Moriaki Inoko

Increased Expression of Interleukin-1β and Monocyte Chemotactic and Activating Factor/Monocyte Chemoattractant Protein-1 in the Hypertrophied and Failing Heart With Pressure Overload

Studies on the effects of proinflammatory cytokines on the heart suggest that they play some roles in the pathogenesis of congestive heart failure (CHF). To determine the involvement of proinflammatory cytokine in cardiac hypertrophy and CHF induced by mechanical overload, we investigated the expression of interleukin (IL)-1 beta and monocyte chemotactic and activating factor (MCAF)/monocyte chemoattractant protein-1 (MCP-1) in the left ventricle (LV) of Dahl salt-sensitive (DS) rats that showed hypertrophy of the LV induced by hypertension and subsequently developed CHF. The IL-1 beta mRNA content in the LV of DS rats increased 3.9-fold when LV hypertrophy developed, and the increase reached 6.2-fold at the CHF stage compared with that of age-matched Dahl salt-resistant (DR) rats. The amount of IL-1 beta in the LV was positively correlated with the LV weight/body weight ratio. Most of the IL-1 beta immunoreactivity was localized in the endothelial cells and interstitial macrophages. The mRNA levels of MCAF in the LV increased 3.6-fold at 11 weeks and reached 4.8-fold at the CHF stage relative to the age-matched DR rats. MCAF protein was localized to the endothelial cells and interstitial macrophages. In DS rats, the number of interstitial macrophages increased diffusely throughout the LV. We suggest that increased chemokine expression, macrophage infiltration, and proinflammatory cytokine expression play some role in the pathogenesis of cardiac hypertrophy and failure induced by chronic mechanical overload.

Initial Surgical Versus Conservative Strategies in Patients With Asymptomatic Severe Aortic Stenosis.

BACKGROUND Current guidelines generally recommend watchful waiting until symptoms emerge for aortic valve replacement (AVR) in asymptomatic patients with severe aortic stenosis (AS). OBJECTIVES The study sought to compare the long-term outcomes of initial AVR versus conservative strategies following the diagnosis of asymptomatic severe AS. METHODS We used data from a large multicenter registry enrolling 3,815 consecutive patients with severe AS (peak aortic jet velocity >4.0 m/s, or mean aortic pressure gradient >40 mm Hg, or aortic valve area <1.0 cm(2)) between January 2003 and December 2011. Among 1,808 asymptomatic patients, the initial AVR and conservative strategies were chosen in 291 patients, and 1,517 patients, respectively. Median follow-up was 1,361 days with 90% follow-up rate at 2 years. The propensity score-matched cohort of 582 patients (n = 291 in each group) was developed as the main analysis set for the current report. RESULTS Baseline characteristics of the propensity score-matched cohort were largely comparable, except for the slightly younger age and the greater AS severity in the initial AVR group. In the conservative group, AVR was performed in 41% of patients during follow-up. The cumulative 5-year incidences of all-cause death and heart failure hospitalization were significantly lower in the initial AVR group than in the conservative group (15.4% vs. 26.4%, p = 0.009; 3.8% vs. 19.9%, p < 0.001, respectively). CONCLUSIONS The long-term outcome of asymptomatic patients with severe AS was dismal when managed conservatively in this real-world analysis and might be substantially improved by an initial AVR strategy. (Contemporary Outcomes After Surgery and Medical Treatment in Patients With Severe Aortic Stenosis Registry; UMIN000012140).

Late Adverse Events After Implantation of Sirolimus-Eluting Stent and Bare-Metal Stent Long-Term (5–7 Years) Follow-Up of the Coronary Revascularization Demonstrating Outcome Study-Kyoto Registry Cohort-2

Background—Late adverse events such as very late stent thrombosis (VLST) or late target-lesion revascularization (TLR) after first-generation sirolimus-eluting stents (SES) implantation have not been yet fully characterized at long term in comparison with those after bare-metal stent (BMS) implantation. Methods and Results—Among 13 058 consecutive patients undergoing first percutaneous coronary intervention in the Coronary REvascularization Demonstrating Outcome study-Kyoto registry Cohort-2, 5078 patients were treated with SES only, and 5392 patients were treated with BMS only. During 7-year follow-up, VLST and late TLR beyond 1 year after SES implantation occurred constantly and without attenuation at 0.24% per year and at 2.0% per year, respectively. Cumulative 7-year incidence of VLST was significantly higher in the SES group than that in the BMS group (1.43% versus 0.68%, P<0.0001). However, there was no excess of all-cause death beyond 1 year in the SES group as compared with that in the BMS group (20.8% versus 19.6%, P=0.91). Cumulative incidences of late TLR (both overall and clinically driven) were also significantly higher in the SES group than in the BMS group (12.0% versus 4.1%, P<0.0001 and 8.5% versus 2.6%, P<0.0001, respectively), leading to late catch-up of the SES group to the BMS group regarding TLR through the entire 7-year follow-up (18.8% versus 25.2%, and 10.6% versus 10.2%, respectively). Clinical presentation as acute coronary syndrome was more common at the time of late SES TLR compared with early SES TLR (21.2% and 10.0%). Conclusions—Late catch-up phenomenon regarding stent thrombosis and TLR was significantly more pronounced with SES than that with BMS. This limitation should remain the target for improvements of DES technology.

