Ryota Morimoto

Corticotropin releasing hormone receptor 2 exacerbates chronic cardiac dysfunction

Heart failure occurs when the heart is unable to effectively pump blood and maintain tissue perfusion. Despite numerous therapeutic advancements over previous decades, the prognosis of patients with chronic heart failure remains poor, emphasizing the need to identify additional pathophysiological factors. Here, we show that corticotropin releasing hormone receptor 2 (Crhr2) is a G protein–coupled receptor highly expressed in cardiomyocytes and continuous infusion of the Crhr2 agonist, urocortin 2 (Ucn2), reduced left ventricular ejection fraction in mice. Moreover, plasma Ucn2 levels were 7.5-fold higher in patients with heart failure compared to those in healthy controls. Additionally, cardiomyocyte-specific deletion of Crhr2 protected mice from pressure overload-induced cardiac dysfunction. Mice treated with a Crhr2 antagonist lost maladaptive 3′-5′-cyclic adenosine monophosphate (cAMP)–dependent signaling and did not develop heart failure in response to overload. Collectively, our results indicate that constitutive Crhr2 activation causes cardiac dysfunction and suggests that Crhr2 blockade is a promising therapeutic strategy for patients with chronic heart failure.

Nutrition Status Predicts Severity of Vascular Calcification in Non-Dialyzed Chronic Kidney Disease

BACKGROUND Vascular calcification is a major complication in chronic kidney disease (CKD) that increases the risk of adverse clinical outcomes. Geriatric nutritional risk index (GNRI) is a simple nutritional assessment tool that predicts poor prognosis in elderly subjects. The purpose of the present study was to evaluate the correlation between GNRI and severity of vascular calcification in non-dialyzed CKD patients.Methods and Results:We enrolled 323 asymptomatic CKD patients. To evaluate abdominal aortic calcification (AAC), we used aortic calcification index (ACI) determined on non-contrast computed tomography. The patients were divided into three groups according to GNRI tertile. Median ACI significantly decreased with increasing GNRI tertile (15.5%, 13.6%, and 7.9%, respectively; P=0.001). On multivariate regression analysis GNRI was significantly correlated with ACI (β=-0.15, P=0.009). We also investigated the combination of GNRI and C-reactive-protein (CRP) for predicting the severity of AAC. Low GNRI and high CRP were significantly associated with severe AAC, compared with high GNRI and low CRP (OR, 4.07; P=0.004). CONCLUSIONS GNRI was significantly associated with AAC in non-dialyzed CKD patients.

Prognostic Impact of Combined Late Gadolinium Enhancement on Cardiovascular Magnetic Resonance and Peak Oxygen Consumption in Ambulatory Patients With Nonischemic Dilated Cardiomyopathy

BACKGROUND Peak oxygen consumption (peak VO₂) and late gadolinium enhancement (LGE) on cardiovascular magnetic resonance (CMR) are prognostic in heart failure. We investigated whether LGE-CMR and peak VO₂combined had additive value in risk stratifying patients with nonischemic dilated cardiomyopathy (DCM). METHODS AND RESULTS Fifty-seven DCM patients underwent CMR and cardiopulmonary exercise testing. Cardiac events were cardiac death, hospitalization for decompensated heart failure, or lethal arrhythmia. Twenty-five (44%) were LGE-positive. The median peak VO₂was 18.5 mL·kg(-1)·min(-1). On multivariate analysis, positive LGE (P = .048) and peak VO₂(P = .003) were independent cardiac event predictors. Cardiac event risk was significantly higher with positive LGE and peak VO₂< 18.5 mL ·kg⁻¹ ·min⁻¹ than with negative LGE and peak VO₂≥ 18.5 mL · kg⁻¹ · min⁻¹ (hazard ratio 12.5; 95% CI 1.57-100; P = .017). In 3 patient groups (group A: no LGE, peak VO₂≥ 18.5 mL · kg⁻¹ · min⁻¹, n = 18; group B: positive LGE or peak VO₂< 18.5 mL · kg⁻¹ · min⁻¹, n = 24; group C: positive LGE and peak VO₂< 18.5 mL · kg⁻¹ · min⁻¹, n = 15) during follow-up (71 ± 32 months), group C had higher cardiac event rates than the others. CONCLUSIONS Combined assessment of LGE-CMR and peak VO₂provides additive prognostic information in ambulatory DCM.

Cardiopulmonary exercise testing to evaluate the exercise capacity of patients with inoperable chronic thromboembolic pulmonary hypertension: an endothelin receptor antagonist improves the peak PETCO2.

