Yuko Ishiguro

Moderate hypothermia increases the chance of spiral wave collision in favor of self-termination of ventricular tachycardia/fibrillation

In cardiac arrest due to ventricular fibrillation (VF), moderate hypothermia (MH, 33 degrees C) has been shown to improve defibrillation success compared with normothermia (NR, 37 degrees C) and severe hypothermia (SH, 30 degrees C). The underlying mechanisms remain unclear. We hypothesized that MH might prevent reentrant excitations rotating around functional obstacles (rotors) that are responsible for the genesis of VF. In two-dimensional Langendorff-perfused rabbit hearts prepared by cryoablation (n = 13), action potential signals were recorded by a high-resolution optical mapping system. During basic stimulation (2.5-5.0 Hz), MH and SH caused significant prolongation of action potential duration and significant reduction of conduction velocity. Wavelength was unchanged at MH, whereas it was shortened significantly at SH at higher stimulation frequencies (4.0-5.0 Hz). The duration of direct current stimulation-induced ventricular tachycardia (VT)/VF was reduced dramatically at MH compared with NR and SH. The spiral wave (SW) excitations documented during VT at NR were by and large organized, whereas those during VT/VF at MH and SH were characterized by disorganization with frequent breakup. Phase maps during VT/VF at MH showed a higher incidence of SW collision (mutual annihilation or exit from the anatomical boundaries), which caused a temporal disappearance of phase singularity points (PS-0), compared with that at NR and SH. There was an inverse relation between PS-0 period in the observation area and VT/VF duration. MH data points were located in a longer PS-0 period and a shorter VT/VF duration zone compared with SH. MH causes a modification of SW dynamics, leading to an increase in the chance of SW collision in favor of self-termination of VT/VF.

Early termination of spiral wave reentry by combined blockade of Na+ and L-type Ca2+ currents in a perfused two-dimensional epicardial layer of rabbit ventricular myocardium.

BACKGROUND Modification of spiral wave (SW) reentry by antiarrhythmic drugs is a central issue to be challenged for better understanding of their benefits and risks. OBJECTIVE We investigated the effects of pilsicainide and/or verapamil, which block sodium and L-type calcium currents (I(Na) and I(Ca,L)), respectively, on SW reentry. METHODS A two-dimensional epicardial ventricular muscle layer was created in rabbit hearts by cryoablation (n = 32), and action potential signals were analyzed by high-resolution optical mapping. RESULTS During constant stimulation, pilsicainide (3-5 microM) caused a frequency-dependent decrease of conduction velocity (CV; by 20%-54% at 5 Hz) without affecting action potential duration (APD). Verapamil (3 microM) caused APD shortening (by 16% at 5 Hz) without affecting CV. Ventricular tachycardias (VTs) that were induced were more sustained in the presence of either pilsicainide or verapamil. The incidence of sustained VTs (>30 s)/all VTs per heart was 58% +/- 9% for 5 microM pilsicainide vs. 22% +/- 9% for controls and 62% +/- 10% for 3 microM verapamil vs. 22% +/- 8% for controls. The SWs with pilsicainide were characterized by slower rotation around longer functional block lines (FBLs), whereas those with verapamil were characterized by faster rotation around shorter FBLs. Combined application of 3 microM pilsicainide and 3 microM verapamil resulted in early termination of VTs (sustained VTs/all VTs per heart: 2% +/- 2% vs. 29% +/- 9% for controls); SWs showed extensive drift and decremental conduction, leading to their spontaneous annihilation. CONCLUSION Blockade of either I(Na) or I(Ca,L) stabilizes SWs in a two-dimensional epicardial layer of rabbit ventricular myocardium to help their persistence, whereas blockade of both currents destabilizes SWs to facilitate their termination.

