Hiroki Usuku

Chronic C-Type Natriuretic Peptide Infusion Attenuates Angiotensin II-Induced Myocardial Superoxide Production and Cardiac Remodeling

Myocardial oxidative stress and inflammation are key mechanisms in cardiovascular remodeling. C-type natriuretic peptide (CNP) is an endothelium-derived cardioprotective factor, although its effect on cardiac superoxide generation has not been investigated in vivo. This study tested the hypothesis that suppression of superoxide production contributes to the cardioprotective action of CNP. Angiotensin II (Ang II) or saline was continuously infused subcutaneously into mice using an osmotic minipump. Simultaneously with the initiation of Ang II treatment, mice were infused with CNP (0.05 μg/kg/min) or vehicle for 2 weeks. The heart weight to tibial length ratio was significantly increased by Ang II in vehicle-treated mice. Treatment with CNP decreased Ang II-induced cardiac hypertrophy without affecting systolic blood pressure. Echocardiography showed that CNP attenuated Ang II-induced increase in wall thickness, left ventricular dilatation, and decrease in fractional shortening. CNP reduced Ang II-induced increases in cardiomyocyte size and interstitial fibrosis and suppressed hypertrophic- and fibrosis-related gene expression. Finally, CNP decreased Ang II-induced cardiac superoxide production. These changes were accompanied by suppression of NOX4 gene expression. Our data indicate that treatment with CNP attenuated Ang II-induced cardiac hypertrophy, fibrosis, and contractile dysfunction which were accompanied by reduced cardiac superoxide production.

Akt1-Mediated Skeletal Muscle Growth Attenuates Cardiac Dysfunction and Remodeling after Experimental Myocardial Infarction

Background— It is appreciated that aerobic endurance exercise can attenuate unfavorable myocardial remodeling following myocardial infarction. In contrast, little is known about the effects of increasing skeletal muscle mass, typically achieved through resistance training, on this process. Here, we utilized transgenic (TG) mice that can induce the growth of functional skeletal muscle by switching Akt1 signaling in muscle fibers to assess the impact of glycolytic muscle growth on post-myocardial infarction cardiac remodeling. Methods and Results— Male-noninduced TG mice and their nontransgenic littermates (control) were subjected to left anterior coronary artery ligation. Two days after surgery, mice were provided doxycycline in their drinking water to activate Akt1 transgene expression in a skeletal muscle-specific manner. Myogenic Akt1 activation led to diminished left ventricular dilation and reduced contractile dysfunction compared with control mice. Improved cardiac function in Akt1 TG mice was coupled to diminished myocyte hypertrophy, decreased interstitial fibrosis, and increased capillary density. ELISA and protein array analyses demonstrated that serum levels of proangiogenic growth factors were upregulated in Akt1 TG mice compared with control mice. Cardiac eNOS was activated in Akt1 TG mice after myocardial infarction. The protective effect of skeletal muscle Akt activation on cardiac remodeling and systolic function was abolished by treatment with the eNOS inhibitor L-NAME. Conclusions— Akt1–mediated skeletal muscle growth attenuates cardiac remodeling after myocardial infarction and is associated with an increased capillary density in the heart. This improvement appears to be mediated by skeletal muscle to cardiac communication, leading to activation of eNOS-signaling in the heart.

Long-term use of oral nicorandil stabilizes coronary plaque in patients with stable angina pectoris

OBJECTIVE The Impact of Nicorandil in Angina (IONA) trial demonstrated that the use of nicorandil, an anti-anginal drug, reduced future cardiovascular events in patients with stable angina. We hypothesized that nicorandil has beneficial effects on coronary arterial plaque characteristics and atherosclerogenesis. METHODS AND RESULTS Preintervention intravascular ultrasound-virtual histology was performed prospectively in 65 consecutive patients with stable angina pectoris. There were no differences in coronary risk factors between the nicorandil (n = 16) and non-nicorandil (n = 49) groups. However, the nicorandil group demonstrated a larger %fibrous tissue (68 ± 10 vs. 62 ± 11%, P = 0.049) and a smaller %necrotic core tissue (11 ± 7 vs. 16 ± 10%, P = 0.049) compared with the non-nicorandil group. Multiple regression analysis showed that %necrotic core tissue (P = 0.045) was negatively and %fibrous tissue (P = 0.026) was positively associated with the use of nicorandil independent of statin use. We also analyzed the effect of nicorandil on atherosclerotic lesion formation in a mouse model of atherosclerosis. Lipid profiles were unaffected, but the area of atherosclerotic lesion and plaque necrosis were significantly reduced following 8-week nicorandil treatment in ApoE-deficient mice fed an atherogenic diet. Nicorandil significantly reduced the expression levels of endoplasmic reticulum stress markers, C/EBP homologous protein (CHOP) and glucose regulated protein/BiP (GRP78) in atherosclerotic lesions. Nicorandil significantly attenuated tunicamycin-induced CHOP upregulation in cultured THP-1 macrophages. CONCLUSIONS Nicorandil exerts its anti-atherogenic effect by mechanisms different from those of statins. Long-term nicorandil treatment is a potentially suitable second-line prevention therapy for patients with coronary artery disease.

