Sympathetic Nerve Activity In Patients Research Articles

Abstract 10858: Significant Association Between Washout Ratio of Renal 123i-metaiodobenzylguanidine and Muscle Sympathetic Nerve Activity in Patients With Hypertension

Background: Simplicity HTN-3 trial showed the negative result for renal denervation (RDN) in patient with resistant hypertension. One of limitations was that no appreciate evaluation of renal sympathetic nerve activity (RSNA) was applied before and after RDN. 123I-MIBG has been used to assess the cardiac sympathetic nerve activity. However, it remains unclear whether 123I-MIBG in kidney would reflect sympathetic nerve activity. In this study, we investigated the relationship renal 123I- MIBG and muscle sympathetic nerve activity (MSNA). Methods: 31 hypertensive patients were included in this study. MSNA was recorded from the peroneal nerve to evaluate direct sympathetic nerve activity to peripheral vascular bed. Images of 123I-MIBG were taken using the low-medium-energy general purpose collimator. An 111MBq dose of 123I-MIBG was injected intravenously at rest for the MIBG study. 123I-MIBG planar and SPECT studies were performed at 20min (early) and 3hr (delayed) after injection. In the planar study, a region of interest (ROI) was set over the heart and a rectangular ROI on the upper third of the mediastium and kidney cortex. The early and delayed heart-to-mediastinum average count ratios (H/M) and kidney-to-mediastinum average count ratios (K/M) were calculated. Washout rate (WR) of heart and kidney were also calculated. Results: Average systolic and diastolic blood pressure was 118±18/67±15 mmHg. Average estimated glomerular filtration rate was 71.5±22.4 ml/min/1.73m2 that was not related to renal 123I-MIBG. As expected, MSNA had significant negative relationship with delayed H/M in cardiac 123I-MIBG image (r=-0.37, p<0.01) and positive relationship with WR of cardiac 123I-MIBG (r=0.45, p<0.01). With regard to kidney, WR of 123I-MIBG of each left and right renal MIBG showed a significant correlation with MSNA (right kidney: r=0.56, p<0.01, left kidney: r=0.60, p<0.01, respectively), but not with early and delayed K/M in renal 123I-MIBG. Conclusions: Our study showed that WR of renal 123I-MIBG was associated with MSNA, indicating that WR of renal 123I-MIBG might reflect RSNA. These results suggest that renal 123I-MIBG might be available to assess sympathetic nerve activity as well as MSNA.

Direct recordings of muscle and cutaneous sympathetic nerve activity in patients with familial dysautonomia

desaturations (p = 0.001) and 1 arousal (p N 0.05). No apneas were followed by desaturation and arousal. Hypopneas were the most frequent respiratory event and occurred primarily during sleep stage 1 and 2. In all FD-patients, we recorded 362 hypopneas with subsequent oxygen-desaturation that were followed by only 51 arousals. 12 hypopneas (p b 0.001) occurred in 3 controls (p= 0.085) and were followed by 3 arousals (p= 0.002).

The effect of renal denervation on endothelial function and inflammatory markers in patients with resistant hypertension

Hypertension is an important risk factor in the development and progression of cardiovascular disease. Renal denervation (RDN) has been shown to reduce blood pressure (BP) and muscle sympathetic nerve activity in patients with resistant hypertension (RH) [1,2]. Irrespective of the effects of RDN on BP, there is little data to date to describe the impact of this procedure on other systems and organs.

Effects of exercise training on neurovascular control and skeletal myopathy in systolic heart failure.

Neurohormonal excitation and dyspnea are the hallmarks of heart failure (HF) and have long been associated with poor prognosis in HF patients. Sympathetic nerve activity (SNA) and ventilatory equivalent of carbon dioxide (VE/VO2) are elevated in moderate HF patients and increased even further in severe HF patients. The increase in SNA in HF patients is present regardless of age, sex, and etiology of systolic dysfunction. Neurohormonal activation is the major mediator of the peripheral vasoconstriction characteristic of HF patients. In addition, reduction in peripheral blood flow increases muscle inflammation, oxidative stress, and protein degradation, which is the essence of the skeletal myopathy and exercise intolerance in HF. Here we discuss the beneficial effects of exercise training on resting SNA in patients with systolic HF and its central and peripheral mechanisms of control. Furthermore, we discuss the exercise-mediated improvement in peripheral vasoconstriction in patients with HF. We will also focus on the effects of exercise training on ventilatory responses. Finally, we review the effects of exercise training on features of the skeletal myopathy in HF. In summary, exercise training plays an important role in HF, working synergistically with pharmacological therapies to ameliorate these abnormalities in clinical practice.