Importance of ischemic preconditioning and collateral circulation for left ventricular functional recovery in patients with successful intracoronary thrombolysis for acute myocardial infarction

We studied the effects of myocardial ischemic preconditioning and preexistent collateral circulation on the preservation of left ventricular function in 30 patients who had successful intracoronary thrombolysis within 6 hours after the onset of a first acute anterior myocardial infarction. The existence of ischemic preconditioning was defined as the episode of recurrent ischemic chest pain within 4 hours before the onset of acute myocardial infarction. In 16 patients with ischemic preconditioning (group A), the left ventricular ejection fraction during the convalescence of myocardial infarction was 57% +/- 11% (mean +/- SD); regional wall motion in the infarct area was 13% +/- 9%. In 14 patients without ischemic preconditioning (group B), the left ventricular ejection fraction and regional wall motion in the infarct area were 46% +/- 9% and 5% +/- 9% (both p < 0.05 vs group A). Moreover, among group A patients, seven patients having a well-developed collateral circulation during the acute stage of myocardial infarction showed a more prominent improvement in regional wall motion in the infarct area compared with nine patients having poor or no collateral circulation (18% +/- 8% vs 9% +/- 7%, p < 0.05). These data indicate that ischemic preconditioning is effective for the preservation of left ventricular function in patients with successful intracoronary thrombolysis and that preexistent coronary collateral circulation potentiates this favorable effect of ischemic preconditioning.

Myocardial Contractile Efficiency and Oxygen Cost of Contractility Are Preserved During Transition From Compensated Hypertrophy to Failure in Rats With Salt-Sensitive Hypertension

In Dahl-Iwai rats, salt-sensitive hypertension causes concentric left ventricular hypertrophy (LVH) at the age of 11 weeks, which is followed by LV dilatation with global hypokinesis and pulmonary congestion, ie, LV failure (LVF), at 16 to 18 weeks of age. To address the question of whether the cardiac remodeling from LVH to LVF is associated with modulations of mechanoenergetic properties, we serially measured the LV pressure-volume area (PVA) and myocardial oxygen consumption (MVO2) in isolated, isovolumically contracting hearts from this animal model. The end-systolic pressure-volume relationships obtained by stepwise changes of the LV volume were fit into a binominal regression model, which provided a value of LV contractility (E(es)) and a volume intercept (V0). A slope (the reciprocal of the LV contractile efficiency) and a PVA-independent MVO2 were determined by a regression analysis of the MVO2-PVA relation. The procedure was repeated at different Ca2+ concentrations in perfusate to estimate the oxygen cost of contractility (dMVO2/dE(es)). The MVO2 was further evaluated during K+-induced cardiac arrest to delineate the basal metabolism, which was independent of the E-C coupling. During the transition from LVH to LVF, the E(es) was decreased by 50% (from 681 to 338 mm Hg x g x mL(-1), P<.001), which was associated with a substantial increase in V0 (from 0.002 to 0.07 mL, P<.01). These alterations in both the inotropic state and the ventricular shape were associated with a 45% decrease in the PVA-independent MVO2 (from 800 to 440 mL O2 x beat(-1) x g(-1), P<.01). Despite these marked changes between the two stages, both the LV contractile efficiency and the oxygen cost of contractility remained unchanged. The MVO2 during cardiac arrest also showed an equal level among the groups; hence, from LVH to LVF, the nonmechanical O2 consumption by the E-C coupling decreased in a manner parallel to the basal contractile state. We conclude that (1) in this animal model, the heart failure transition is associated with a marked decrease in myocardial contractility and with ventricular remodeling; (2) despite these changes, the efficiency of the chemomechanical conversion is highly preserved; and consequently, (3) the total energy consumption per unit of failing myocardium is diminished along with its reduced nonmechanical energy expenditure for E-C coupling. These mechanoenergetic properties might constitute an adaptive mechanism in the energy-starved condition of chronically diseased myocardium.

Mechanisms of negative inotropic effects of class Ic antiarrhythmic agents : comparative study of the effects of flecainide and pilsicainide on intracellular calcium handling in dog ventricular myocardium

We studied the subcellular mechanisms responsible for the negative inotropic effects of the two Ic drugs flecainide and pilsicainide. Aequorin luminescence (Ca2+i) and isometric tension were recorded simultaneously in isolated trabeculae from the dog ventricle. In isolated myocytes from the same ventricle, the slow inward current (ICa) was recorded. Both flecainide and pilsicainide decreased peak Ca2+i, peak tension, and peak ICa concentration dependently. Each effect with flecainide was more marked than that with pilsicainide; however, Ca2+i and ICa paralleled each other in changes in tension, and the tension-Ca2+i-ICa relationship showed the same curve for each drug. We conclude that the difference in negative inotropic effects of these class Ic drugs are primarily related to their effects on L-type Ca2+ channels and the subsequent decreases in the amount of Ca2+ released from the sarcoplasmic reticulum (SR) during each cardiac cycle. Therefore, their negative inotropic effects may not be directly correlated with the essential mechanisms responsible for their antiarrhythmic action.