The synergistic combined effect of anemia with high plasma levels of B-type natriuretic peptide significantly predicts an enhanced risk for major adverse cardiac events

The prevalence of anemia in patients with heart failure (HF) increases according to disease severity as a consequence of renal insufficiency, cytokine production, plasma volume expansion, and/or malnutrition. B-type natriuretic peptide (BNP) has been recognized as a biochemical marker of ventricular dysfunction. The aim of this study was to evaluate the clinical significance of anemia in HF patients and furthermore, to investigate whether a significant correlation exists between anemia, BNP, and poor clinical outcomes in HF patients. We studied 185 consecutive HF patients. We assessed the occurrence of major adverse cardiac events (MACE) post hospital discharge. Anemia was defined as Hb concentrations <12.9 g/dl in men and <11.3 g/dl in women, respectively. Kaplan-Meier analysis revealed that anemia and high BNP levels (>259 pg/ml) were significantly associated with the occurrence of MACE. Multiple logistic analysis revealed that the most predictive independent risk factor for the occurrence of MACE was high BNP levels, followed by anemia (relative risk [RR] = 2.803 and 2.241, respectively). We divided the patients with or without anemia and high or low BNP levels into four groups according to their respective Hb and BNP levels. The hazard ratio for MACE in the group with anemia and high BNP levels was 10.3 in comparison to the group without anemia and with low BNP levels (P = 0.0002). Both anemia and high plasma levels of BNP are significantly and independently associated with the occurrence of MACE in HF patients; furthermore, the synergistic effect of anemia combined with high BNP levels significantly predicts an enhanced risk for MACE.

Pump failure death and sudden cardiac death in patients with cardiac dysfunction: A search for prognostic predictive factors-A long-term follow-up study

BACKGROUND There have been few reports that have analyzed the predictive factors for heart failure death, which is sub-divided into pump failure death and sudden cardiac death, in the long term. METHODS AND RESULTS We followed 186 consecutive patients with myocardial infarction (MI) and 115 consecutive patients with non-ischemic heart failure (NIHF) during 73+/-3 months. In the MI group, 26 died from pump failure and 12 died from sudden cardiac death. In the NIHF group, 21 died from pump failure and 9 died from sudden cardiac death. Multivariate analysis revealed that the log B-type natriuretic peptide (BNP) was an independent predictor for pump failure death in both groups. In the MI group, the estimated glomerular filtration rate (eGFR) was an independent predictor for sudden cardiac death. Kaplan-Meier analysis revealed that a high BNP level was a risk factor for pump failure death in either MI or NIHF patients. On the other hand, the sudden cardiac death rate was significantly higher in the MI patients with low eGFR than in those with high eGFR. CONCLUSIONS The plasma BNP level is an independent predictor for pump failure death in both MI and NIHF patients. The eGFR is an independent predictor for sudden cardiac death in MI patients.

Usefulness of plasma B-type natriuretic peptide as a prognostic marker of cardiac function in senile systemic amyloidosis and in familial amyloidotic polyneuropathy

Abstract Objective: In senile systemic amyloidosis (SSA), a common age-related amyloidosis, wild-type transthyretin accumulates in tissues, with a primary result being cardiac dysfunction. Here, we aimed to clarify the usefulness of B-type natriuretic peptide (BNP) as a prognostic marker of cardiac function in SSA and in familial amyloidotic polyneuropathy (FAP). Methods and results: We studied 13 patients with severe SSA and 14 patients with FAP. SSA patients, but not FAP patients, demonstrated a significant correlation of log BNP with the echocardiographic diastolic marker E/e′ ratio (r = 0.78, p < 0.01). SSA patients also showed significant correlations between log BNP and log C-reactive protein or log high-sensitive troponin T (r = 0.70, p < 0.01; r = 0.64, p < 0.05). FAP patients, however, had significant correlations between log BNP and left ventricular wall thickness (intraventricular septum thickness diastole and posterior wall thickness diastole) (r = 0.73, p < 0.01; r = 0.77, p < 0.01). The mean log BNP level in the follow-up period was significantly higher than that in the diagnostic period in SSA patients (2.65 ± 0.45 versus 2.36 ± 0.40, p < 0.01) but not in FAP patients (1.91 ± 0.56 versus 1.93 ± 0.45, p = 0.87). An especially notable phenomenon was the high plasma BNP level (≥180 pg/ml) in SSA patients. Conclusion: Plasma BNP levels may be a useful prognostic marker of cardiac function in SSA.

