Hiroshi Furusho

Altered firing pattern of single‐unit muscle sympathetic nerve activity during handgrip exercise in chronic heart failure

Sympathetic activation in chronic heart failure (CHF) is greatly augmented at rest but the response to exercise remains controversial. We previously demonstrated that single‐unit muscle sympathetic nerve activity (MSNA) provides a more detailed description of the sympathetic response to physiological stress than multi‐unit nerve recordings. The purpose of this study was to determine whether the reflex response and discharge properties of single‐unit MSNA are altered during handgrip exercise (HG, 30% of maximum voluntary contraction for 3 min) in CHF patients (New York Heart Association functional class II or III, n= 16) compared with age‐matched healthy control subjects (n= 13). At rest, both single‐unit and multi‐unit indices of sympathetic outflow were augmented in CHF compared with controls (P < 0.05). However, the percentage of cardiac intervals that contained one, two, three or four single‐unit spikes were not different between the groups. Compared to the control group, HG elicited a larger increase in multi‐unit total MSNA (Δ1002 ± 50 compared with Δ636 ± 76 units min−1, P < 0.05) and single‐unit MSNA spike incidence (Δ27 ± 5 compared with Δ8 ± 2 spikes (100 heart beats)–1), P < 0.01) in the CHF patients. More importantly, the percentage of cardiac intervals that contained two or three single‐unit spikes was increased (P < 0.05) during exercise in the CHF group only (Δ8 ± 2% and Δ5 ± 1% for two and three spikes, respectively). These results suggest that the larger multi‐unit total MSNA response observed during HG in CHF is brought about in part by an increase in the probability of multiple firing of single‐unit sympathetic neurones.

Rho-Kinase Activation in Leukocytes Plays a Pivotal Role in Myocardial Ischemia/Reperfusion Injury

The Rho/Rho-kinase pathway plays an important role in many cardiovascular diseases such as hypertension, atherosclerosis, heart failure, and myocardial infarction. Although previous studies have shown that Rho-kinase inhibitors reduce ischemia/reperfusion (I/R) injury and cytokine production, the role of Rho-kinase in leukocytes during I/R injury is not well understood. Mice were subjected to 30-min ischemia and reperfusion. Rho-kinase activity was significantly greater in leukocytes subjected to myocardial I/R compared to the sham-operated mice. Administration of fasudil, a Rho-kinase inhibitor, significantly reduced the I/R-induced expression of the proinflammatory cytokines interleukin (IL)-6, C-C motif chemoattractant ligand 2 (CCL2), and tumor necrosis factor (TNF)-α, in leukocytes, compared with saline as the vehicle. Furthermore, fasudil decreased I/R-induced myocardial infarction/area at risk (IA) and I/R-induced leukocyte infiltration in the myocardium. Interestingly, IA in fasudil-administered mice with leukocyte depletion was similar to that in fasudil-administered mice. I/R also resulted in remarkable increases in the mRNA expression levels of the proinflammatory cytokines TNF-α, IL-6, and CCL2 in the heart. Inhibition of Rho-kinase activation in leukocytes has an important role in fasudil-induced cardioprotective effects. Hence, inhibition of Rho-kinase may be an additional therapeutic intervention for the treatment of acute coronary syndrome.

Optimal Force-Time Integral for Pulmonary Vein Isolation According to Anatomical Wall Thickness Under the Ablation Line.

Background Low contact force and force–time integral (FTI) during catheter ablation are associated with ineffective lesion formation, whereas excessively high contact force and FTI may increase the risk of complications. We sought to evaluate the optimal FTI for pulmonary vein (PV) isolation based on atrial wall thickness under the ablation line. Methods and Results Contact force parameters and FTI during anatomical ipsilateral PV isolation for atrial fibrillation and atrial wall thickness were assessed retrospectively in 59 consecutive patients for their first PV isolation procedure. The PV antrum was divided into 8 segments, and the wall thickness of each segment under the ablation line was determined using multidetector computed tomography. The FTI for each ablation point was divided by the wall thickness of the PV antrum segment where each point was located to obtain FTI/wall thickness. In total, 5335 radiofrequency applications were delivered, and 85 gaps in PV isolation ablation lines and 15 dormant conductions induced by adenosine were detected. The gaps or dormant conductions were significantly associated with low contact force, radiofrequency duration, FTI, and FTI/wall thickness. Among them, FTI/wall thickness had the best prediction value for gaps or dormant conductions by receiver operating characteristic curve analysis. FTI/wall thickness of <76.4 gram‐seconds per millimeter (gs/mm) predicted gaps or dormant conductions with sensitivity (88.0%) and specificity (83.6%), and FTI/wall thickness of <101.1 gs/mm was highly predictive (sensitivity 97.0%; specificity 69.6%). Conclusions FTI/wall thickness is a strong predictor of gap and dormant conduction formation in PV isolation. An FTI/wall thickness ≈100 gs/mm could be a suitable target for effective ablation.

