Magnitude Of Heart Rate Reduction Research Articles

Persistent Autonomic Engagement and Cardiac Control After Four or More Years of Autonomic Regulation Therapy Using Vagus Nerve Stimulation.

IntroductionAlthough heart failure (HF) outcomes have improved dramatically with the use of guideline directed medical therapy and implantable devices, the overall prognosis of patients with HF and reduced ejection fraction (HFrEF) remains poor. Autonomic Regulation Therapy (ART) using chronic vagus nerve stimulation (VNS) has been evaluated in the ANTHEM-HF study, using changes in heart rate (HR) dynamics as a biomarker of autonomic nervous system engagement and cardiac control to guide VNS titration. ART was associated with sustained improvement in cardiac function and HF symptoms in patients with HFrEF and persistent HF symptoms despite guideline-directed medical therapy (GDMT). We sought to determine whether the responsiveness of the autonomic nervous system to ART, as reflected in HR response to vagus stimulation during the VNS duty cycle, is maintained after long-term chronic VNS administration.MethodsFifteen patients with HFrEF and implanted with a VNS systems in the ANTHEM-HF study were evaluated after 4.7 ± 0.3 years (range: 4.0–5.0 years) of chronic ART. ECG electrodes were placed on each patient’s wrists, and ECG rhythm strips were recorded. Instantaneous HR time series was computed at each patient’s chronically programmed VNS intensity and during progressively increasing VNS intensity. HR during active stimulation (on-time) was compared to HR just prior to initiation of each stimulation cycle (off-time).ResultsPersistent autonomic engagement was observed in a majority of patients (11 of 15, 73%) after chronic ART for four or more years. The average magnitude of HR reduction during ART on-time in all patients was 2.4 ± 3.2 bpm at the chronically programmed VNS pulse parameter settings.ConclusionAutonomic responsiveness to VNS persists in patients with HFrEF who received chronic ART for up to 5 years as a supplement to GDMT. This suggests that the effects of ART on autonomic engagement and cardiac control remain durable over time.Clinical Trial Registration[ClinicalTrials.gov], identifier [#NCT01823887, CTRI registration #CTRI/2012/05/002681].

How Heart Rate Should Be Controlled in Patients with Atherosclerosis and Heart Failure.

Resting heart rate is an independent risk factor for all-cause and cardiovascular mortality in patients with heart failure. The main objectives are to discuss the prognosis of heart rate, its association with coronary atherosclerosis, and the modalities of control of the heart rate in sinus rhythm and in the rhythm of atrial fibrillation in patients with chronic heart failure. As a therapeutic option for control heart rate, medications such as beta-blockers, digoxin, and finally ivabradine have been studied. Non-dihydropyridine calcium channel blockers are contraindicated in patients with heart failure and reduced ejection fraction. The influence of the magnitude of heart rate reduction and beta-blocker dose on morbidity and mortality will be discussed. Regarding the patients with heart failure and atrial fibrillation, there are different findings in heart rate control with the use of a beta-blocker. Patients eligible for ivabradine have clinical benefits and increased ejection fraction. Vagal nerve stimulation has low efficacy for the control of heart rate. Complementary therapies such as tai chi and yoga showed no effect on heart rate. In this review, we discuss the main therapeutic options for the control of heart rate in patients with atherosclerosis and heart failure. More research is needed to examine the effects of therapeutic options for heart rate control in different population types, as well as their effects on clinical outcomes and impact on morbidity and mortality.

Comparison of efficacy and safety of cilnidipine and losartan in patients of hypertension with or without diabetes from Gwalior, India