Testosterone deficiency increases hospital readmission and mortality rates in male patients with heart failure.

BackgroundTestosterone deficiency in patients with heart failure (HF) is associated with decreased exercise capacity and mortality; however, its impact on hospital readmission rate is uncertain. Furthermore, the relationship between testosterone deficiency and sympathetic activation is unknown.ObjectiveWe investigated the role of testosterone level on hospital readmission and mortality rates as well as sympathetic nerve activity in patients with HF.MethodsTotal testosterone (TT) and free testosterone (FT) were measured in 110 hospitalized male patients with a left ventricular ejection fraction < 45% and New York Heart Association classification IV. The patients were placed into low testosterone (LT; n = 66) and normal testosterone (NT; n = 44) groups. Hypogonadism was defined as TT < 300 ng/dL and FT < 131 pmol/L. Muscle sympathetic nerve activity (MSNA) was recorded by microneurography in a subpopulation of 27 patients.ResultsLength of hospital stay was longer in the LT group compared to in the NT group (37 ± 4 vs. 25 ± 4 days; p = 0.008). Similarly, the cumulative hazard of readmission within 1 year was greater in the LT group compared to in the NT group (44% vs. 22%, p = 0.001). In the single-predictor analysis, TT (hazard ratio [HR], 2.77; 95% confidence interval [CI], 1.58–4.85; p = 0.02) predicted hospital readmission within 90 days. In addition, TT (HR, 4.65; 95% CI, 2.67–8.10; p = 0.009) and readmission within 90 days (HR, 3.27; 95% CI, 1.23–8.69; p = 0.02) predicted increased mortality. Neurohumoral activation, as estimated by MSNA, was significantly higher in the LT group compared to in the NT group (65 ± 3 vs. 51 ± 4 bursts/100 heart beats; p < 0.001).ConclusionThese results support the concept that LT is an independent risk factor for hospital readmission within 90 days and increased mortality in patients with HF. Furthermore, increased MSNA was observed in patients with LT.

Prognostic Significance of LV Global Strain and Cardiac Sympathetic Nerve Activity in Patients with AMI Treated with Primary PCI

Prognostic Significance of LV Global Strain and Cardiac Sympathetic Nerve Activity in Patients with AMI Treated with Primary PCI

Differential effects of azelnidipine and amlodipine on sympathetic nerve activity in patients with primary hypertension.

Calcium channel blockers (CCBs) are used as antihypertensive agents and have a strong vasodilatory effect; however, the sympathetic activation mediated by baroreflex might cause adverse effects. A recently developed CCB, azelnidipine, decreases the heart rate (HR) while lowering blood pressure (BP), possibly by inhibiting sympathetic nerve activity in animal models. In this study, we evaluated whether azelnidipine inhibited sympathetic nerve activity, compared to amlodipine, in primary hypertensive patients. We conducted a prospective, randomized, open-label, and crossover study of 14 patients. We measured the patients' BP, HR and baroreflex sensitivity, and directly recorded muscle sympathetic nerve activity (MSNA), via microneurography, after treatment with either CCB for 8 weeks. Although systolic and diastolic BPs did not differ between the azelnidipine and amlodipine groups, the HR in the azelnidipine group significantly decreased compared with that in the amlodipine group. MSNA was significantly reduced in the azelnidipine compared with the amlodipine group (47.7 ± 14.9 vs. 61.5 ± 10.7 bursts per 100 beats, P < 0.05). However, no significant difference was observed in terms of the baroreflex control of HR, or MSNA, between the two groups. Our data show, first, that azelnidipine, compared with amlodipine, exerted a favorable effect on sympathetic nerve activity, without affecting baroreflex sensitivity, in hypertensive patients. These results indicate that azelnidipine might be useful for treating hypertensive patients, in whom hypertension is complicated by heart failure and ischemic heart disease.

Slow and deep respiration suppresses steady-state sympathetic nerve activity in patients with chronic heart failure: from modeling to clinical application.

