection fraction, peak V02, and N-terminal pro-hormone brain natriuretic peptide failed to show superiority compared to the control group. However, there were statistically significant improvements in quality of life for the Minnesota Living with Heart Failure Questionnaire (P = 0.049), New York Heart Association class (P = 0.032), and the SF-36 Physical Component (P = 0.016) in the therapy group. Conclusion Vagal nerve stimulation as delivered in the NECTAR-HF trial failed to demonstrate a significant effect on primary and secondary endpoint measures of cardiac remodelling and functional capacity in symptomatic heart failure patients, but quality-of-life measures showed significant improvement.

Vagus nerve stimulation improves left ventricular function in a canine model of chronic heart failure.

Autonomic dysfunction is a feature of chronic heart failure (HF). This study tested the hypothesis that chronic open‐loop electrical vagus nerve stimulation (VNS) improves LV structure and function in canines with chronic HF.

Effect of Peri-Infarct Pacing Early After Myocardial Infarction Results of the Prevention of Myocardial Enlargement and Dilatation Post Myocardial Infarction Study

Background— Left ventricular (LV) remodeling has been attributed to the segmental loss of viable myocardium due to myocardial infarction (MI), which results in redistribution of cardiac workload, with increased regional wall stress in and around the infarct zone. Because ventricular pacing has been shown to reduce regional wall stress and workload in regions near the pacing site, this trial was designed to test whether chronic pacing near the infarct attenuates LV remodeling.nnMethods and Results— Eighty patients with an anterior MI, peak creatine kinase >2000 mU/mL, ejection fraction ≤35%, wall motion abnormality (WMA) in >5 of 16 segments, and QRS 0.05). In a hypothesis-generating secondary analysis, there was a sustained reduction in the WMA score at 12 months in paced patients (CRT, −0.16±0.28; ICD, −0.01±0.24, 2-sample t test P =0.03). No differences were found in the therapy-related event rate, hospitalizations, or mortality (all P >0.05).nnConclusions— Chronic pacing in the infarct region did not alter the primary end point of LV remodeling over 1 year.nnClinical Trial Registration— URL: . Unique identifier: [NCT00605631][1].nn [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00605631&atom=%2Fcirchf%2F3%2F6%2F650.atomBackground—Left ventricular (LV) remodeling has been attributed to the segmental loss of viable myocardium due to myocardial infarction (MI), which results in redistribution of cardiac workload, with increased regional wall stress in and around the infarct zone. Because ventricular pacing has been shown to reduce regional wall stress and workload in regions near the pacing site, this trial was designed to test whether chronic pacing near the infarct attenuates LV remodeling. Methods and Results—Eighty patients with an anterior MI, peak creatine kinase >2000 mU/mL, ejection fraction ⩽35%, wall motion abnormality (WMA) in >5 of 16 segments, and QRS <120 ms, were randomized to either control (implantable cardioverter-defribillator [ICD]) or biventricular pacing with peri-infarct LV lead placement (cardiac resynchronization therapy [CRT]-D) arms between 2 and 14 days after the MI. The primary end point—change in LV end-diastolic volume (LVEDV) from baseline to 12 months—was not significantly different between the 2 groups (CRT, 10.6±27.7 mL; ICD, 11.2±31.2 mL; 2-sample t test P>0.05). In a hypothesis-generating secondary analysis, there was a sustained reduction in the WMA score at 12 months in paced patients (CRT, −0.16±0.28; ICD, −0.01±0.24, 2-sample t test P=0.03). No differences were found in the therapy-related event rate, hospitalizations, or mortality (all P>0.05). Conclusions—Chronic pacing in the infarct region did not alter the primary end point of LV remodeling over 1 year. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00605631.

Plasma Galectin-3 and Heart Failure Outcomes in MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy)

BACKGROUNDnElevated circulating levels of the protein galectin-3, a mediator of fibrogenesis, have previously been associated with adverse outcomes in heart failure (HF) patients and appear to modify response to certain pharmacologic therapies. This study investigated the relationship between galectin-3 level and clinical outcomes in HF patients randomized to implantable cardioverter defibrillator (ICD-only) or cardiac resynchronization therapy (CRT-D).nnnMETHODS AND RESULTSnPlasma galectin-3 concentrations were measured in 654 New York Heart Association functional class I/II patients participating in the MADIT-CRT trial. A heterogeneity of response was detected between pre-implantation galectin-3 and randomization group (CRT-D or ICD-only) on the primary MADIT-CRT trial end point of nonfatal HF event or death (Pxa0=xa0.045). Among patients with baseline galectin-3 levels in the top quartile of the distribution, CRT-D was associated with a 65% reduction in risk of the primary end point (hazard ratio [HR] 0.35, 95% confidence interval [CI] 0.19-0.67), whereas among patients with lower baseline galectin-3 values CRT-D was associated with a 25% decrease in risk (HR 0.75, 95% CI. 0.51-1.11). Baseline galectin-3 level also was observed to be an independent predictor of the primary end point (multivariable adjusted HR per log unit increase: 1.55; 95% CI 1.01-2.38; Pxa0=xa0.043).nnnCONCLUSIONSnElevated galectin-3 was found to be an independent predictor of adverse HF outcome in patients with mildly symptomatic HF. A significant interaction of device randomization group with pre-implantation galectin-3 level was detected, with HF patients with the highest baseline galectin-3 levels deriving a disproportionately larger benefit from CRT-D.