Preferential dilation of recipient coronary arteries of the collateral circulation by intracoronary administration of nitroglycerin

OBJECTIVES The purpose of this study was to test the hypothesis that the sensitivity to nitroglycerin of collateral vessels and recipient arteries is greater than that of donor arteries of the collateral circulation. BACKGROUND The collateral circulation responds vigorously to nitroglycerin. However, the mechanisms of the efficacy of nitroglycerin for improving collateral circulation are not fully elucidated. METHODS The diameter of donor and recipient arteries of the collateral circulation was measured with a computer-assisted analysis system in eight patients with well developed collateral vessels. Coronary angiography was repeated before and after the intracoronary injection of 50 micrograms of nitroglycerin. RESULTS After nitroglycerin, the mean diameter +/- SD of donor arteries increased to 1.61 +/- 0.53 from 1.29 +/- 0.39 mm (p < 0.01), whereas the diameter of recipient arteries increased to 1.59 +/- 0.50 from 1.10 +/- 0.49 mm (p < 0.01). The change in the diameter of recipient arteries was significantly greater than that of donor arteries (52.3 +/- 24.6% vs. 24.7 +/- 11.5%, p < 0.05). These changes induced by the intracoronary injection of nitroglycerin were accompanied by a decrease in pacing-induced ST segment depression (0.16 +/- 0.06 to 0.06 +/- 0.04 mV, p < 0.01), suggesting increased flow reserve through collateral channels. CONCLUSIONS These findings indicate that the sensitivity to nitroglycerin of recipient arteries of the collateral circulation is significantly greater than that of donor arteries. This observation may explain the strong response of the collateral circulation to nitroglycerin in patients with functionally significant collateral channels.

Sodium/calcium exchange modulates intracellular calcium overload during posthypoxic reoxygenation in mammalian working myocardium. Evidence from aequorin-loaded ferret ventricular muscles.

We tested the hypothesis that the intracellular Ca2+ overload of ventricular myocardium during the period of posthypoxic reoxygenation is mediated by transsarcolemmal Ca2+ influx via Na+/Ca2+ exchange. In aequorin-loaded, ferret right ventricular papillary muscles, blockers of the sarcolemmal and the sarcoplasmic reticulum Ca2+ channels, slowed the Cai2+ transient, producing a convex ascent during membrane depolarization, followed by a concave descent during repolarization. The magnitude of the Cai2+ transient was affected by changes in the membrane potential, Nai+, Nao+, and Cao2+, and was blocked by Ni2+, or dichlorbenzamil. The calculated Na+/Ca2+ exchange current was in the reverse mode (Ca2+ influx) during the ascending phase of the Cai2+ transient, and was abruptly switched to the forward mode (Ca2+ efflux) at repolarization, matching the time course of the Cai2+ transient. During hypoxic superfusion, the Cai2+ transient was abbreviated, which was associated with a shorter action potential duration. In contrast, immediately after reoxygenation, the Cai2+ transient increased to a level greater than that of the control, even though the action potential remained abbreviated. This is the first demonstration on a beat-to-beat basis that, during reoxygenation, Ca2+ influx via Na+/Ca2+ exchange is augmented and transports a significant amount of Ca2+ into the ventricular myocardial cell. The activation of the exchanger at the time of reoxygenation appears to be mediated by Nai+ accumulation, which occurs during hypoxia.

Endovascular Treatment of a Giant Aortic Arch Aneurysm With a Triple-Branched Stent Graft

An 86-year-old woman was referred for treatment of a rapidly enlarging aortic arch aneurysm, which had been monitored for 2 years with serial computed tomography (CT) scans. The size of the aneurysm had been 65 mm 2 years previously, but it had enlarged to 110 mm at the most recent examination (Figure 1). The patient complained of hemosputum and back pain. The risk of rupture was considered very high if the aneurysm was left untreated; however, thoracotomy was considered high risk because of the patient’s age. After obtaining the informed …

Two Cases of Reversible Left Ventricular Hypertrophy during Recovery from Takotsubo Cardiomyopathy

We report 2 cases of reversible ventricular hypertrophy in patients with takotsubo cardiomyopathy (stress‐induced cardiomyopathy) during recovery of cardiac function. The first case involved a 72‐year‐old woman who presented with cerebral infarction. On admission, an elevated troponin I and decreased apical wall motion were observed with normal myocardial perfusion imaging. The second case involved a 79‐year‐old woman who presented with angina, anxiety resulting from emotional stress, slightly decreased apical wall motion, and normal epicardial arteries. In both cases, apical hypertrophy of the left ventricle was observed at approximately 3 weeks after onset, when the wall motion had improved. The ventricular wall gradually became thinner over time. To our knowledge, this is the first report of reversible ventricular hypertrophy in patients with takotsubo cardiomyopathy. We hypothesize the hypertrophic signaling in the myocardium was stimulated by catecholamines, which are the suggested etiology of takotsubo cardiomyopathy, and the hypertrophied myocardium gradually returned to normal as the syndrome receded.