Rate-dependent shortening of action potential duration increases ventricular vulnerability in failing rabbit heart

Congestive heart failure (CHF) predisposes to ventricular fibrillation (VF) in association with electrical remodeling of the ventricle. However, much remains unknown about the rate-dependent electrophysiological properties in a failing heart. Action potential properties in the left ventricular subepicardial muscles during dynamic pacing were examined with optical mapping in pacing-induced CHF (n=18) and control (n=17) rabbit hearts perfused in vitro. Action potential durations (APDs) in CHF were significantly longer than those observed for controls at basic cycle lengths (BCLs)>1,000 ms but significantly shorter at BCLs<400 ms. Spatial APD dispersions were significantly increased in CHF versus control (by 17-81%), and conduction velocity was significantly decreased in CHF (by 6-20%). In both groups, high-frequency stimulation (BCLs<150 ms) always caused spatial APD alternans; spatially concordant alternans and spatially discordant alternans (SDA) were induced at 60% and 40% in control, respectively, whereas 18% and 82% in CHF. SDA in CHF caused wavebreaks followed by reentrant excitations, giving rise to VF. Incidence of ventricular tachycardia/VFs elicited by high-frequency dynamic pacing (BCLs<150 ms) was significantly higher in CHF versus control (93% vs. 20%). In CHF, left ventricular subepicardial muscles show significant APD shortenings at short BCLs favoring reentry formations following wavebreaks in association with SDA. High-frequency excitation itself may increase the vulnerability to VF in CHF.

A single intracoronary injection of midkine reduces ischemia/reperfusion injury in Swine hearts: a novel therapeutic approach for acute coronary syndrome

Several growth factors are effective for salvaging myocardium and limiting infarct size in experimental studies with small animals. Their benefit in large animals and feasibility in clinical practice remains to be elucidated. We investigated the cardioprotective effect of midkine (MK) in swine subjected to ischemia/reperfusion (I/R). I/R was created by left anterior descending coronary artery occlusion for 45 min using a percutaneous over-the-wire balloon catheter. MK protein was injected as a bolus through the catheter at the initiation of reperfusion [MK-treated (MKT) group]. Saline was injected in controls (CONT). Infarct size/area at risk (24 h after I/R) in MKT was almost five times smaller than in CONT. Echocardiography in MKT revealed a significantly higher percent wall thickening of the interventricular septum, a higher left ventricular (LV) fractional shortening, and a lower E/e′ (ratio of transmitral to annular flow) compared with CONT. LV catheterization in MKT showed a lower LV end-diastolic pressure, and a higher dP/dtmax compared with CONT. Terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end-labeling-positive myocytes and CD45-positive cell infiltration in the peri-infarct area were significantly less in MKT than in CONT. Here, we demonstrate that a single intracoronary injection of MK protein in swine hearts at the onset of reperfusion dramatically reduces infarct size and ameliorates systolic/diastolic LV function. This beneficial effect is associated with a reduction of apoptotic and inflammatory reactions. MK application during percutaneous coronary intervention may become a promising adjunctive therapy in acute coronary syndromes.

Acute amiodarone promotes drift and early termination of spiral wave re-entry

Intravenous application of amiodarone is commonly used in the treatment of life-threatening arrhythmias, but the underlying mechanism is not fully understood. The purpose of the present study is to investigate the acute effects of amiodarone on spiral wave (SW) re-entry, the primary organization machinery of ventricular tachycardia/fibrillation (VT/VF), in comparison with lidocaine. A two-dimensional ventricular myocardial layer was obtained from 24 Langendorff-perfused rabbit hearts, and epicardial excitations were analyzed by high-resolution optical mapping. During basic stimulation, amiodarone (5 μM) caused prolongation of action potential duration (APD) by 5.6%–9.1%, whereas lidocaine (15 μM) caused APD shortening by 5.0%–6.4%. Amiodarone and lidocaine reduced conduction velocity similarly. Ventricular tachycardias induced by DC stimulation in the presence of amiodarone were of shorter duration (sustained-VTs >30 s/total VTs: 2/58, amiodarone vs 13/52, control), whereas those with lidocaine were of longer duration (22/73, lidocaine vs 14/58, control). Amiodarone caused prolongation of VT cycle length and destabilization of SW re-entry, which is characterized by marked prolongation of functional block lines, frequent wavefront-tail interactions near the rotation center, and considerable drift, leading to its early annihilation via collision with anatomical boundaries. Spiral wave re-entry in the presence of lidocaine was more stabilized than in control. In the anisotropic ventricular myocardium, amiodarone destabilizes SW re-entry facilitating its early termination. Lidocaine, in contrast, stabilizes SW re-entry resulting in its persistence.