Early diastolic overinflation in diastolic mitral regurgitation.

An 81-year-old man presented with exertional dyspnea at our hospital. An electrocardiogram was recorded, which showed 2:1 atrioventricular (AV) block. Transthoracic 2-dimensional echocardiography showed that the left ventricular (LV) wall thickness and wall motion were normal. Color Doppler echocardiography showed no significant valvular heart disease. Pulsed Doppler echocardiography at the mitral valve showed a high early diastolic inflow (E) wave (111 cm/s) with a short deceleration time (125 ms) and diastolic mitral regurgitation (MR) in early diastole (Fig. 1, right panel, arrow). By raising the baseline to reveal the full profile of the diastolic regurgitant flow, pulsed Doppler echocardiography showed that the pressure gradient at the mitral cusp was 8.3 mmHg (Fig. 1, left panel, arrow). There have been reports about the mechanisms of diastolic MR. As coaptation of the mitral valve is not isolated to the tips but, rather, is the result of the overlap of several millimeters of tissue, LV contraction is necessary for definite mitral valve closure. Thus, AV block of any degree may become a cause of diastolic MR [1]. The reversed AV pressure gradient during atrial relaxation may also contribute to this. Without AV block, diastolic MR may be present in a high LV diastolic pressure setting, such as that during aortic regurgitation [2]. In the present case, a longitudinal global strain from speckle tracking showed that the left ventricle was already dilated to the level of end-diastole (Fig. 2, dotted line, arrow). This suggests that LV early diastolic pressure might be as high as end-diastolic pressure. Along with the decrease in left atrial pressure after atrial contraction, there might be a reversed pressure gradient between the left ventricle and the left atrium. The global strain decreased during mid-diastole, suggesting gradual decrease in LV size due to diastolic MR (Fig. 2). Thus, global strain was useful in estimating the LV volume change during diastole in this patient.

Deceased left ventricular compliance contributing to diastolic mitral regurgitation in a patient with atrioventricular block

A 79-year-old woman temporarily lost consciousness and was admitted to our hospital. She had been treated for hypertension and diabetes mellitus. Upon admission, her blood pressure was 112/51 mm Hg; pulse rate, 37/min; and pulse oxygen saturation, 95 %. On auscultation, her heart and breath sounds were normal. Blood examination results showed normal cardiac enzyme levels but high plasma B-type natriuretic peptide levels (381.7 pg/mL). A 12-lead electrocardiogram showed advanced atrioventricular (AV) block. Slight ST-segment elevation and terminal T inversion were observed in leads III and aVF. A chest radiograph showed a cardiothoracic ratio of 57 %. Twodimensional transthoracic echocardiography showed normal left ventricular (LV) wall thickness and hypokinesis at the inferior wall. LV end-diastolic and end-systolic dimensions and fractional shortening were normal (44 mm, 26 mm, and 41 %, respectively). A pulsed Doppler echocardiogram of the mitral inflow (Fig. 1, arrows) and color Doppler imaging (Fig. 2, top, arrow) showed diastolic mitral regurgitation (DMR). The estimated peak pressure gradient of DMR was 8 mm Hg. The patient underwent cardiac catheterization. Simultaneous recording of pulmonary artery wedge (PAW) and LV pressures showed that the LV pressure was elevated abruptly by atrial contraction and remained elevated until late diastole (Fig. 2, bottom). As the PAW pressure decreased after the atrial contraction, AV pressure reversal occurred and continued to late diastole. Coronary arteriography revealed severe stenosis at the right coronary artery, for which percutaneous coronary intervention was performed. The next day, the AV block was abolished. A transthoracic echocardiogram showed that the DMR had disappeared. Complete mitral valve closure needs effective LV contraction, and mitral regurgitation may occur whenever the LV pressure exceeds the left atrial (LA) pressure during diastole. In any degree of AV block, atrial relaxation without succeeding LV contraction may cause reversed AV pressure gradient and DMR [1]. In the present case, we recorded the PAW and LV pressures simultaneously. The LV pressure abruptly elevated to higher than 15 mm Hg in mid-diastole by atrial contraction and decreased LV compliance owing to myocardial ischemia. However, the LA volume was already so small in atrial systole that the LA and PAW pressures became lower in mid-diastole. This case suggests that early atrial emptying and decreased LV compliance might play pivotal roles in the DMR in AV block.

Mid-diastolic mitral regurgitation in a patient with diastolic heart failure.