Influences of slow and deep respiration on steady-state sympathetic nerve activity remain controversial in humans and could vary depending on disease conditions and basal sympathetic nerve activity. To elucidate the respiratory modulation of steady-state sympathetic nerve activity, we modeled the dynamic nature of the relationship between lung inflation and muscle sympathetic nerve activity (MSNA) in 11 heart failure patients with exaggerated sympathetic outflow at rest. An autoregressive exogenous input model was utilized to simulate entire responses of MSNA to variable respiratory patterns. In another 18 patients, we determined the influence of increasing tidal volume and slowing respiratory frequency on MSNA; 10 patients underwent a 15-min device-guided slow respiration and the remaining 8 had no respiratory modification. The model predicted that a 1-liter, step increase of lung volume decreased MSNA dynamically; its nadir (-33 ± 22%) occurred at 2.4 s; and steady-state decrease (-15 ± 5%), at 6 s. Actually, in patients with the device-guided slow and deep respiration, respiratory frequency effectively fell from 16.4 ± 3.9 to 6.7 ± 2.8/min (P < 0.0001) with a concomitant increase in tidal volume from 499 ± 206 to 1,177 ± 497 ml (P < 0.001). Consequently, steady-state MSNA was decreased by 31% (P < 0.005). In patients without respiratory modulation, there were no significant changes in respiratory frequency, tidal volume, and steady-state MSNA. Thus slow and deep respiration suppresses steady-state sympathetic nerve activity in patients with high levels of resting sympathetic tone as in heart failure.

Tetrahydrobiopterin lowers muscle sympathetic nerve activity in patients with chronic kidney disease (852.8)

Chronic kidney disease (CKD) is characterized by chronic overactivation of the sympathetic nervous system (SNS) that contributes to increased blood pressure and cardiovascular risk. One contributing factor to SNS overactivation in this population is decreased nitric oxide (NO) bioavailability. Tetrahydrobiopterin (BH4) is a necessary cofactor for endothelial nitric oxide synthase (eNOS) that has been shown to increase NO bioavailability in experimental models of CKD. We conducted a randomized, double‐masked, placebo‐controlled trial testing the potential benefits of oral BH4 treatment on SNS activity in CKD patients. 36 patients with CKD and hypertension were randomized to 12 weeks of: 1) 200mg BH4 twice daily + 1mg folic acid once daily; versus 2) matching placebo twice daily + 1mg folic acid once daily. The primary endpoint was change in muscle sympathetic nerve activity (MSNA) assessed via microneurography. Secondary endpoints included ambulatory and clinic blood pressures, endothelial function via brachial artery flow‐mediated dilatation, oxidative stress biomarkers, and proteinuria. We observed a significant reduction in MSNA after 12 weeks of BH4 treatment, compared to treatment with placebo, in hypertensive CKD patients. Chronic BH4 treatment may have beneficial effects on central sympathetic output in hypertensive patients with CKD.Grant Funding Source: Supported by K grant HL098744

Differing Effects of Adaptive Servoventilation and Continuous Positive Airway Pressure on Muscle Sympathetic Nerve Activity in Patients With Heart Failure

Long-term adaptive servoventilation (ASV) increases cardiac function more effectively than continuous positive airway pressure (CPAP), possibly via alleviation of sympathetic overactivation. The present study evaluated the effect of ASV and CPAP at comparable pressure on muscle sympathetic nerve activity (MSNA) in patients with heart failure (HF) and with or without periodic breathing (PB). A total of 57 patients with HF (ejection fraction <0.45) were randomized to receive CPAP (n=28) or ASV (n=29). Respiratory profiles and MSNA were continuously monitored before and during CPAP and ASV (30min) at pressures of 6.5 and 6.6cmH2O, respectively. The severity of respiratory instability was determined using the coefficient of variation of tidal volume (CV-TV). Although heart rate and blood pressure remained unchanged, only ASV improved CV-TV. MSNA decreased in the ASV (P<0.001), but not in the CPAP group. The change in CV-TV independently predicted changes in MSNA (P<0.001). Device type and PB significantly interacted with changes in MSNA (P<0.05) and ASV exerted sympathoinhibitory effects in patients with PB, whereas CPAP did not. A sympathoinhibitory effect in patients without PB was not evident in either treatment arm. ASV probably exerts its sympathoinhibitory effects in patients with HF and PB through pressure support.

