Hisashi Yokoshiki

Regression of Left Ventricular Hypertrophy Prevents Ischemia-Induced Lethal Arrhythmias Beneficial Effect of Angiotensin II Blockade

To evaluate the preventive effect of regression of left ventricular hypertrophy (LVH) on sudden cardiac death (SCD), the incidence of ventricular tachycardia or ventricular fibrillation (VT/Vf) after left coronary artery occlusion in Langendorff preparations was studied in the following five groups: (1) spontaneously hypertensive rats (SHR) without treatment (SHR-N), (2) SHR treated with captopril (SHR-C), (3) SHR treated with the angiotensin II receptor antagonist TCV-116 (SHR-A), (4) SHR treated with hydralazine (SHR-H), and (5) Wistar-Kyoto (WKY) rats. Although blood pressure was equally lowered in all treated groups, SHR-C and SHR-A but not SHR-H showed regression of LVH. The incidence of VT/Vf was 5% in WKY rats, 63% in SHR-N (P < .005 versus WKY rats), 0% in SHR-C, 10% in SHR-A, and 45% in SHR-H (P < .05 versus WKY rats). Further evaluation of the effect of TCV-116 revealed that SHR treated with a low dose of TCV-116 (1 mg/kg per day) showed a decrease in left ventricular mass with only a little decrease in blood pressure and that the incidence of VT/Vf was reduced in association with the degree of regression of LVH. Electrophysiological study using microelectrode techniques revealed that in the LVH groups (SHR-N and SHR-H), the action potential duration (APD) of the left ventricular papillary muscle was more prolonged than in WKY rats, whereas APD shortened to a greater extent during superfusion with a hypoxia/no-glucose solution. APD showed no difference in the regression groups (SHR-C and SHR-A) compared with the WKY group.(ABSTRACT TRUNCATED AT 250 WORDS)

Vasodilating mechanisms of levosimendan.

Levosimendan, a new Ca2+-sensitizing and positive inotropic agent [1–4], has been reported to be useful for treatment of patients with severe low-output heart failure [5–8]. In addition to its positive inotropy, it exerts vasodilatory actions on several vasculatures including coronary, pulmonary and systemic arteries [5,6,9,10]. Although high doses of levosimendan (1 mM) are likely to inhibit phosphodiesterase (PDE) (thereby increasing cAMP) in vascular smooth muscle (VSM) [11], the mechanism of increase in coronary flow by levosimendan was different from milrinone [12,13], a PDE-III inhibitor, and independent of activation of the cAMPand cGMP-dependent protein kinases [12]. Activation of the ATP-sensitive K+ (KATP) channel by levosimendan was demonstrated in VSM cells from rat small mesenteric artery (prearteriole; diameter <300 μm) [14], human portal vein [15], and cat pulmonary vasculature [16]. In addition, increase in coronary flow by levosimendan in in vivo dog hearts, as well as in Langendorff-perfused guinea-pig hearts, was blunted by glibenclamide [17,18], a KATP channel blocker. Hyperpolarization by KATP channel openings reduces excitability and lowers intracellular Ca2+ ([Ca2+]i) by decreasing the open probability of the L-type Ca2+ channel and by stimulating the forward mode of the Na+/Ca2+ exchanger (NCX; i.e., 3 Na+ in/1 Ca2+ out) [19]. The former action would decrease Ca2+ influx into the cell, whereas the latter would increase Ca2+ efflux. Both effects act to lower [Ca2+]i and thereby promote relaxation of the VSM cell. Therefore, stimulation of KATP channels in VSM cells probably contributes to the vasodilating action of levosimendan. Contractile agonists increase the Ca2++ sensitivity of smooth muscles by activation of protein kinase C (PK-C) [19]. It was proposed that hyperpolarization by K+ channel opening drugs reduces agonistinduced PIP2 hydrolysis, thereby suppressing both the Ca2+ mobilization from IP3-sensitive stores and the activation of PK-C [19]. Therefore, hyperpolarization by K+ channel activation may decrease not only the Ca2+ availability but also the Ca2+ sensitivity of contractile proteins (i.e., Ca2+ desensitization) [19]. Consistent with this proposal, levosimendan actually decreased the Ca2+ sensitivity of the contractile proteins in porcine coronary artery [13], which is opposite to the Ca2+ sensitization in cardiac muscle. The Ca2+ desensitization produced by levosimendan may be mediated through a direct action on contractile proteins or may be secondary to hyperpolarization. Ca++ desensitization probably is one of the mechanisms for the levosimendan-induced coronary vasodilation. Two studies [20,21] have focused on the Ca2+dependent vasorelaxant activity of levosimendan. Under physiological K+ concentration, levosimendan produced glibenclamide-insensitive vasorelaxation of bovine coronary arteries that was unmasked by high extracellular Ca2+ ([Ca2+]o = 6.8 mM) [20]. In contrast, the vasodilatory effect of levosimendan on precontracted (30 mM K+) epicardial coronary arteries of pig and human hearts was diminished by elevation of [Ca2+]o from 1.5 mM to 7.5 mM [21]. This seeming discrepancy might arise from the different experimental conditions. In the present issue of Cardiovascular Drugs and Therapy, Pataricza et al. found that levosimendan activates two additional K+ channels: the voltagedependent K+ (KV) channel and the Ca2+-activated K+ (KCa) channels [22]. They used 20 mM K+ to produce the contractions in porcine epicardial coronary artery, and the relaxations by levosimendan and cromakalim (another KATP channel opener) were compared in absence or presence of various K+ channel blockers. The cromakalim-induced relaxation was inhibited by 1 μM glibenclamide. In contrast, the relaxation produced by levosimendan was insensitive to glibenclamide, but it was partially inhibited by 2 mM tetraethylammonium, a non-specific blocker of K+ channels, and 100 nM iberiotoxin, a blocker of the largeconductance Ca2+-activated K+ channel. Moreover, 4-aminopyridine (5 mM), a relatively selective blocker of KV channels [23], greatly attenuated the levosimendan-induced relaxation. Therefore, levosimendan produces vasorelaxation through activation of the various types of K+ channels: KV and KCa channels

