Takehiko Miyashita

The prognostic importance of objective nutritional indexes in patients with chronic heart failure

BACKGROUND Although malnutrition indicates an unfavorable prognosis in some clinical settings, the association between nutritional indexes and outcomes for patients with chronic heart failure (CHF) is unclear. METHODS AND RESULTS All the previously established objective nutritional indexes were evaluated. The controlling nutritional status score (CONUT), prognostic nutritional index (PNI), and geriatric nutritional risk index (GNRI) were determined for 388 consecutive patients with CHF (mean age 69.6±12.3 years). The prevalence of malnutrition in this cohort was 60-69%. Patients were followed prospectively, with the endpoints being death due to a cardiovascular event or re-hospitalization. There were 130 events, including 33 deaths and 97 re-hospitalizations, during a mean follow-up period of 28.4 months. Patients experiencing cardiovascular events showed impaired nutritional status, higher CONUT scores, lower PNI scores, and lower GNRI scores, compared with those who did not experience cardiovascular events. CONUT score [hazard ratio 40.9, 95% confidence interval (CI) 10.8-154.8], PNI score (hazard ratio 6.4, 95% CI 5.4-25.1), and GNRI score (hazard ratio 11.6, 95% CI 3.7-10.0) were independently associated with cardiovascular events. Kaplan-Meier analysis showed that there was a significantly higher incidence of cardiovascular events in patients who were malnourished than in those who were not. CONCLUSION Malnutrition was common in patients with CHF. Evaluation of nutritional status may provide additional prognostic information in patients with CHF.

Elevated plasma brain natriuretic peptide levels predict left atrial appendage dysfunction in patients with acute ischemic stroke.

BACKGROUND It is well known that left atrial appendage (LAA) dysfunction plays an important role in the occurrence of cardioembolic stroke. The atrium is the main source of brain natriuretic peptide (BNP) in patients with atrial fibrillation (AF). We hypothesized that the plasma BNP level would be a sensitive predictor of LAA dysfunction in patients with acute ischemic stroke. METHODS AND RESULTS Transesophageal echocardiography was performed and plasma BNP levels were measured in 223 patients (145 males, age 69 ± 14 years), within 7 days after the onset of acute ischemic stroke. None of the patients had a history of congestive heart failure. LAA thrombus was detected in 23 of 77 (30%) patients with AF. Plasma BNP levels were markedly higher in patients with cardioembolic stroke compared to those without (144 pg/ml vs. 35 pg/ml, p<0.05). Plasma BNP levels were significantly correlated with LAA emptying flow velocity regardless of sinus rhythm (R=-0.352) or AF (R=-0.436). Furthermore, among patients with cardioembolic stroke, plasma BNP levels were markedly higher in patients with cardiogenic stroke, as diagnosed by transesophageal echocardiography, than in those with cryptogenic stroke (193 pg/ml vs. 14 pg/ml, p<0.05). Multivariate logistic regression analysis showed that a BNP concentration >90 pg/ml was an independent predictor of cardiogenic stroke (odds ratio 41.39, 95% confidence interval 1.28-138; p=0.0358). CONCLUSION Elevated plasma BNP concentrations may be a reliable surrogate marker for the prediction of LAA dysfunction and cardiogenic stroke in patients with acute ischemic stroke.

Relation of Serum Heat Shock Protein 60 Level to Severity and Prognosis in Chronic Heart Failure Secondary to Ischemic or Idiopathic Dilated Cardiomyopathy

Heat shock protein (HSP) 60 is induced by a variety of stressors, including oxidative stress and inflammation, and it plays a protective role against stress-induced cardiomyocyte injury. Recently, it has been reported that HSP 60 exists in the circulation. Chronic heart failure (CHF) is characterized by systemic abnormalities, and the myocardium is exposed to various stressors. However, the clinical significance of serum HSP 60 has not been examined in CHF. Therefore, the purpose of this study was to examine whether HSP 60 is correlated with the severity of CHF and whether HSP 60 can predict clinical outcomes in patients with CHF. Serum HSP 60 levels were measured in 112 patients with CHF and 62 control subjects. Serum HSP 60 levels were higher in patients with CHF than in control subjects and increased with advancing New York Heart Association functional class. There were 37 cardiac events during a mean follow-up period of 569 +/- 476 days (range 17 to 1,986). Serum HSP 60 levels were higher in patients with cardiac events than in event-free patients. Patients were divided into 4 groups on the basis of HSP 60 level. Cox proportional-hazards regression analysis and Kaplan-Meier analysis revealed that the fourth quartile was associated with the greatest risk for cardiac events. In conclusion, serum HSP 60 level was related to the severity of CHF and associated with a high risk for adverse cardiac events in patients CHF.