AIMS The 6-min walking distance is often used for assessing the exercise capacity under the treatment with an endothelin receptor antagonist (ERA) in patients with chronic thromboembolic pulmonary hypertension (CTEPH). The cardiopulmonary exercise testing (CPX) was reported to be more useful for the patients with pulmonary arterial hypertension (PAH), however, few reports exist in patients with inoperable CTEPH. The aim of this study was to investigate the effects of an oral dual ERA, bosentan, on exercise capacity using CPX in patients with PAH and inoperable CTEPH. MAIN METHODS This study included all patients diagnosed with 17 PAH and 12 CTEPH in the World Health Organization functional classes II-IV who started treatment with bosentan therapy. They underwent CPX, which was performed before bosentan therapy and at 3 to 6 months of the treatment. KEY FINDINGS In PAH patients, peak VO2 significantly increased after the bosentan treatment (p=0.009). On the other hand, in CTEPH patients, there were no significant differences in the peak VO2. However, the peak PETCO2 was significantly increased from 23.9±5.2 mm Hg at baseline to 29.3±10.7 mm Hg after the bosentan treatment (p=0.040). In addition, peak heart rate during exercise tended to decrease after the bosentan therapy (p=0.089). SIGNIFICANCE Bosentan therapy improved peak PETCO2 but not peak VO2 in patients with inoperable CTEPH. These findings demonstrated that CPX is useful for assessing the exercise capacity of patients with PAH and inoperable CTEPH under the treatment with an ERA.

Sirolimus-eluting stent implantation for ostial stenosis of left main coronary artery after Bentall operation in aortitis syndrome.

We describe a 66-year-old woman with aortitis syndrome, successfully treated with percutaneous coronary intervention using sirolimus-eluting stent (SES) for ostial stenosis of left main coronary artery after Bentall operation. At one-year follow-up, she had no evidence of restenosis and no clinical events. Stent implantation with SES may be useful for ostial left main coronary stenosis after Bentall operation in selected patients with aortitis syndrome.

Impact of Renal Functional/Morphological Dynamics on the Calcification of Coronary and Abdominal Arteries in Patients with Chronic Kidney Disease

Aim: Fast-progressing vascular calcification (VC) is accompanied by renal atrophy and functional deterioration along with atherosclerosis in patients with chronic kidney disease (CKD). However, the relationship between VC progression and renal functional and/or morphological changes remains unclear. Methods: We included 70 asymptomatic patients with CKD without hemodialysis in our study. To identify temporal variations, the coronary artery calcification score (CACS), abdominal aortic calcification index (ACI), and renal parenchymal volume index (RPVI) were determined via spiral computed tomography scans taken during the study. We investigated significant factors related to annualized variations of CACS (ΔCACS/y) and ACI (ΔACI/y). Results: During the follow-up period (4.6 years), median values of CACS [in Agatston units (AU)] and ACI increased from 40.2 to 113.3 AU (p = 0.053) and from 13.2 to 21.7% (p = 0.036), respectively. Multivariate analysis revealed that CACS at baseline (p < 0.001) and diabetes mellitus (DM) status (p = 0.037) for ΔCACS/y and ACI at baseline (p = 0.017) and hypertension (HT) status (p = 0.046) for ΔACI/y were significant independent predictors. Furthermore, annualized RPVI variation was significantly related to both ΔCACS/y and ΔACI/y (R = −0.565, p < 0.001, and R = −0.289, p = 0.015, respectively). On the other hand, independent contributions of the estimated glomerular filtration rate (eGFR) and annualized eGFR variation to VC progression were not confirmed. Conclusion: The degree of VC at baseline, DM, HT, and changes in renal volume, but not eGFR, had a strong impact on VC progression in patients with CKD.

Abnormal Circadian Blood Pressure Profile as a Prognostic Marker in Patients with Nonischemic Dilated Cardiomyopathy

Objectives: An abnormal circadian blood pressure (BP) profile is considered a risk factor for cardiovascular disease. However, its significance in heart failure patients with nonischemic etiology is unknown. Herein, we investigated the prognostic value of a circadian BP profile in patients with nonischemic dilated cardiomyopathy (NIDCM). Methods: We enrolled 114 NIDCM patients (76 males, mean age 53.1 years). The percent nighttime BP fall (%NBPF) was defined using ambulatory BP monitoring as a percent decrease in mean systolic BP in nighttime from daytime. All patients were divided into three groups: dipper (%NBPF ≥10), non-dipper (0 ≤ %NBPF < 10), and riser (%NBPF <0). Results: Riser patients had the highest serum creatinine levels (dipper, 0.78 ± 0.20 mg/dl; non-dipper, 0.85 ± 0.21 mg/dl; riser, 0.99 ± 0.23 mg/dl; p = 0.006). In survival analysis, riser patients had the highest cumulative cardiac-related deaths (log-rank, p = 0.001), which was an independent predictor of cardiac-related deaths (hazard ratio, 12.6; 95% confidence interval, 1.76-253; p = 0.01). Multivariate analysis revealed that the norepinephrine level at 24-hour collected urine (24 h U-NE) and the serum creatinine level were independent determinants of %NBPF (adjusted R2 = 0.20; 24 h U-NE, p = 0.0001; serum creatinine, p = 0.04). Conclusions: The riser profile was associated with poor prognosis of NIDCM, which may reflect impaired sympathetic nervous system activity. Evaluating the circadian BP profile may be useful for risk stratification in NIDCM patients.