Hyperuricemia predicts adverse outcomes in patients with heart failure.

BACKGROUND Hyperuricemia is associated with worse outcomes of patients with chronic heart failure (HF). However, it is unknown in an unselected HF patients encountered in routine clinical practice. We thus assessed the impact of hyperuricemia on long-term outcomes including mortality and rehospitalization among patients hospitalized with worsening HF. METHODS The Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD) studied prospectively the characteristics and treatments in a broad sample of hospitalized HF patients and the outcomes were followed for 2.1 years after discharge. Study cohorts (n=1869) were divided into 2 groups according to serum uric acid (UA) at discharge; ≥ 7.4 mg/dL (n=908) and <7.4 mg/dL (n=961). RESULTS Of the total cohort of HF patients, 56% had hyperuricemia defined as UA ≥ 7.0mg/dl. Patients with UA ≥ 7.4 mg/dL had higher rates of all-cause death, cardiac death, rehospitalization, and all-cause death or rehospitalization due to worsening HF. After multivariable adjustment, higher UA levels were a significant and independent predictor for all-cause death (adjusted hazard ratio [HR] 1.413, 95% confidence interval [CI] 1.094-1.824, P=0.008) and cardiac death (adjusted HR 1.399, 95% CI 1.020-1.920, P=0.037). CONCLUSIONS Hyperuricemia was common in patients with HF encountered in clinical practice and higher UA was independently associated with long-term adverse outcomes in these patients.

Conduction and refractory disorders in the diabetic atrium

Diabetes mellitus (DM) is an independent risk of atrial fibrillation. However, its arrhythmogenic substrates remain unclear. This study sought to examine the precise propagation and the spatiotemporal dispersion of the action potential (AP) in the diabetic atrium. DM was induced by streptozotocin (65 mg/kg) in 8-wk-old male Wister rats. Optical mapping and histological analysis were performed in the right atrium (RA) from control (n = 26) and DM (n = 27) rats after 16 wk. Rate-dependent alterations of conduction velocity (CV) and its heterogeneity and the spatial distribution of AP were measured in RA using optical mapping. The duration of atrial tachyarrhythmia (AT) induced by rapid atrial stimulation was longer in DM (2.4 ± 0.6 vs. 0.9 ± 0.3 s, P < 0.05). CV was decreased, and its heterogeneity was greater in DM than control. Average action potential duration of 80% repolarization (APD(80)) at pacing cycle length (PCL) of 200 ms from four areas within the RA was prolonged (53 ± 2 vs. 40 ± 3 ms, P < 0.01), and the coefficient of variation of APD(80) was greater in DM than control (0.20 ± 0.02 vs. 0.15 ± 0.01%, P < 0.05). The ratio of APD(80) at PCL shorter than 200 ms to that at 200 ms was smaller (P < 0.001), and the incidence of APD alternans was higher in DM than control (100 vs. 0%, P < 0.001). Interstitial fibrosis was greater and connexin 40 expression was lower in DM than control. The remodeling of the diabetic atrium was characterized as follows: greater vulnerability to AT, increased conduction slowing and its heterogeneity, the prolongation of APD, the increase in spatial dispersion and frequency-dependent shortening of APD, and increased incidence of APD alternans.

