Pacemaker-Based Cardiac Neuromodulation Therapy in Patients With Hypertension: A Pilot Study.

Background In prior unblinded studies, cardiac neuromodulation therapy (CNT) employing a sequence of variably timed short and longer atrioventricular intervals yielded sustained reductions of systolic blood pressure (SBP) in patients with hypertension. The effects of CNT on SBP were investigated in this double-blind randomized pilot study. Methods and Results Eligible patients had daytime ambulatory SBP (aSBP) ≥130 mm Hg and office SBP ≥140 mm Hg despite taking ≥1 antihypertensive medication, and an indication for a dual-chamber pacemaker.

Rationale and evidence for the development of a durable device-based cardiac neuromodulation therapy for hypertension.

We assessed the feasibility of achieving acute, sustained blood pressure reductions through the use of cardiac pacing algorithms delivered via standard dual-chamber pacing based on introducing short atrio-ventricular (AV) delays (SAVD). Eighteen hypertensive subjects (57.3 ± 9.

Pacemaker-Mediated Programmable Hypertension Control Therapy.

Background: Many patients requiring a pacemaker have persistent hypertension with systolic blood pressures above recommended levels. We evaluated a pacemaker-based Programmable Hypertension Control (PHC) therapy that uses a sequence of variably timed shorter and longer atrioventricular intervals.

Methods And Results: Patients indicated for dual-chamber pacing with office systolic blood pressure (oSBP) >150 mm Hg despite stable medical therapy were implanted with a Moderato™ pulse generator that delivers PHC therapy.

Subgroup analysis of a randomized controlled trial evaluating the safety and efficacy of cardiac contractility modulation in advanced heart failure.

Background: Cardiac contractility modulation (CCM) signals are nonexcitatory electrical signals delivered during the absolute refractory period intended to improve contraction. We previously tested the safety and efficacy of CCM in 428 NYHA functional class III/IV heart failure patients with EF ≤35% and narrow QRS randomized to optimal medical treatment (OMT) plus CCM (n = 215) versus OMT alone (n = 213) and found no significant effect on ventilatory anaerobic threshold (VAT), the study's primary end point. In the present analysis, we sought to identify if there was a subgroup of patients who showed a response to CCM.

A randomized controlled trial evaluating the safety and efficacy of cardiac contractility modulation in advanced heart failure.

Background: Cardiac contractility modulation (CCM) delivers nonexcitatory electrical signals to the heart during the absolute refractory period intended to improve contraction.

Methods: We tested CCM in 428 New York Heart Association class III or IV, narrow QRS heart failure patients with ejection fraction (EF) ≤ 35% randomized to optimal medical therapy (OMT) plus CCM (n = 215) versus OMT alone (n = 213). Efficacy was assessed by ventilatory anaerobic threshold (VAT), primary end point, peak Vo₂ (pVo₂), and Minnesota Living with Heart Failure Questionnaire (MLWFQ) at 6 months.

Ca(2+)-binding proteins in dogs with heart failure: effects of cardiac contractility modulation electrical signals.

Background: In dogs with heart failure (HF), chronic therapy with cardiac contractility modulation (CCM) electrical signals delivered to left ventricular (LV) muscle during the absolute refractory period improves LV function. This study examined the effects of CCM therapy on the expression of calcium (Ca(2+))-binding proteins (CBPs) in dogs with HF.

Methods And Results: Studies were performed in LV tissue from seven CCM-treated HF dogs, seven untreated HF dogs, and six normal (NL) dogs.

Cardiac contractility modulation electrical signals normalize activity, expression, and phosphorylation of the Na+-Ca2+ exchanger in heart failure.

Background: Expression and phosphorylation of the cardiac Na(+)-Ca(2+) exchanger-1 (NCX-1) are up-regulated in heart failure (HF). We examined the effects of chronic cardiac contractility modulation (CCM) therapy on the expression and phosphorylation of NCX-1 and its regulators GATA-4 and FOG-2 in HF dogs.

Methods And Results: Studies were performed in LV tissue from 7 CCM-treated HF dogs, 7 untreated HF dogs, and 6 normal (NL) dogs.

Effects of chronic therapy with cardiac contractility modulation electrical signals on cytoskeletal proteins and matrix metalloproteinases in dogs with heart failure.

Objectives: Therapy with cardiac contractility modulation (CCM) electrical signals delivered to left ventricular (LV) muscle during the absolute refractory period improves LV systolic and diastolic function in dogs with heart failure (HF). This study examined the effects of CCM therapy on mRNA and protein expression of cytoskeletal proteins, matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) in the LV myocardium of dogs with HF.

Methods: HF was produced in 14 dogs by coronary microembolizations.

Therapy with cardiac contractility modulation electrical signals improves left ventricular function and remodeling in dogs with chronic heart failure.

Objectives: This study examined the effects of long-term delivery of cardiac contractility modulation (CCM) electric signals on left ventricular (LV) function and global, cellular, and molecular remodeling in dogs with chronic heart failure (HF).

Background: Acute studies in dogs with experimentally induced HF showed that CCM signals applied to the failing myocardium during the absolute refractory period improved LV function without increasing myocardial oxygen consumption.

Methods: In one study, dogs with intracoronary microembolization-induced HF were randomized to 3 months of active CCM monotherapy or to a sham-operated control group.

Treating heart failure with cardiac contractility modulation electrical signals.