Effect of Peri-Infarct Pacing Early After Myocardial InfarctionClinical Perspective

Background— Left ventricular (LV) remodeling has been attributed to the segmental loss of viable myocardium due to myocardial infarction (MI), which results in redistribution of cardiac workload, with increased regional wall stress in and around the infarct zone. Because ventricular pacing has been shown to reduce regional wall stress and workload in regions near the pacing site, this trial was designed to test whether chronic pacing near the infarct attenuates LV remodeling.nnMethods and Results— Eighty patients with an anterior MI, peak creatine kinase >2000 mU/mL, ejection fraction ≤35%, wall motion abnormality (WMA) in >5 of 16 segments, and QRS 0.05). In a hypothesis-generating secondary analysis, there was a sustained reduction in the WMA score at 12 months in paced patients (CRT, −0.16±0.28; ICD, −0.01±0.24, 2-sample t test P =0.03). No differences were found in the therapy-related event rate, hospitalizations, or mortality (all P >0.05).nnConclusions— Chronic pacing in the infarct region did not alter the primary end point of LV remodeling over 1 year.nnClinical Trial Registration— URL: . Unique identifier: [NCT00605631][1].nn [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00605631&atom=%2Fcirchf%2F3%2F6%2F650.atomBackground—Left ventricular (LV) remodeling has been attributed to the segmental loss of viable myocardium due to myocardial infarction (MI), which results in redistribution of cardiac workload, with increased regional wall stress in and around the infarct zone. Because ventricular pacing has been shown to reduce regional wall stress and workload in regions near the pacing site, this trial was designed to test whether chronic pacing near the infarct attenuates LV remodeling. Methods and Results—Eighty patients with an anterior MI, peak creatine kinase >2000 mU/mL, ejection fraction ⩽35%, wall motion abnormality (WMA) in >5 of 16 segments, and QRS <120 ms, were randomized to either control (implantable cardioverter-defribillator [ICD]) or biventricular pacing with peri-infarct LV lead placement (cardiac resynchronization therapy [CRT]-D) arms between 2 and 14 days after the MI. The primary end point—change in LV end-diastolic volume (LVEDV) from baseline to 12 months—was not significantly different between the 2 groups (CRT, 10.6±27.7 mL; ICD, 11.2±31.2 mL; 2-sample t test P>0.05). In a hypothesis-generating secondary analysis, there was a sustained reduction in the WMA score at 12 months in paced patients (CRT, −0.16±0.28; ICD, −0.01±0.24, 2-sample t test P=0.03). No differences were found in the therapy-related event rate, hospitalizations, or mortality (all P>0.05). Conclusions—Chronic pacing in the infarct region did not alter the primary end point of LV remodeling over 1 year. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00605631.

Long-term vagal stimulation for heart failure: Eighteen month results from the NEural Cardiac TherApy foR Heart Failure (NECTAR-HF) trial

BACKGROUNDnThe NECTAR-HF study evaluated safety and feasibility of vagal nerve stimulation (VNS) for the treatment of heart failure patients. The first six-month randomized phase of the study did not show improvement in left ventricular remodelling in response to VNS. This study reports the 18-month results and provides novel findings aiming to understand the lack of efficacy of VNS, including a new technique assessing the effects of VNS.nnnMETHODSnNinety-six patients were randomized 2:1 to active or inactive VNS for 6months, thereafter VNS was activated for all patients. The primary safety endpoint was 18-month all-cause mortality.nnnRESULTSnNinety-one patients continued in the long-term evaluation with active VNS. The on-therapy survival estimate at 18months was 95% with a 95% one-sided lower confidence limit of 91%, (better than the predefined criterion). Left ventricular systolic volume decreased in the crossover group (VNS OFF→ON; 144±37 to 139±40, p<0.05) after VNS activation; LVESD (5.02±0.77 to 4.96±0.82, p>0.05) and LVEF (33.2±4.9 to 33.3±6.5, p>0.05) did not change. A new technique to detect subtle heart rate changes during Holter recordings, i.e. heat maps, revealed that VNS evoked heart rate response in only 13/106 studies (12%) at 6 and 12months with active VNS.nnnCONCLUSIONSnAlthough a favourable long-term safety profile was found, improvements in the efficacy endpoints were not seen with VNS. A new technique for detecting acute heart rate responses to VNS suggests that the recruitment of nerve fibres responsible for heart rate changes were substantially lower in NECTAR-HF than in pre-clinical models.