Augmented single‐unit muscle sympathetic nerve activity in heart failure with chronic atrial fibrillation

Non‐technical summary  Augmentation of sympathetic nerve activity plays an important role in the deterioration of heart failure (HF). Atrial fibrillation (AF) is a well known and common complication in chronic HF. However, it remains unclear the relationship between sympathetic nerve activity and irregular ventricular rhythm induced by AF in HF. We examined the different sympathetic firing characteristics between HF patients with and without AF using a single‐unit muscle sympathetic nerve activity (MSNA) method, which is a newly developed assessment of direct recording of sympathetic nerve activity. The firing frequency of single‐unit MSNA was increased in HF patients with AF compared with HF patients without AF; particularly, those with a prolonged long RR interval showed multiple firings of single‐unit MSNA. More intense single‐unit MSNA within one cardiac interval occurred in HF patients with AF than patients without AF, even in AF patients receiving heart rate control therapy. Accordingly, our results suggest that AF per se augments central sympathetic activity and the restoration of sinus rhythm may be more effective in the treatment of HF patients with AF.

Detection of the Earliest Ventricular Contraction Site in Patients with Wolff-Parkinson-White Syndrome Using Two-Dimensional Guided M-Mode Tissue Doppler Echocardiography

Objective: The purpose of this study was to examine the feasibility of M-mode tissue Doppler imaging for localizing the accessory pathway in patients with Wolff-Parkinson-White (WPW) syndrome. Methods: Two-dimensional guided tissue Doppler M-mode was recorded at the mitral and tricuspid annular levels in 13 WPW patients. Time intervals were measured from the onset of the δ wave or the R wave to the beginning of the ventricular systolic motion. The earliest contraction site was defined as the site demonstrating the shortest time interval, and compared with the earliest activated site determined by body surface mapping and the successful ablation site. Results: In 6 patients with a left-sided pathway, tissue Doppler localization was identical to the ablation site. In 3 with a left-sided pathway and 3 with a right-sided pathway, localization was judged as an adjacent region of the ablation site. In 1 patient with a right lateral pathway, the pathway location was misdiagnosed. The tissue Doppler diagnosis for the left-sided pathways correlated well with the ablation site, in contrast to the right-sided pathways (p = 0.05). Prediction of the accessory pathway localization by tissue Doppler M-mode was equivalent to localization based on body surface mapping. Conclusions: In WPW syndrome, tissue Doppler M-mode can detect the earliest contraction sites and seems helpful in localizing the left-sided accessory pathways, but is of limited use for right-sided pathways.

Inflammation of left atrial epicardial adipose tissue is associated with paroxysmal atrial fibrillation

BACKGROUND Although an increased epicardial adipose tissue (EAT) volume around the left atrium (LA) is related to the atrial fibrillation (AF) burden, the role of EAT inflammation in AF is unclear. We investigated the association between AF and inflammation of the EAT around the LA. METHODS We retrospectively identified regions of EAT around the LA and measured the density of these areas using computed tomography (CT). RESULTS A total of 32 patients who underwent their first catheter ablation for paroxysmal AF (PAF) were enrolled (mean age 62.5±11.1 years). Patients without a history of AF (n=32), but who underwent cardiac CT and were matched by age, sex, and metabolic risk factors, were enrolled in the control group (62.2±12.1 years). The mean EAT density around the LA was significantly higher in the PAF group than in the control group (-108.1±6.7 vs. -111.6±5.5 Hounsfield units; p=0.02), while the densities of subcutaneous adipose tissue (SAT) in the abdomen and thorax did not differ between the two groups. In a multiple logistic regression analysis, a higher EAT density was significantly associated with the presence of PAF after adjusting for other risk factors (odds ratio: 1.25; 95% confidence interval: 1.08-1.45, p=0.003). CONCLUSIONS This study supports the hypothesis that inflammation of EAT around the LA, but not SAT, is related to the presence of PAF.