Background: Hypertension (HTN) is the most common cardiovascular disease. The objectives of present study are to investigate the comparison between cilnidipine and losartan with respect to changes in blood pressure (BP) and heart rate (HR) in hypertensive patients with or without type 2 diabetes mellitus (DM).Methods: We conducted a longitudinal, prospective, open labelled, comparative clinical study of hypertensive patients with or without type 2 DM. Of 161 enrolled hypertensives, 130 completed the study with follow up over a period of one year. Group I (n=34); and Group III (n = 32) patients with type 2 DM received cilnidipine 10-20mg orally OD. Group II (n =33); and Group IV (n = 31) patients with type 2 DM received losartan 50-100mg orally OD. The dosages were adjusted if the magnitude of reduction was insufficient. The parameters were monitored during follow – up at 4, 8 and 12 weeks.Results: Levels of systolic and diastolic BP and HR significantly decreased with both drugs. However, magnitude of HR reduction was greater with cilnidipine groups as compared to losartan groups with statistically significant difference (group I 70.79±9.21 versus group II 79.42±8.25, p = 0.000 and group III 76.25±7.08 versus group IV 81±7.15, p = 0.010). Of 161 patients, only 1 patient experienced hot flushes from group I.Conclusions: The present study demonstrated that therapy with cilnidipine can be used safely and effectively in hypertensive patients with or without diabetes. Cilnidipine was equally efficacious in lowering BP, while it more effectively reduced HR as compared to losartan. Cilnidipine can, therefore, be recommended as an alternative especially when there is associated tachycardia.

Effect of Carvedilol on Serum Heart-type Fatty Acid-binding Protein, Brain Natriuretic Peptide, and Cardiac Function in Patients With Chronic Heart Failure.

To observe the changes of serum heart-type fatty acid-binding protein (h-FABP) and brain natriuretic peptide (BNP) in children with chronic heart failure (CHF) and evaluate the effects of carvedilol. A total of 36 patients with CHF, including 17 of endocardial fibroelastosis and 19 of dilated cardiomyopathy, were enrolled and were randomly divided into a carvedilol treatment group (group A) and a conventional treatment group (group B). Group A (n = 16) was treated with carvedilol and conventional treatment and group B (n = 20) was managed with conventional treatment only. Thirty healthy children were enrolled as controls. The concentrations of serum h-FABP and BNP were measured by enzyme-linked immunosorbent assay, and the left ventricular end-systolic diameter, left ventricular end-diastolic diameter, left ventricular ejection fraction (LVEF), left ventricular fractional shortening (LVFS), and cardiac index (CI) were measured by echocardiography. The concentrations of serum h-FABP and BNP in patients with CHF were significantly higher than in the control group (21.7 ± 4.3 ng/mL vs. 6.3 ± 1.7 ng/mL, 582.4 ± 180.6 pg/mL vs.31.2 ± 9.8 pg/mL, all P < 0.01), positively correlated with the degree of heart failure (all P < 0.01), and were both higher in groups endocardial fibroelastosis and dilated cardiomyopathy than in the control group (all P < 0.01), but there was no statistically significant difference between the 2 groups (P > 0.05). h-FABP concentration in patients with CHF was positively correlated with BNP (r = 0.78, P < 0.01) but negatively correlated with LVEF, LVFS, and CI (r = -0.65, -0.64, and -0.71, respectively; all P < 0.01). BNP concentration was also negatively correlated with LVEF, LVFS, and CI (r = -0.75, -0.61, and -0.79, respectively; all P<0.01). After treatment with carvedilol, the serum concentrations of h-FABP and BNP in group A were lower than in group B, and the magnitude of heart rate reduction, improvement of LVEF, LVFS, and CI, and reduction of left ventricular end-systolic diameter and left ventricular end-diastolic diameter in group A were all greater than in group B (all P < 0.01). Treatment with carvedilol had no adverse events. Serum concentrations of h-FABP and BNP can be used as biomarkers to evaluate the severity of heart failure, and carvedilol can significantly improve heart function in children with CHF.