Soluble ST2 and Risk of Arrhythmias, Heart Failure, or Death in Patients with Mildly Symptomatic Heart Failure: Results from MADIT-CRT

Soluble ST2 is an established biomarker of heart failure (HF) progression. Data about its prognostic implications in patients with mildly symptomatic HF eligible to receive cardiac resynchronization therapy defibrillators (CRT-D) are limited. In a cohort of 684 patients enrolled in Multicenter Automated Defibrillator Implantation Trial (MADIT)-CRT, levels of soluble ST2 (sST2) were serially assessed at baseline and 1xa0year (nu2009=u2009410). In multivariable-adjusted models, elevated baseline sST2 was associated with an increased risk of death, death or HF, and death or ventricular arrhythmia (VA) even when adjusting for baseline brain natriuretic protein (BNP) levels. In addition, patients with lower baseline sST2 levels had greater risk reduction with CRT-D (pu2009=u20090.006). Serial assessment revealed increased risk of VA and death or VA (HR per 10xa0% increase in sST2 1.11 (1.04–1.20), pu2009=u20090.004). Among patients with mildly symptomatic HF and eligibility for CRT-D, baseline and serial assessments sST2 may provide important information for risk stratification.

Vagal Nerve Stimulation Evoked Heart Rate Changes and Protection from Cardiac Remodeling

This study investigated whether vagal nerve stimulation (VNS) leads to improvements in ischemic heart failure via heart rate modulation. At 7u2009±u20091xa0days post left anterior descending artery (LAD) ligation, 63 rats with myocardial infarctions (MI) were implanted with ECG transmitters and VNS devices (MIu2009+u2009VNS, Nu2009=u200944) or just ECG transmitters (MI, Nu2009=u200917). VNS stimulation was active from 14u2009±u20091xa0days to 8u2009±u20091xa0weeks post MI. The average left ventricular (LV) end diastolic volumes at 8u2009±u20091xa0weeks were MIu2009=u2009672.40xa0μl and MIu2009+u2009VNSu2009=u2009519.35xa0μl, pu2009=u20090.03. The average heart weights, normalized to body weight (±std) at 14u2009±u20091xa0weeks were MIu2009=u20093.2u2009±u20090.6xa0g*kg−1 and MIu2009+u2009VNSu2009=u20092.9u2009±u20090.3xa0g*kg−1, pu2009=u20090.03. The degree of cardiac remodeling was correlated with the magnitude of acute VNS-evoked heart rate (HR) changes. Further research is required to determine if the acute heart rate response to VNS activation is useful as a heart failure biomarker or as a tool for VNS therapy characterization.

Effect of Peri-Infarct Pacing Early After Myocardial InfarctionClinical Perspective: Results of the Prevention of Myocardial Enlargement and Dilatation Post Myocardial Infarction Study

Background— Left ventricular (LV) remodeling has been attributed to the segmental loss of viable myocardium due to myocardial infarction (MI), which results in redistribution of cardiac workload, with increased regional wall stress in and around the infarct zone. Because ventricular pacing has been shown to reduce regional wall stress and workload in regions near the pacing site, this trial was designed to test whether chronic pacing near the infarct attenuates LV remodeling.nnMethods and Results— Eighty patients with an anterior MI, peak creatine kinase >2000 mU/mL, ejection fraction ≤35%, wall motion abnormality (WMA) in >5 of 16 segments, and QRS 0.05). In a hypothesis-generating secondary analysis, there was a sustained reduction in the WMA score at 12 months in paced patients (CRT, −0.16±0.28; ICD, −0.01±0.24, 2-sample t test P =0.03). No differences were found in the therapy-related event rate, hospitalizations, or mortality (all P >0.05).nnConclusions— Chronic pacing in the infarct region did not alter the primary end point of LV remodeling over 1 year.nnClinical Trial Registration— URL: . Unique identifier: [NCT00605631][1].nn [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00605631&atom=%2Fcirchf%2F3%2F6%2F650.atomBackground—Left ventricular (LV) remodeling has been attributed to the segmental loss of viable myocardium due to myocardial infarction (MI), which results in redistribution of cardiac workload, with increased regional wall stress in and around the infarct zone. Because ventricular pacing has been shown to reduce regional wall stress and workload in regions near the pacing site, this trial was designed to test whether chronic pacing near the infarct attenuates LV remodeling. Methods and Results—Eighty patients with an anterior MI, peak creatine kinase >2000 mU/mL, ejection fraction ⩽35%, wall motion abnormality (WMA) in >5 of 16 segments, and QRS <120 ms, were randomized to either control (implantable cardioverter-defribillator [ICD]) or biventricular pacing with peri-infarct LV lead placement (cardiac resynchronization therapy [CRT]-D) arms between 2 and 14 days after the MI. The primary end point—change in LV end-diastolic volume (LVEDV) from baseline to 12 months—was not significantly different between the 2 groups (CRT, 10.6±27.7 mL; ICD, 11.2±31.2 mL; 2-sample t test P>0.05). In a hypothesis-generating secondary analysis, there was a sustained reduction in the WMA score at 12 months in paced patients (CRT, −0.16±0.28; ICD, −0.01±0.24, 2-sample t test P=0.03). No differences were found in the therapy-related event rate, hospitalizations, or mortality (all P>0.05). Conclusions—Chronic pacing in the infarct region did not alter the primary end point of LV remodeling over 1 year. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00605631.