Effect of pioglitazone on muscle sympathetic nerve activity in type 2 diabetes mellitus with alpha-glucosidase inhibitor

Activation of the sympathetic nervous system is augmented in patients with type 2 diabetes mellitus (DM). Pioglitazone, an anti-diabetic drug, improves insulin resistance, but its influence on sympathetic nerve activity is not clear. To identify the relationship between insulin resistance and sympathetic activity, we examined muscle sympathetic nerve activity (MSNA) in controlled type 2 DM patients with alpha-glucosidase inhibitor (GI). We measured MSNA and calculated homeostasis model assessment of insulin resistance index (HOMA-IR) in twelve DM patients treated with alpha-GI and thirteen age-matched healthy subjects. In DM patients with alpha-GI, all parameters were reexamined after three months of treatment with pioglitazone. MSNA and HOMA-IR were significantly greater in DM patients with alpha-GI compared to healthy subjects. Hemoglobin A1c did not differ in DM patients before and after pioglitazone. However, pioglitazone significantly decreased MSNA in DM patients compared with alpha-GI (21.7±5.2 vs. 32.0±6.8 burst/min, p<0.01). Furthermore, MSNA level in pioglitazone was similar to that in healthy subjects. HOMA-IR significantly decreased after pioglitazone, and a significant relationship was found between the absolute change in MSNA and HOMA-IR (r=0.65, p<0.05). These results suggest that improved insulin resistance with pioglitazone provides an additional effect on inhibition of sympathetic nerve activity.

Two-dimensional guided M-mode color tissue Doppler echocardiography in artificial preexcitation models.

The purpose of this study was to analyze the left ventricular contraction patterns in artificial preexcitation models by using 2-dimensional guided M-mode color tissue Doppler echocardiography. Three types of preexcitation models were produced in 12 patients by right atrio-mitral annular sequential pacing, carried out at the left ventricular lateral, posterior, and posteroseptal walls. Tissue Doppler M-mode was recorded at anteroseptal, posterior, lateral, and posteroseptal sites in the parasternal short-axis view. The time interval from the onset of the QRS complex during sinus rhythm or from the annular pacing spike during fusion beats to the beginning of systolic motion was measured. During sinus rhythm, the time interval at the anteroseptal wall was shortest. During fusion beats, the time intervals at the mitral annular pacing sites were shortest. In preexcitation models, tissue Doppler M-mode could clearly distinguish the difference of left ventricular contraction patterns and detect the earliest contraction site of the left ventricle.

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

Objective: 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. Design and methods: 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. Results: 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. Conclusion: 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.

Usefulness of Electrocardiographic Voltage to Determine Myocardial Fibrosis in Hypertrophic Cardiomyopathy.

Classic electrocardiographic (ECG) voltage indexes have been applied to screen for left ventricular (LV) hypertrophy in hypertrophic cardiomyopathy (HC). However, it is unclear whether low ECG voltage reflects deteriorated electrical forces because of replacement of the myocardium by fibrotic tissues in HC. We investigated correlations between classic ECG voltage indexes (Cornell, total QRS voltage, and Sokolow-Lyon) and cardiac magnetic resonance (CMR) parameters focusing on the impact of low ECG voltage on the LV ejection fraction (LVEF) and myocardial fibrosis in HC. We studied 108 consecutive patients with HC who underwent CMR imaging with late gadolinium enhancement (LGE). Nineteen patients with complete right or left bundle branch block were excluded, leaving 89 patients for analysis (age 61.0 ± 13.9 years; 58 men). Of the 3 voltage indexes, the total QRS voltage and Sokolow-Lyon indexes were positively correlated with LVEF. For discriminating patients with end-stage HC (LVEF <50%) from patients with HC and preserved LVEF (≥ 50%), receiver-operating characteristic analysis revealed an excellent area under the curve of 0.87 for the total QRS voltage index and 0.90 for the Sokolow-Lyon index, whereas the area under the curve for the Cornell index was only 0.54 (p <0.01). Moreover, these 2 voltage indexes were negatively correlated with the extent of LGE-determined myocardial fibrosis when adjusted by the LV maximal wall thickness. In conclusion, low ECG voltage indexes may reflect increased myocardial fibrosis in patients with HC.