Spironolactone use at discharge was associated with improved survival in hospitalized patients with systolic heart failure

BACKGROUND The RALES trial demonstrated that spironolactone improved the prognosis of patients with heart failure (HF). However, it is unknown whether the discharge use of spironolactone is associated with better long-term outcomes among hospitalized systolic HF patients in routine clinical practice. We examined the effects of spironolactone use at discharge on mortality and rehospitalization by comparing with outcomes in patients who did not receive spironolactone. METHODS The JCARE-CARD studied prospectively the characteristics and treatments in a broad sample of patients hospitalized with worsening HF and the outcomes were followed with an average of 2.2 years of follow-up. RESULTS A total of 946 patients had HF with reduced left ventricular ejection fraction (LVEF) (<40%), among whom spironolactone was prescribed at discharge in 435 patients (46%), but not in 511 patients (54%). The mean age was 66.3 years and 72.2% were male. Etiology was ischemic in 39.7% and mean LVEF was 27.1%. After adjustment for covariates, discharge use of spironolactone was associated with a significant reduction in all-cause death (adjusted hazard ratio 0.612, P=.020) and cardiac death (adjusted hazard ratio 0.524, P=.013). CONCLUSIONS Among patients with HF hospitalized for systolic dysfunction, spironolactone use at the time of discharge was associated with long-term survival benefit. These findings provide further support for the idea that spironolactone may be useful in patients hospitalized with HF and reduced LVEF.

Characteristics, management, and outcomes for patients during hospitalization due to worsening heart failure—A report from the Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD)

BACKGROUND The characteristics, in-hospital management, and outcomes of patients hospitalized with worsening heart failure (HF) have been described by large-scale registries performed mainly in the USA and Europe. However, little information is available in Japan. We thus clarified the characteristics and clinical status as well as in-hospital management and outcomes among patients hospitalized with worsening HF in Japan and compared them with those reported in previous studies. METHODS The Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD) studied prospectively the characteristics and treatments in patients hospitalized with worsening HF. From the total cohort of JCARE-CARD, 1677 patients were randomly selected and their detailed data during acute phase were collected as another registry database in the present study. The characteristics, in-hospital management, and outcomes were analyzed. RESULTS The mean age was 70.7 years and 59.4% were male. Etiology was ischemic in 34.0% and mean left ventricular ejection fraction was 42.5%. Carperitide was highly used as in-hospital management in Japan (33.5%) compared to the use of nesiritide in the USA (8-11%). The use of angiotensin-converting enzyme inhibitors was lower and angiotensin II receptor blockers (ARB) were more commonly used in this study compared to other studies in the USA and Europe. In-hospital crude mortality rate was comparable among studies (4-8%), however, length of stay was longer in Japan (15-20 versus 4-9 days). CONCLUSIONS The characteristics, clinical status, and laboratory data on admission in patients hospitalized with worsening HF were similar between the present study and previous Japanese and western studies. Management was also similar except for higher use of carperitide and ARB. The most striking difference between Japanese registries and those from the USA and Europe was the longer length of stay.

L-type Ca2+ currents in ventricular myocytes from neonatal and adult rats.

Postnatal changes in the slow Ca2+ current (I(Ca)(L)) were investigated in freshly isolated ventricular myocytes from neonatal (1-7 days old) and adult (2-4 months old) rats, using whole-cell voltage clamp and single-channel recordings. The membrane capacitance (mean+/-SEM) averaged 23.2+/-0.5 pF in neonates (n = 163) and 140+/-4.1 pF in adults (n = 143). I(Ca)(L) was measured as the peak inward current at a test potential of +10 mV (or +20 mV) by applying a 300-ms pulse from a holding potential of -40 mV; 1.8 mM Ca2+ was used as charge carrier. The basal ICa(L) density was 6.7+/-0.2 pA/pF in neonatal and 7.8+/-0.2 pA/pF in adult cells (p < 0.05). The time course of inactivation of the fast component (at +10 ms) was significantly longer in the neonatal (10.7+/-1.4 ms) than in the adult (6.6+/-0.4 ms) cells (p < 0.05). Ryanodine (10+/-M) significantly increased this value to 18.0+/-1.9 in neonate (n = 8) and to 17.7+/-2.0 in adult (n = 9). For steady-state inactivation, the half-inactivation potential (Vh) was not changed in either group. For steady-state activation, Vh was 5.1 mV in the neonatal (n = 6) and -7.9 mV in the adult cells (n = 7). Single-channel recordings revealed that long openings (mode-2 behavior) were occasionally observed in the neonatal cells (11 events from 1080 traces/11 cells), but not in the adult cells (400 traces/4 cells). Slope conductance was 24 pS in both the neonatal and adult cells. Results in rat ventricular myocytes suggest the following: (i) the peak Ca2+ current density is already well developed in the neonatal period (being about 85% of the adult value); (ii) the fast component of inactivation is slower in neonates than in adults; and (iii) naturally occurring long openings are occasionally observed in the neonatal stage but not in the adult. Thus, the L-type Ca2+ channels of the neonate were slightly lower in density, were inactivated more slowly, and occasionally exhibited mode-2 behavior as compared with those of the adult.