A 94-year-old woman who had been treated with hypertension was referred to our department because of paroxysmal nocturnal dyspnea. Her blood pressure was 154/84 mmHg and her pulse rate was 67/min. A chest radiograph showed pulmonary congestion and high cardiothoracic ratio (65 %). Blood test results indicated a high plasma B-type natriuretic peptide level (521.3 pg/ mL). A 12-lead electrocardiogram showed a sinus rhythm with high voltage in the left ventricle (S in V1 ? R in V5 = 4.1 mV). A transthoracic echocardiogram showed left ventricular hypertrophy (interventricular septal thickness was 13.0 mm and posterior wall thickness was 12.5 mm) with normal systolic function (left ventricular end-diastolic and end-systolic dimensions, 49 and 32 mm, respectively; ejection fraction, 63 %). Left ventricular mass was 294 g and left atrial volume was 81 cm. Thickening of both the anterior and posterior mitral valves and moderate systolic mitral regurgitation (MR) were observed. A continuous Doppler echocardiogram indicated that the estimated peak pressure gradient at the tricuspid regurgitation (TR) was 44 mmHg. The pulsed Doppler echocardiogram of the mitral inflow revealed a short E-wave deceleration time (131 ms) and mid-diastolic mitral regurgitation (Fig. 1, top panel, arrows). In addition, a color Doppler M-mode echocardiogram also demonstrated diastolic MR (Fig. 1, bottom panel, arrows). Tissue Doppler echocardiography at the mitral annulus revealed left ventricular diastolic dysfunction (e0 wave of 6.6 cm/s and E/e0 ratio of 15.9). After diuretics were administered for treating heart failure, the patient improved in terms of estimated peak pressure gradient at the TR (27 mmHg). Diastolic MR was no longer observed in both pulsed Doppler (Fig. 2, top panel) and color Doppler M-mode (Fig. 2, bottom panel) echocardiograms. Effective left ventricular contraction is essential to complete mitral valve closure, and diastolic MR occurs whenever the left ventricular pressure exceeds the left atrial (LA) pressure. In the present case, degenerative thickening of the mitral valve might have contributed to diastolic MR. In atrioventricular (AV) block of any degree, lowering the LA pressure during atrial diastole may cause diastolic MR [1]. In cases of atrial flutter with a variable advanced AV block, to-and-fro diastolic transmitral flow may be observed [2]. In severe aortic regurgitation or left ventricular diastolic failure, high left ventricular pressure may cause end-diastolic MR [3, 4]. As mid-diastole is a quiescent phase, the left ventricular pressure does not usually exceed the LA pressure between the early diastolic E wave and atrial systolic A wave. However, in the present case, diastolic MR was observed immediately after the end of the E-wave, suggesting an overshoot of the diastolic left ventricular pressure after H. Usuku I. Misumi (&) K. Kusuhara T. Rokutanda R. Akahoshi M. Matsumoto Internal Medicine, Kumamoto Saisyunsou Hospital, 2659 Suya, Koushi, Kumamoto 861-1196, Japan e-mail: misumi@saisyunsou1.hosp.go.jp

Coronary blood flow volume change is negatively associated with platelet aggregability in patients with non-obstructive ischemic heart disease who have no anti-platelet agents

BACKGROUND Thrombus formation is one of the main pathogeneses of acute coronary syndrome with atherosclerotic rupture. Previous studies have reported that atherosclerosis increases platelet aggregability and that vascular endothelial dysfunction reflects early change of atherosclerosis. However, the relationship between coronary endothelial dysfunction and platelet reactivity remains unclear. Therefore, in this study, we investigated the relationship between them in non-obstructive ischemic heart disease (IHD) patients. METHODS Three hundred sixty-eight consecutive stable patients with suspected angina presenting non-obstructive coronary arteries (<50% diameter) in coronary angiography were investigated with the intracoronary acetylcholine provocation test and measured adenosine triphosphate-induced coronary flow reserve. Finally, 25 non-obstructive IHD patients who had no anti-platelet agents were assessed for the relationship between coronary blood flow volume (CBFV) change and platelet aggregability as P2Y12 reaction unit (PRU) by VerifyNow P2Y12 assay system. RESULTS CBFV change by intracoronary 20 μg/kg per minute acetylcholine provocation showed a significant negative correlation with platelet aggregability as PRU (r = 0.44, P = 0.03). Conversely, there was no significant correlation between PRU and endothelial function as coronary flow reserve. Furthermore, multivariable linear regression analysis indicated that an incremental CBFV change was independently associated with PRU (β = 0.63, P < 0.001) in non-obstructive IHD patients. CONCLUSIONS In patients with non-obstructive IHD, CBFV change was significantly associated with platelet aggregability, indicating that coronary endothelial dysfunction might mediate higher platelet aggregability.