Acute electromyostimulation Decreases Muscle Sympathetic Nerve Activity in Patients with Advanced Chronic Heart Failure (EMSICA Study)

BackgroundMuscle passive contraction of lower limb by neuromuscular electrostimulation (NMES) is frequently used in chronic heart failure (CHF) patients but no data are available concerning its action on sympathetic activity. However, Transcutaneous Electrical Nerve Stimulation (TENS) is able to improve baroreflex in CHF. The primary aim of the present study was to investigate the acute effect of TENS and NMES compared to Sham stimulation on sympathetic overactivity as assessed by Muscle Sympathetic Nerve Activity (MSNA).MethodsWe performed a serie of two parallel, randomized, double blinded and sham controlled protocols in twenty-two CHF patients in New York Heart Association (NYHA) Class III. Half of them performed stimulation by TENS, and the others tested NMES.ResultsCompare to Sham stimulation, both TENS and NMES are able to reduce MSNA (63.5 ± 3.5 vs 69.7 ± 3.1 bursts / min, p < 0.01 after TENS and 51.6 ± 3.3 vs 56.7 ± 3.3 bursts / min, p < 0, 01 after NMES). No variation of blood pressure, heart rate or respiratory parameters was observed after stimulation.ConclusionThe results suggest that sensory stimulation of lower limbs by electrical device, either TENS or NMES, could inhibit sympathetic outflow directed to legs in CHF patients. These properties could benefits CHF patients and pave the way for a new non-pharmacological approach of CHF.

Respiratory Modulation of Sympathetic Nerve Activity in Patients with Chronic Heart Failure: From Modeling to Clinical Application

Respiratory Modulation of Sympathetic Nerve Activity in Patients with Chronic Heart Failure: From Modeling to Clinical Application

Hyponatremia is associated with increased muscle sympathetic nerve activity in patients with heart failure

Backgrounds: Hyponatremia frequently occurs in patients with severe heart failure (HF), and is associated with poor prognosis. Previous studies demonstrated that hyponatremia was associated with neurohumoral activation, renal dysfunction and diuretic treatment. However, widespread use of standard therapy might influence the results. Additionally, it remains unknown the relation between hyponatremia and direct measure of sympathetic nerve activity in HF settings. Methods: We determined resting muscle sympathetic nerve activity (MSNA) in 96 patients with HF (63±14 years, ejection fraction (EF) < 0.45). Patients were classified into 2 groups with and without hyponatremia (<136 mEq/L). Results: Twenty patients (18%) had hyponatremia. Age, gender, body mass index, heart rate, hemoglobin level and medications except use of aldosterone receptor blockers did not significantly differ between the 2 groups. However, specific activity scale, blood pressure, ejection fraction and estimated glomerular filtration rate were lower, plasma renin activity, aldosterone concentration, natriuretic peptide levels were higher in hyponatremia group compared with normonatremia group. MSNA values were significantly higher in hyponatremia group than in normonatremia group (burst rate, 58±18 vs. 39±11 bursts/minute, p<0.001; burst incidence, 81±19 vs. 62±19 bursts/100 beats, p<0.001). Multivariate analysis revealed that blood pressure (p=0.014), plasma renin activity (p<0.001) and burst rate (p<0.001) were significant predictors of sodium level in patients with HF. In addition, hyponatremia was a common independent predictor for increased burst rate and burst incidence. ![Figure][1] Figure 1. Relation between Na level and MSNA (n=96) Conclusions: These findings suggest that hyponatremia is associated with increased MSNA in patients with HF. [1]: pending:yes

Adaptive servo‐ventilation therapy improves cardiac sympathetic nerve activity in patients with heart failure

This study investigated whether abnormal cardiac sympathetic nerve activity (SNA) is associated with the severity of central sleep apnoea (CSA) and whether adaptive servo-ventilation (ASV) therapy can improve cardiac SNA in heart failure (HF) patients with predominant CSA. Overnight polysomnography was conducted to diagnose CSA. Cardiac SNA was analysed by [123I]metaiodobenzylguanidine scintigraphy in 26 consecutive HF patients with predominant CSA. Of the 26 patients, 10 agreed to ASV therapy. Cardiac SNA was analysed 6 months after initiating ASV based on a non-randomized protocol. The apnoea-hypopnoea index and central apnoea index were significantly correlated with the washout rate (WR) and a delayed heart to mediastinal (H/M) ratio, suggesting that SNA is associated with abnormal breathing patterns. The WR, H/M ratio, plasma BNP level, and LVEF were significantly improved (WR, 40.0 ± 11.6% vs. 34.6 ± 11.4%, P = 0.046; H/M ratio, 1.5 ± 0.1 vs.1.8 ± 0.3, P = 0.013; ln BNP, 5.4 ± 1.0 vs. 4.6 ± 1.2, P = 0.007; and LVEF, 43.8 ± 10.4% vs. 47.0 ± 10.6%, P < 0.001) in the ASV group patients, but not in the non-ASV group patients. Multiple linear regression analyses showed that a decreased WR was strongly associated with an increased LVEF (coefficient = -0.454, P = 0.013). Abnormal cardiac SNA could be significantly correlated with the severity of CSA in HF patients. ASV therapy might improve cardiac function in these patients by partially mediating cardiac SNA regulation.