Evidence for presence of ATP-sensitive K+ channels in rat colonic smooth muscle cells.

Coexpression of sulfonylurea receptor (SUR) and inward-rectifying K+ channel (Kir6.1 or 6.2) subunit yields ATP-sensitive K+ (K(ATP)) channels. Three subtypes of SUR have been cloned: pancreatic (SUR1), cardiac (SUR2A), and vascular smooth muscle (SUR2B). The distinct responses to K+ channel openers (KCOs) produced in different tissues may depend on the SUR isoform of K(ATP) channel. Therefore, we investigated the effects of pinacidil and diazoxide, two KCOs, on K(ATP) currents in intestinal smooth muscle cells of the rat colon (circular layer) using whole-cell voltage clamp. Pinacidil stimulated a time-independent K+ current evoked by various test potentials from a holding potential of -70 mV. The reversal potential of the stimulated current was about -75 mV, which is close to the equilibrium potential for K+ (E(K)). Both pinacidil and diazoxide dose-dependently stimulated K+ currents (evoked by ramp pulses), with EC50 values of 1.3 and 34.2 microM, respectively. The stimulated current was completely reversed by glybenclamide (3 microM). Since the EC50 values are close to those reported for vascular smooth muscle (VSM) cells, the SUR subtype may be similar to that in VSM cells, and could form the functional K(ATP) channel in rat colonic smooth muscle cells.

Abrupt augmentation of ST segment elevation associated with successful reperfusion: A sign of diminished myocardial salvage

To investigate the significance of abrupt augmentation of ST segment elevation immediately after reperfusion, 36 patients with an initial acute anterior myocardial infarction successfully treated with thrombolysis were studied. Immediately after reperfusion was performed, 17 (47%) patients showed abrupt augmentation of ST segment elevation of anterior area (E group), and 19 (53%) patients did not (N group). The time to reperfusion was not significantly different between the two groups. In the E group the peak level of creatine kinase MB isozyme was higher (p < 0.05) than in the N group. The left ventricular ejection fraction (EF) did not increase in the E group from acute to chronic phase. However, in the N group EF increased significantly. The difference in EF in the chronic phase was significant between the two groups (p < 0.05). The infarcted regional wall motion (RWM) did not increase in the E group, whereas in the N group it increased markedly (p < 0.05). In addition, the infarcted RWM in the chronic phase was worse in the E group than in the N group (p < 0.05). Abrupt augmentation of ST segment elevation associated with successful reperfusion appears to reflect diminished myocardial salvage.

Discharge use of angiotensin receptor blockers provides comparable effects with angiotensin-converting enzyme inhibitors on outcomes in patients hospitalized for heart failure

Large-scale, placebo-controlled, randomized clinical trials have shown that angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) reduce mortality and hospitalization in patients with heart failure (HF) caused by left ventricular systolic dysfunction (LVSD). However, it is unknown whether ACE inhibitors and ARBs have similar effects on the long-term outcomes in HF patients encountered in routine clinical practice. The Japanese Cardiac Registry of Heart Failure in Cardiology enrolled HF patients hospitalized with worsening symptoms and they were followed during an average of 2.2 years. The outcome data were compared in patients with LVSD by echocardiography (ejection fraction, EF <40%) according to the predischarge use of ACE inhibitors (n=356) or ARBs (n=372). The clinical characteristics were similar between patients with ACE inhibitor and ARB use, except for higher prevalence of hypertensive etiology and diabetes mellitus. There was no significant difference between ACE inhibitor and ARB use in all-cause death (adjusted hazard ratio 0.958, 95% confidence interval 0.601–1.527, P=0.858) and rehospitalization (adjusted hazard ratio 0.964, 95% confidence interval 0.683–1.362, P=0.836). The effects of ACE inhibitor and ARB use on the outcomes were generally consistent across all clinically relevant subgroups examined, including age, sex, etiology, EF, hypertension, diabetes mellitus, and β-blocker use. Discharge use of ARBs provided comparable effects with ACE inhibitors on outcomes in patients hospitalized for HF. These findings provide further support for guideline recommendations that ARBs can be used in patients with HF and LVSD as an alternative of ACE inhibitors.