Chronotropic and pressor effects of water ingestion at rest and in response to incremental dynamic exercise

Ingestion of water attenuates the chronotropic response to submaximal exercise. However, it is not known whether this effect is equally manifested during dynamic exercise below and above the ventilatory threshold (VT). We explored the effects of water ingestion on the heart rate response to an incremental cycle-ergometer protocol. In a randomized fashion, 19 healthy adults (10 men and nine women, age 20.9 ± 1.8 years) ingested 50 and 500 ml of water before completing a cycle-ergometer protocol on two separate days. The heart rate and oxygen uptake ( ) responses to water ingestion were analysed both at rest and during exercise performed below and above the VT. The effects of water intake on brachial blood pressure were measured only at rest. Resting mean arterial pressure increased and resting heart rate decreased, but only after 500 ml of water (P < 0.05). Compared with that seen after 50 ml of water, the 500 ml volume elicited an overall decrease in submaximal heart rate (P < 0.05). In contrast, drinking 500 ml of water did not affect submaximal . The participants' maximal heart rate, maximal and VT were similar between conditions. Our results therefore indicate that, owing to its effects on submaximal heart rate over a broad spectrum of intensities, the drinking of water should be recognized as a potential confounder in cardiovascular exercise studies. However, by showing no differences between conditions for submaximal , they also suggest that the magnitude of heart rate reduction after drinking 500 ml of water may be of minimal physiological significance for exercise cardiorespiratory capacity.

Role of atropine in prevention of reflex bradycardia in response to awaked intubation in neonatal anesthesia

Background: Neonates (0–1 months) have different anesthetic requirements. Safe anesthetic management depends on full appreciation of the physiological, anatomic, and pharmacological characteristics of this age group. One of important difference in neonates is easy development of reflex bradycardia and cardiac standstill during anesthesia. These characteristics, differentiate them from adults, and necessitate modification of anesthetic equipment, medications, and techniques.&#x0D; Objectives: To evaluate the role of atropine in prevention of reflex bradycardia in neonatal anesthesia.&#x0D; Patients and methods: This is a prospective study done on 30 neonate patients in Baghdad teaching hospital/Baghdad /Iraq during the period from January - July/ 2009. Neonates that underwent major surgical operations, were randomly allocated into two groups, group (A) received atropine(0.015mg/kg) 5 minutes before awake intubation and group (B) (control group) received no atropine. Heart rate was recorded at pre-induction and during intubation then anesthesia was maintained in a similar way in both groups.&#x0D; Result: the results reported in this study indicate that the pre-induction with i.v. atropine was associated with a statistically significant decrease in the incidence rate of reflex bradycardia (below 100 beat/min or reduction in HR &gt; 20% of basal heart rate) during intubation from 96.65% in the group (B) (control group) to 26.6 % in the group (A) (atropine group) In addition the magnitude of reduction in heart rate was lower by a mean of 22% in the atropine group compared to the mean reduction 41% in group (B&#x0D; Conclusion: Pre-induction with IV atropine decrease in the incidence of reflex bradycardia during intubation from 96.65% in the control group (B) to 26.6% in the atropine group (A). Pre-induction of atropine reduces the magnitude of heart rate reduction during intubation by a mean of 22% compared to 41% in control group.

Clinical perspective: the importance of heart rate reduction in heart failure

Clinical perspective: the importance of heart rate reduction in heart failure

Inhibition of Ion Channels and Heart Beat in Drosophila by Selective COX-2 Inhibitor SC-791

Recent findings suggest that modulation of ion channels might be implicated in some of the clinical effects of coxibs, selective inhibitors of cyclooxygenase-2 (COX-2). Celecoxib and its inactive analog 2,5-dimethyl-celecoxib, but not rofecoxib, can suppress or augment ionic currents and alter functioning of neurons and myocytes. To better understand these unexpected effects, we have recently investigated the mechanism of inhibition of human Kv2.1 channels by a highly selective COX-2 inhibitor SC-791. In this study we have further explored the SC-791 action on ion channels and heartbeat in Drosophila, which lacks cyclooxygenases and thus can serve as a convenient model to study COX-2-independent mechanisms of coxibs. Using intracellular recordings in combination with a pharmacological approach and utilizing available Drosophila mutants, we found that SC-791 inhibited voltage-activated K+ and L-type Ca2+ channels in larval body-wall muscles and reduced heart rate in a concentration-dependent manner. Unlike celecoxib and several other K+ channel blockers, SC-791 did not induce arrhythmia. Instead, application of SC-791 resulted in a dramatic slowing of contractions and, at higher concentrations, in progressively weaker contractions with gradual cessation of heartbeat. Isradipine, a selective blocker of L-type Ca2+ channels, showed a similar pattern of heart arrest, though no prolongation of contractions was observed. Ryanodine was the only channel modulating compound of those tested additionally that was capable of slowing contractions. Like SC-791, ryanodine reduced heart rate without arrhythmia. However, it could not stop heartbeat completely even at 500 µM, the highest concentration used. The magnitude of heart rate reduction, when SC-791 and ryanodine were applied together, was smaller than expected for independent mechanisms, raising the possibility that SC-791 might be interfering with excitation-contraction coupling in Drosophila heart.