Heart rate variability biofeedback reduces stress in patients with preterm labour

Background and objectives: Preterm birth is a highly prevelant phenomenon that was shown to be provoked by an increased sympathetic activity induced by mental stress during pregnancy. In previous studies heart rate variability (HRV)-biofeedback was demonstrated to decrease sympathetic nerve activity in patients with mental stress due to anxiety and depression. We aimed to assess the effects of HRV-biofeedback in patients with preterm labour.

Evaluation of muscle sympathetic nerve activity in patients with chronic severe aortic insufficiency

The aim of this study is to evaluate the activity of sympathetic nerve sistem by microneurography in asymptomatic patients with aortic insufficiency (AoI) chronic important.Were included 10 asymptomatic patients with anatomically important AoI of rheumatic etiology with normal left ventricular function (ejection fraction&gt;; 55%) by echocardiogram.Exclusion criteriadiabetes mellitus, renal failure, neuropathy, or beta‐blockers. A control group of normotensive volunteers (control group, n=11) with age, sex and body mass index‐ matched was included. MNSA by microneuragraphy, and blood pressure (BP) by FINOMETER® were evaluated in supine rest position. Continuous variables are described as mean ± SD and categorical variables as relative frequencies. Student t test and a multivariate analysis model were used, p &lt;0.05 was considered statistically significant.AoI group and control group showed no statistically significant regarding age, sex and BMI. Systolic BP in AoI group was 148 +16 mmHg vs. 120±4 mmHg in control group (p = 0.0001), Diastolic BP was 60±6 mmHg in AoI and 73±3 mmHg in control group (p = 0.0001). The MSNA was in the AoI group 25±3 vs. 15±2 in the control group (p &lt;0.001). Aortic insufficiency was associated independently with a higher MSNA (p = 0.02).AoI important chronic and asymptomatic is associated with increased MSNA.

Effect of Adaptive Servoventilation on Muscle Sympathetic Nerve Activity in Patients With Chronic Heart Failure and Central Sleep Apnea

BackgroundAdaptive servoventilation (ASV) improves cardiac function and sympathetic nerve activity in patients with heart failure (HF). However, the mechanisms underlying these improvements remain obscure. Methods and ResultsWe compared muscle sympathetic nerve activity (MSNA) and cardiorespiratory polygraphy and echocardiography findings at baseline and at 3.5 ± 0.8 months’ follow-up in 32 patients with HF (New York Heart Association functional class II or III; ejection fraction <45%) and central sleep apnea (CSA; apnea-hypopnea index [AHI] ≥15/h) who consented (n = 20; ASV group) or declined (n = 12; non-ASV group) to undergo ASV treatment. Compliance with ASV and changes in AHI were determined from data collected by integral counters in devices and from cardiorespiratory polygraphic findings, respectively. Ejection fraction and MSNA significantly changed in the ASV (both P < .001) but not the non-ASV group. Although changes in AHI and MSNA correlated, the average use of ASV did not. In contrast, changes in AHI and the average use of ASV were independent predictors of changes in ejection fraction (both P < .01). ConclusionsASV decreases MSNA and improves cardiac function in association with suppression of CSA in patients with HF.