Association of left atrial phasic volumes with systemic arterial stiffness and ankle-brachial index in hypertensive patients.

Left atrial (LA) phasic volumes consist of reservoir, conduit and booster pump volumes. Arterial stiffness is linked to lower systemic arterial compliance (SAC) contributing to cardiac afterload. Arterial stiffness may be a modulator of LA phasic volumes. Echocardiography was performed in 161 hypertensive patients and in 50 normotensive subjects in order to assess biplane LA volumes (maximum, before atrial contraction, minimum), early and late diastolic mitral annular velocity (e′ and a′), and LV stroke volume. LA emptying volumes (total, passive, active) were calculated from these LA volumes. Blood pressures were measured using an automated oscillometric device simultaneously at the four limbs for evaluating pulse pressure (PP) and ankle–brachial index (ABI). SAC was estimated by the ratio of LV stroke volume indexed by body surface area (BSA) divided by PP. All three LA volumes, LA total volume and LA active emptying volume were greater in hypertensive patients than in normotensive subjects. A multiple linear regression analysis indicated that LA passive emptying volume (reservoir=early diastole)/BSA correlated positively with ABI after being adjusted for age, gender, BSA, LV mass, max LA volume, e′ and SAC in hypertensive patients. LA active emptying volume (booster=late diastole)/BSA correlated positively with SAC after being adjusted for age, gender, BSA, LV mass, LA volume before atrial contraction, a′ and ABI. LA reservoir volume was associated with ABI, and LA booster volume was related to systemic arterial stiffness in hypertensive patients, suggesting the LA–arterial coupling in this clinical setting.

Association of tricuspid regurgitation within normal range on the development of left ventricular diastolic dysfunction in patients with uncomplicated hypertension

Abstract Aim: Tricuspid regurgitation (TR) with the maximum velocity >2.8m/s has been newly integrated into the diagnostic criteria for left ventricular (LV) diastolic dysfunction. Although the maximum velocity of TR within the normal range (TR < 2.8m/s) is frequently detected in hypertensive patients and is associated with enlarged left atrial (LA) volumes, the influence of TR < 2.8m/s on LV diastolic dysfunction remains unknown in uncomplicated hypertension. Methods: Echocardiography was performed to assess the mitral annular velocity (e’), E/e’, LV mass, and LA phasic volumes and emptying fractions (total, passive, and active) in 100 patients with uncomplicated hypertension with TR within the normal range and in 77 of those without measurable TR. Patients were defined as having normal, inclusive, or dysfunction of LV diastolic function, according to how many parameters met the cut-off levels (maximum LA volume index >34ml/mm2, e’<7 cm/s, and E/e’>15). Pulmonary artery systolic pressure (PASP) was estimated by the formula; PASP =4 (maximum velocity of TR)2 + 5 mmHg. Results: The maximum velocity of TR or PASP saw a positive correlation, and LA total or passive emptying fractions saw an inverse correlation with LV diastolic dysfunction in hypertensive patients with TR < 2.8. In contrast, pulse pressure and LV mass saw positive correlation in hypertensive patients without TR. A stepwise ordinal logistic regression analysis indicated that PASP and LA passive emptying fractions were associated with LV diastolic dysfunction in hypertensive patient with TR < 2.8m/s. Conclusion: The presence of TR may be related to the development of LV diastolic dysfunction in hypertensive patients with TR <2.8m/s.