Effects on Outcomes of Heart Rate Reduction by Ivabradine in Patients With Congestive Heart Failure: Is There an Influence of Beta-Blocker Dose?: Findings From the SHIFT (Systolic Heart failure treatment with the If inhibitor ivabradine Trial) Study

This study used the SHIFT (Systolic Heart failure treatment with the I(f) inhibitor ivabradine Trial) database to assess the impact of background beta-blocker dose on response to ivabradine. In systolic heart failure, reduction in relatively high heart rates improves clinical outcomes when achieved with beta-blockers and even more so when the sinus node inhibitor ivabradine also is added. Among patients with systolic heart failure, sinus rhythm, and heart rate ≥70 beats/min on recommended background therapy, maximally tolerated beta-blocker doses were subgrouped as no beta-blocker, <25%, 25% to <50%, 50% to <100%, and 100% of European Society of Cardiology–suggested target doses. The impact of ivabradine on cardiovascular death or heart failure hospitalization (primary endpoint) was analyzed in each subgroup as time-to-first event using Cox models adjusted for heart rate. The statistical models assessed heterogeneity and trend of the treatment effect across subgroups, and an additional analysis was made adjusting for the interaction of randomized treatment with baseline heart rate. The primary endpoint and heart failure hospitalizations were significantly reduced by ivabradine in all subgroups with <50% of target beta-blocker dose, including no beta-blocker (p = 0.012). Despite an apparent trend to reduction in treatment-effect magnitude with increasing beta-blocker dose, no variation in treatment effect was seen in general heterogeneity interaction tests (p = 0.35). Across beta-blocker subgroups, treatment effect was borderline nonsignificant only for the primary endpoint (p = 0.056), and significance was further lost after adjusting for interaction between baseline heart rate and ivabradine effect (p = 0.14). The magnitude of heart rate reduction by beta-blocker plus ivabradine, rather than background beta-blocker dose, primarily determines subsequent effect on outcomes. (Effects of ivabradine on cardiovascular events in patients with moderate to severe chronic heart failure and left ventricular systolic dysfunction. A three-year randomised double-blind placebo-controlled international multicentre study; ISRCTN70429960)

Delta-opioid augments cardiac contraction through β-adrenergic and CGRP-receptor co-signaling

Cardiac epinephrine and calcitonin gene-related peptide (CGRP) are produced by intrinsic cardiac adrenergic cells (ICA cells) residing in human and animal hearts. ICA cells are neuroparicine cells expressing δ-opioid receptors (DOR). We hypothesized that δ-opioid stimulation of ICA cells enhances epinephrine and CGRP release, which results in the augmentation of heart contraction. Rats were injected with DOR-agonist DPDPE (100μg/kg) with or without 10-min pretreatment with either β-adrenergic receptor (β-AR) blocker propranolol (2mg/kg) or CGRP-receptor (CGRPR) blocker CGRP8–37 (300μg/kg), or their combination. Hemodynamics were monitored with echocardiogram and systolic blood pressure (SBP) was monitored via a tail arterial catheter. Changes in left ventricular fraction-shortening (LVFS) and heart rate (HR) were observed at 5-min after DPDPE infusion. At 5-min DPDPE induced a 36±18% (p<0.001) increase of the LVFS, which continues to increase to 51±24% (p<0.0001) by 10min, and 68±19% (p<0.001) by 20min. The increase in LVFS was accompanied by the decrease of HR by 9±5% (p<0.01) by 5min and 11±6% (p<0.001) by 15min post DPDPE infusion. This magnitude of HR reduction was observed for the remainder of the 20min. Despite the HR-reduction, cardiac output was increased by 17±8% (p<0.05) and 28±5% (p<0.001) by 5- and 20-min post DPDPE administration, respectively. There was a modest (9±9%, p=0.03) decrease in SBP that was not apparent until 20min post DPDPE infusion. The positive inotropism of DPDPE was abrogated in animals pretreated with propranolol, CGRP8–37, or combined propranolol+CGRP8–37. Furthermore, in whole animal and cardiomyocyte cell culture preparations, DPDPE induced myocardial protein-kinase A (PKA) activation which was abrogated in the animals pretreated with propranolol+CGRP8–37. DOR agonists augment myocardial contraction through enhanced β-AR and CGRPR co-signaling.