Major advances have been made over the past two decades in the pharmacologic treatment of chronic heart failure (HF). Angiotensin-converting enzyme inhibitors, beta-blockers, and aldosterone antagonists have had a substantial impact on reducing mortality and morbidity in patients with HF and low left ventricular ejection fraction. These treatments delayed the progression toward advanced intractable HF but did not arrest progressive worsening of the disease.

Electrical signals applied during the absolute refractory period: an investigational treatment for advanced heart failure in patients with normal QRS duration.

Cardiac resynchronization therapy has been shown to be an effective treatment for patients with systolic ventricular dysfunction, prolonged (>120 ms) QRS duration, and New York Heart Association (NYHA) functional class III or IV symptoms despite optimal medical therapy. However, studies show that a majority of heart failure patients have QRS duration <120 ms. We have been investigating the potential utility of cardiac contractility modulating (CCM) signals as a treatment option for such patients.

Cardiac contractility modulation by non-excitatory currents: studies in isolated cardiac muscle.

Background: Myocardial contractility can be altered using voltage clamp techniques by modulating amplitude and duration of the action potential resulting in enhanced calcium entry in the cell of isolated muscle strips (Non-Excitatory Currents; NEC). Extracellular electrical stimuli delivered during the absolute refractory period (Cardiac Contractility Modulation; CCM) have recently been shown to produce inotropic effects in-vivo.

Aim: Understanding the cellular mechanism, underlying the CCM effect, is essential for evaluating its clinical potential.

Cardiac contractility modulation by non-excitatory electrical currents. The new frontier for electrical therapy of heart failure.

Heart failure (HF) may complicate ischemic heart disease in both its acute and chronic manifestations, representing a prevalent health problem throughout the world. Development of therapies to improve heart function, relieve symptoms, reduce hospitalizations and improve survival is a high priority in cardiovascular medicine. The available pharmacological strategies, including angiotensin-converting enzyme inhibitors, angiotensin receptor antagonists, beta-blockers, and aldosterone receptor antagonists have recently been complemented by new electrical therapy, including implantable cardioverter-defibrillators for "MADIT II" patients and cardiac resynchronization for the 30% of HF patients with concomitant intraventricular conduction delay.

First human chronic experience with cardiac contractility modulation by nonexcitatory electrical currents for treating systolic heart failure: mid-term safety and efficacy results from a multicenter study.

Introduction: Conventional electrical therapies for heart failure (HF) encompass defibrillation and ventricular resynchronization for patients at high risk for lethal arrhythmias and/or with inhomogeneous ventricular contraction. Cardiac contractility modulation (CCM) by means of nonexcitatory electrical currents delivered during the action potential plateau has been shown to acutely enhance systolic function in humans with HF. The aim of this multicenter study was to assess the chronic safety and preliminary efficacy of an implantable device delivering this novel form of electrical therapy.

Chronic electrical stimulation during the absolute refractory period of the myocardium improves severe heart failure.

Aim: In experimental studies, nonexcitatory electrical stimulation delivered at the time of absolute myocardial refractoriness resulted in cardiac contractility modulation (CCM) with improved systolic function. This study reports the initial experience with CCM in patients with chronic heart failure.

Methods And Results: Twenty-five patients, 23 males, with a mean age of 62+/-9 years and drug-refractory NYHA class III heart failure were assigned to CCM-generator implantation.

Long-term effects of non-excitatory cardiac contractility modulation electric signals on the progression of heart failure in dogs.

Objective: We previously showed that acute delivery of non-excitatory cardiac contractility modulation (CCM) electric signal during the absolute refractory period improved LV function in dogs with chronic heart failure (HF). In the present study we examined the long-term effects of CCM signal delivery on the progression of LV dysfunction and remodeling in dogs with chronic HF.

Methods: Chronic HF was produced in 12 dogs by multiple sequential intracoronary microembolizations.

Cardiac contractility modulation with nonexcitatory electric signals improves left ventricular function in dogs with chronic heart failure.

Background: Nonexcitatory electrical, signals termed cardiac contractility modulation (CCM) have been shown to improve contractile force of isolated papillary muscles. In this study, we examined the effects of CCM signal delivery on left ventricular function in dogs with chronic heart failure (HF).

Methods And Results: Chronic HF (ejection fraction View Article and Find Full Text PDF

Cardiac contractility modulation by electric currents applied during the refractory period in patients with heart failure secondary to ischemic or idiopathic dilated cardiomyopathy.

We assessed the feasibility of cardiac contractility modulation (CCM) by electric currents applied during the refractory period in patients with heart failure (HF). Extracellular electric currents modulating action potential and calcium transients have been shown to potentiate myocardial contractility in vitro and in animal models of chronic HF. CCM signals were biphasic square-wave pulses with adjustable amplitude, duration, and time delay from sensing of local electric activity.

Electric currents applied during refractory period enhance contractility and systolic calcium in the ferret heart.

We investigated the mechanism of positive inotropism of electric currents applied during the absolute refractory period. Ten Langendorff-perfused ferret hearts were instrumented to measure isovolumic left ventricular pressure (LVP) and the aequorin luminescence. Biphasic square-wave electric currents (+/-20 mA, total duration 30 ms) were delivered between pairs of electrodes.

Cardiac contractility modulation by electric currents applied during the refractory period.

Inotropic effects of electric currents applied during the refractory period have been reported in cardiac muscle in vitro using voltage-clamp techniques. We investigated how electric currents modulate cardiac contractility in normal canine hearts in vivo. Six dogs were instrumented to measure regional segment length, ventricular volume (sonomicrometry), and ventricular pressure.