Cholesterol metabolism as a prognostic marker in patients with mildly symptomatic nonischemic dilated cardiomyopathy

BACKGROUND Little is known about whether the alteration of cholesterol metabolism reflects abdominal organ impairments due to heart failure. Therefore, we investigated the prognostic value of cholesterol metabolism by evaluating serum campesterol and lathosterol levels in patients with early-stage nonischemic dilated cardiomyopathy (NIDCM). METHODS We enrolled 64 patients with NIDCM (median age 57.5 years, 31% female) with New York Heart Association functional class I/II. Serum campesterol and lathosterol levels were measured in all patients. The patients were then divided into four subsets based on the median non-cholesterol sterol levels (campesterol 3.6μg/mL, lathosterol 1.4μg/mL): reference (R-subset), high-campesterol/high-lathosterol; absorption-reduced (A-subset), low-campesterol/high-lathosterol; synthesis-reduced (S-subset), high-campesterol/low-lathosterol; double-reduced (D-subset), low-campesterol/low-lathosterol. Endpoint was a composite of cardiac events, including cardiac-related death, hospitalization for worsening heart failure, and lethal arrhythmia. RESULTS Median brain natriuretic peptide (BNP) level was 114pg/mL. Mean left ventricular ejection fraction was 31.4%. D-subset had the lowest total cholesterol level and cardiac index and the highest BNP level and pulmonary capillary wedge pressure. D-subset also had the highest cardiac event rate during the mean 3.8 years of follow-up (log-rank p=0.001). Multivariate regression analysis showed that D-subset was an independent determinant of cardiac events. The receiver operating characteristic curve analysis revealed that total cholesterol <153mg/dL was a best cut-off value for discrimination of the D-subset. CONCLUSIONS The combined reduction of campesterol and lathosterol that indicated intestinal cholesterol absorption and liver synthesis predicts future cardiac events in patients with mildly symptomatic NIDCM.

Long-Term Pathological Follow-Up of Myocardium in a Carrier of Duchenne Muscular Dystrophy With Dilated Cardiomyopathy

Duchenne muscular dystrophy (DMD) is a fatal X-linked disorder, with an incidence of ≈1 in 3600 to 6000 male births. DMD is caused by mutations in the dystrophin gene located at Xp21.2 and is clinically characterized by progressive muscle degeneration and dilated cardiomyopathy (DCM). Some female DMD carriers show a variety of clinical manifestations, ranging from creatine kinase elevation to severe muscle weakness. DCM has been reported in 8% to 18% of female DMD carriers and sometimes results in a lethal course. Here, we describe long-term follow-up observations of myocardial changes in a DMD carrier with DCM. A 29-year-old female presented with progressive shortness of breath, increasing ankle edema, and orthopnea after a full-term normal delivery. A chest X ray showed cardiomegaly and bilateral pleural effusions, and echocardiography showed a severely reduced left ventricular ejection fraction of 24%, with a markedly increased left ventricular end-diastolic diameter of 71 mm. She was admitted for heart failure, and her symptoms improved with furosemide and inotropes. There were no symptoms to suggest myopathy, and blood analysis revealed no elevation of creatine kinase (60 U/L). Her newborn boy showed extreme elevation of creatine kinase (105 868 U/L) and was diagnosed with DMD …

Biphasic Force-Frequency Relation Predicts Primary Cardiac Events in Patients With Hypertrophic Cardiomyopathy

BACKGROUND The force-frequency relation (FFR) is a hemodynamic index of the chronotropic relationship between left ventricular (LV) systolic function (percent change in dP/dtmax) and elevation of heart rate. FFR is a marker of myocardial contractile reserve and follows an upward slope in healthy myocardium [monophasic FFR (MoF)], a pattern that becomes biphasic (BiF) under pathological conditions. However, it remains uncertain whether the FFR determines a patients prognosis. We investigated the promising role of the FFR as a predictor of cardiac events in the setting of hypertrophic cardiomyopathy (HCM).Methods and Results:A total of 113 consecutive patients with HCM (New York Heart Association (NYHA) class I-II) were retrospectively evaluated; 27 (23.9%) had a BiF pattern and they experienced a higher incidence of cardiac events compared with those showing an MoF pattern (median follow-up, 4.7 years; P<0.001). Furthermore, Cox proportional hazard regression analysis revealed that the LV end-diastolic volume index (hazard ratio: 1.051, P=0.014) and BiF pattern (hazard ratio: 15.260, P=0.001) were independent predictors of primary cardiac events. Interestingly, abnormal reductions in myocardial regulatory molecules related to contractility (SERCA2α) were observed exclusively in the patients exhibiting a BiF pattern. CONCLUSIONS The FFR reflects latent myocardial abnormalities and predicts cardiac events in the setting of HCM, even during the asymptomatic stages of the disease.