L/T-type and L/N-type calcium-channel blockers attenuate cardiac sympathetic nerve activity in patients with hypertension

Sympathetic nerve activity is augmented by calcium-channel blocker treatment as a result of decreased blood pressure. Dihydropyridine calcium-channel blockers are divided into three different types. The purpose of the present study was to investigate whether treatment effects on hemodynamics, cardiac autonomic nerve activity and plasma norepinephrine levels differ among amlodipine (L type), efonidipine (L + T type) and cilnidipine (L + N type). We enrolled 14 hypertensive patients (seven males, seven females, 70 ± 6 years old) undergoing a monotherapy of amlodipine, efonidipine or cilnidipine into this prospective, open-labeled, randomized, crossover study. At baseline and every 6 months of the treatment period, we repeated the evaluation of hemodynamics, spectral analysis of heart rate variability and plasma norepinephrine levels. Blood pressure and pulse rate were comparable among the three treatments. The low-frequency (LF)/high-frequency (HF) power ratio, an index of cardiac sympathovagal balance, was significantly lower with efonidipine and cilnidipine than with amlodipine, while the HF/total power ratio, an index of cardiac vagal activity, revealed the opposite results. There was no significant correlation between the LF/HF ratio and plasma norepinephrine levels. Antihypertensive monotherapy with efonidipine or cilnidipine attenuates cardiac sympathetic nerve activity more effectively than amlodipine monotherapy.

Effect of Pioglitazone on Arterial Baroreflex Sensitivity and Sympathetic Nerve Activity in Patients with Acute Myocardial Infarction and Type 2 Diabetes Mellitus

Pioglitazone has been shown to reduce the occurrence of fatal and nonfatal myocardial infarction (MI) in type 2 diabetes mellitus (DM). However, the mechanisms of such favorable effects remain speculative. The aim of this study was to investigate the effect of pioglitazone on arterial baroreflex sensitivity (BRS) and muscle sympathetic nerve activity (MSNA) in 30 DM patients with recent MI. Patients were randomly assigned to those taking pioglitazone (n = 15) and those not taking pioglitazone (n = 15) at 4 weeks after the onset of MI. BRS, MSNA, calculated homeostasis model assessment of insulin resistance index (HOMA-IR), and plasma adiponectin were measured at baseline and after 12 weeks. Pioglitazone increased plasma adiponectin (from 6.9 ± 3.3 μg/dL to 12.2 ± 7.1 μg/dL) and reduced HOMA-IR (from 4.0 ± 2.2 to 2.1 ± 0.9). In the pioglitazone group, MSNA decreased significantly (from 37 ± 7 bursts/min to 25 ± 8 bursts/min) and BRS increased significantly (from 6.7 ± 3.0 to 9.9 ± 3.2 ms/mm Hg) after 12 weeks. Furthermore, a significant relationship was found between the change in MSNA and HOMA-IR (r = 0.6, P = 0.042). Thus, pioglitazone decreased the sympathetic nerve traffic through the improvement of insulin resistance in DM patients with recent MI, which indicate that the sympathoinhibitory effects of pioglitazone may, at least in part, have contributed to the beneficial effects of pioglitazone.

Basic Science of Cardiac Resynchronization Therapy

Electromechanical dyssynchrony can markedly worsen heart failure (HF) morbidity and mortality, independent of traditional risk factors.1–4 Depending on the metric used, current estimates of the prevalence of dyssynchrony vary from 25–30% in patients with HF (based on QRS widening) up to 60%, based on tissue Doppler or MRI measures of dyssynchronous contraction of the left ventricle (LV).5,6 Cardiac resynchronization therapy (CRT) or biventricular pacing has emerged as a promising option to treat patients with HF and dyssynchronous contraction.7–9 The past few decades have seen the rise of pharmacotherapy, primarily through agents that antagonize the effect of excessive concentrations of circulating neurohormones, yet, HF-related morbidity and mortality remain high.3–6 Biventricular stimulation has been demonstrated to improve contractile performance in patients with mechanical dyssynchrony acutely and chronically while also prolonging long-term survival—something not yet achieved by drug therapy.10 Although the clinical and mechanical effectiveness of CRT are well described, 30% of patients do not benefit from CRT and clinical criteria to identify CRT nonresponders remain elusive8,11,12 Currently, the most widely used predictor of reverse remodeling is the presence of marked mechanical dyssynchrony before CRT, as indexed by the width of the QRS.13 Mechanical dyssynchrony seems important, yet imaging-based measures have not predicted response well14 and even improvement in dyssynchrony after initiation of CRT only weakly predicts chronic response.15 Limited understanding of the molecular mechanisms underlying reverse cardiac remodeling induced by CRT has hampered the selection of potential responders. In this review, we focus on the electrophysiological aspects and molecular networks underlying the benefits of CRT. We will review how CRT homogenizes regional differences in stress kinase signaling and electric remodeling and then review its global effect on myocyte function and its …