Abstract P61: Degree of Beta-Blockade and Outcomes in Patients With Acute Coronary Syndrome

Objective: We sought to determine whether the survival benefits of beta-blockade in the ACS population are associated with the magnitude of heart rate reduction. Background: Atherosclerotic coronary artery disease is the leading cause of morbidity and mortality in the United States with nearly 1.6 million hospitalizations for acute coronary syndrome (ACS) alone in 2004. Beta-blocker therapy along with anti-platelet medications, nitrates, and statins has been the corner stone of medical therapy. ACC guidelines recommend a resting heart rate (HR) goal of 50 to 60 beats per minute (bpm) in patients with ACS. However, these recommendations are not based on randomized clinical trials rather expert opinion. To date, there fails to be evidence-based clinical trials demonstrating the ideal target heart rate after initiation of beta-blockers in ACS patients. Methods: A retrospective analysis was performed from January 2007 to December 2008 in all ACS patients who underwent coronary angiography with or without PCI at Providence Hospital's Heart Institute. Patient charts, medication list and diagnostic reports were reviewed. Patients presenting with cardiogenic shock or contraindications to beta-blocker therapy were excluded. Results: A total of 430 patients were included in the analysis. (210 STEMI and 220 NSTEMI patients) HR was classified as upper (above 80 bpm), middle (67 to 80 bpm), and lower (below 67 bpm) quartiles. Each quartile was classified according to percent change in HR, the absolute change in HR between admission and discharge, and admission HR and discharge HR. Each quartile was correlated to major adverse cardiac events (MACE) and cardiac death at 30 days. There was a statistically significant difference in the composite endpoints between the upper and lower quartile on discharge HR (9% vs. 4%. p value &lt; 0.05) in both STEMI and NSTEMI patients. Conclusion: In those with ACS, primarily STEMI and NSTEMI, lower discharge HR conferred a decrease in composite endpoints at 30 days. It's unclear whether the reduction in MACE will persist beyond the initial follow-up or if there is a long-term mortality benefit with this degree of HR reduction at discharge. Further studies are needed to investigate the clinical benefits of HR reduction in the ACS population.

Heart rate reduction with ivabradine and health related quality of life in patients with chronic heart failure: results from the SHIFT study

Heart failure (HF) has a major impact on health-related quality of life (HQoL). The aim was to evaluate whether heart rate (HR) reduction with ivabradine can translate into increased HQoL in parallel to a reduction of primary outcomes in SHIFT. In symptomatic patients with systolic HF treated with recommended background therapy, HQoL was assessed by Kansas City Cardiomyopathy Questionnaire (KCCQ) containing the following dimensions: overall summary score (OSS) and clinical summary score (CSS), analysed at baseline, and 4, 12, and 24 months, and last post-baseline visit. A total of 1944 patients (968 ivabradine, 976 placebo) were evaluated. At 12 months, incidence of clinical events (cardiovascular death or hospital admission for HF) was inversely associated with KCCQ scores. Ivabradine reduced HR by 10.1 bpm (placebo-corrected, P < 0.001) and improved KCCQ by 1.8 for CSS and 2.4 for OSS (placebo-corrected, P = 0.02 and P < 0.01, respectively); these changes were associated with the change in HR for both CSS (P < 0.001) and OSS (P < 0.001). The relationship was found in both allocation groups though the changes were more pronounced in the ivabradine group. Health-related quality of life at follow-up was better preserved in the ivabradine group compared with placebo; poorest outcomes were seen in the placebo group with lowest KCCQ scores (<50). In patients with systolic HF, low HQoL is associated with an increased rate of cardiovascular death or hospital admission for HF. Reduction in HR with ivabradine is associated with improved HQoL. The magnitude of HR reduction is related to the extent of improvement in HQoL.

Heart Rate and Heart Failure - Not a Simple Relationship -

Resting heart rate (HR) is increased in patients with heart failure (HF). Sustained tachycardia can cause HF. The magnitude of HR reduction in treatment trials of patients with HF is associated with a reduction in mortality. Yet, the mechanistic and causal role of HR in HF is unclear, and recent trials with selective HR reduction have not consistently achieved benefit: the BEAUTIFUL trial in patients with coronary artery disease and left ventricular dysfunction did not achieve a significant benefit in the primary endpoint, and only the coronary outcome, not the HF outcome, was improved; in the SHIFT trial, however, patients with symptomatic heart failure had a significant benefit in the primary endpoint of cardiovascular mortality and hospitalization for worsening HF. The present review addresses the pathophysiology of tachycardia-induced HF, the force-frequency relationship, and the clinical potential of HR reduction in HF.

Meta-analysis: β-Blocker Dose, Heart Rate Reduction, and Death in Patients With Heart Failure

Guidelines recommend that patients with heart failure receive beta-blockers in doses used in the trials that have proven their efficacy. Although the adverse effects of beta-blockade are dose-related, it is unclear whether the benefits are. To determine whether the survival benefits of beta-blockade in heart failure are associated with the magnitude of heart rate reduction or the beta-blocker dose. MEDLINE, EMBASE, CINAHL, SIGLE, Web of Science, and the Cochrane Central Register of Controlled Trials, supplemented by hand-searches of bibliographies. Randomized, placebo-controlled heart failure trials that reported all-cause mortality. Two reviewers independently extracted data on study characteristics, beta-blocker dosing and heart rate reduction, and death. The mean left ventricular ejection fraction in the 23 beta-blocker trials ranged from 0.17 to 0.36, and more than 95% of the 19 209 patients had systolic dysfunction. The overall risk ratio for death was 0.76 (95% CI, 0.68 to 0.84); however, heterogeneity testing revealed moderate heterogeneity among trials (I (2) = 30%), which was associated with the magnitude of heart rate reduction achieved within each trial (P for meta-regression = 0.006). For every heart rate reduction of 5 beats/min with beta-blocker treatment, a commensurate 18% reduction (CI, 6% to 29%) in the risk for death occurred. No significant relationship between all-cause mortality and beta-blocker dosing was observed (risk ratio for death, 0.74 [CI, 0.64 to 0.86]) in high-dose beta-blocker trials vs. 0.78 [CI, 0.63 to 0.96] in low-dose beta-blocker trials; P for meta-regression = 0.69). The analysis is based on aggregate data and resting heart rates. Few patients in these trials had bradycardia or diastolic dysfunction at baseline. The magnitude of heart rate reduction is statistically significantly associated with the survival benefit of beta-blockers in heart failure, whereas the dose of beta-blocker is not.

Abstract 2497: Does Magnitude of Heart Reduction Influence Clinical Outcomes in Patients with Systolic Chronic Heart Failure Receiving Beta-Blockers? A Regression Analysis of Randomised Controlled Trials

Background: Beta-blockers (BBs) improve cardiac function and prolong survival in patients with systolic chronic heart failure (CHF). However, the exact mechanisms underlying these benefits are uncertain. Specifically, it is unclear whether a close relationship exists between heart rate (HR) reduction and clinical outcomes with these agents. We therefore tested this hypothesis within randomised controlled trials (RCTs) of BBs in systolic CHF. Methods: Left ventricular ejection fraction (LVEF) and HR values at baseline and end-study were obtained from available BB RCTs. The relationship between change in HR and all-cause mortality as well as LVEF was determined using regression analysis (SPSS). Results: Thirty-six trials, which included 23,122 patients with mean follow-up of 10.5 months, were analysed for all-cause mortality, LVEF and HR. There was a close relationship between all-cause annualised mortality rate and change in HR (adjusted R2=0.51, p=0.004). A strong correlation between change in HR and change in LVEF (adjusted R2=0.47, p=0.000, Figure ) was also observed. When only trials with &gt;100 patients were included, an even tighter relationship was seen (adjusted R2=0.60, p=0.0004). Conclusions: These analyses indicate that a major contributor to the clinical benefits of BB therapy in systolic CHF is the HR-lowering effect of these agents. Therefore, magnitude of HR reduction may be more important than achievement of target dose in BB treatment of systolic CHF.

An evaluation of the beta-1 adrenergic receptor Arg389Gly polymorphism in individuals with heart failure: a MERIT-HF sub-study.

The Glycine389 variant of the beta-1 adrenergic receptor (beta1AR) generates markedly less cAMP when stimulated in vitro than the more prevalent Arginine389 variant. The aim of this MERIT-HF sub-study was to ascertain whether this Glycine389 variant favourably influences outcome in heart failure similar to that observed with beta-blockers. We identified the genotype at amino acid 389 of the beta1AR in 600 patients enrolled in the MERIT-HF study (UK and Dutch participants). A risk-ratio (RR) for each genotype was calculated using the combined endpoint of all cause mortality or hospitalisation (time to first event). A pharmacogenetic effect of this polymorphism was also sought by evaluating the effect of Metoprolol CR/XL on heart rate amongst the three genotypes. The prevalence of the three genotypes was ArgArg 51.3%, ArgGly 40.2%, GlyGly 8.5%. The presence of the Gly allele was not associated with a significant benefit on the combined endpoint, RR=0.94; confidence intervals (CI), 0.69-1.29 (P=0.72). This is in contrast to the highly significant benefit of Metoprolol CR/XL observed in this sub-study population, RR=0.60; CI, 0.44-0.83 (P=0.002). No effect of the polymorphism was observed on the magnitude of heart rate reduction attained by Metoprolol CR/XL. In contrast to the benefits of beta-1 selective blockade, we have demonstrated that the Gly389 allele does not confer a significant mortality/morbidity benefit in heart failure patients. We have found no evidence of a pharmacogenetic effect of this biochemically functional polymorphism.

Efficacy of intravenous propranolol for suppression of inducibility of ventricular tachyarrhythmias with different electrophysiologic characteristics in coronary artery disease

The efficacy of intravenous propranolol for suppression of inducibility of sustained ventricular tachyarrhythmias (VT) was studied in 24 patients who had failed ≥1 membrane-active antiarrhythmic drug (mean 2.2 ± 1.2 drugs/patient). The response to propranolol was compared in 13 patients who had only stable monomorphic VTs inducible at baseline and another 11 patients who had ≥1 episode of electrically unstable VTs (polymorphic VT, ventricular flutter or ventricular fibrillation) at baseline. Seven patients (29%) became noninducible (responders) and 17 patients (71%) remained inducible to sustained VT (nonresponders) after propranolol. The basal heart rate was faster in responders than in nonresponders (101 ± 14 vs 86 ± 11 beats/min, p < 0.01). The magnitude of heart rate reduction was also greater after propranolol in responders (from 101 ± 14 to 80 ± 9 beats/min, p < 0.001) than in nonresponders (from 86 ± 11 to 74 ± 9 beats/min, p < 0.01) (p < 0.05 between the groups), despite equal plasma propranolol concentrations (84 ± 50 vs 88 ± 43 ng/ml, difference not significant). Seven of 11 patients (64%) who had ≥1 episode of unstable VTs inducible at baseline responded to intravenous propranolol, whereas none of the patients with only stable monomorphic VTs became noninducible after β blockade (p < 0.001). Responders had shorter cycle length of inducible VTs than nonresponders (225 ± 38 vs 302 ± 66 ms, p < 0.001). Thus, intravenous propranolol appears to be efficacious in suppressing fast, electrically unstable VTs, compared to monomorphic VTs with slower rates.