8-Hydroxy-2'-deoxyguanosine is a prognostic mediator for cardiac event.

Eur J Clin Invest 2011; 41 (7): 759–766

Protein kinase C and extracellular signal regulated kinase are involved in cardiac hypertrophy of rats with progressive renal injury

Increased cardiovascular mortality is an unresolved problem in patients with chronic renal failure. Cardiac hypertrophy is observed in the majority of patients with chronic renal failure undergoing haemodialysis. However, the mechanisms, including signal transduction pathways, responsible for cardiac hypertrophy in renal failure remain unknown. We examined the subcellular localization of protein kinase C (PKC) isoforms and phosphorylation activities of 3 mitogen‐activated protein (MAP) kinase families in hypertrophied hearts of progressive renal injury rat model by subtotal nephrectomy (SNx). We also examined the effects of a novel angiotensin II type‐1 receptor antagonist, CS‐866, on the PKC translocation, MAP kinase activity and cardiac hypertrophy in SNx rats. The left ventricle/body weight ratios were significantly larger in SNx rats than in sham rats at 1, 2, and 4 weeks after surgery. The translocation of PKCα and ɛ isoforms to membranous fraction was observed in SNx rat hearts at 1, 2, and 4 weeks after surgery. Activation of extracellular signal regulated kinase (ERK) 1/2, but not p38 MAP kinase and c‐Jun N‐terminal kinase (JNK), was observed at 1 and 2 weeks after surgery. Angiotensin II receptor blockade with CS‐866 (1 mg kg−1 day−1) prevented cardiac hypertrophy, PKC translocation and ERK1/2 activation in SNx rats without significant changes in blood pressure. These data suggest that PKC and ERK1/2 are activated by an angiotensin II receptor‐mediated pathway and might play an important role in the progression of cardiac hypertrophy in renal failure.

The role of epicardial adipose tissue in coronary artery disease in non-obese patients

BACKGROUND Epicardial adipose tissue (EAT) surrounding the heart may contribute to the development of coronary artery disease (CAD) through its local secretion of adipocytokines. Although the quantity of EAT is associated with obesity and metabolic syndrome, the role of EAT in the development of CAD in non-obese patients remains to be determined. METHODS This study included 41 patients with CAD who underwent coronary artery bypass graft surgery and 28 patients without CAD who underwent other cardiac surgery. EAT volume was measured by 64-slice multi-detector computed tomography before the surgery. We obtained pericardial fluid and epicardial and subcutaneous adipose tissue samples at the surgery. We investigated the relationship between EAT volume and adiponectin levels in pericardial fluid and incident CAD in patients with and without obesity (body mass index>25 kg/m(2)). RESULTS There was no significant difference in EAT volume between obese patients with and without CAD (55.5 ± 40.2 mL vs. 40.1 ± 19.7 mL, p=0.323). However, EAT volume was significantly greater in non-obese patients with CAD compared to those without CAD (35.0 ± 18.8 mL vs. 15.7 ± 11.0 mL, p<0.001). Adiponectin concentrations in pericardial fluid were significantly lower in non-obese patients with CAD compared to those without CAD (2.7 ± 2.0 μg/mL vs. 4.3 ± 3.7 μg/mL, p=0.049), whereas the adiponectin levels were decreased in obese patients regardless of the presence of CAD. Non-obese patients with CAD had significantly larger size adipocytes in EAT but not subcutaneous adipose tissue compared to those without CAD. Multiple logistic regression analysis showed that increased EAT volume was independently associated with incident CAD in non-obese patients. CONCLUSION Increased EAT may play a crucial role in development of CAD through impairment of adiponectin secretion in non-obese patients.

Prognostic Value of Low Left Atrial Appendage Wall Velocity in Patients with Ischemic Stroke and Atrial Fibrillation

BACKGROUND It is important to evaluate left atrial appendage (LAA) dysfunction for primary and secondary prevention of stroke in patients with atrial fibrillation (AF). LAA dysfunction can reportedly be evaluated by LAA wall velocity (LAWV) measured by transthoracic echocardiographic (TTE) imaging. The aim of this study was to examine whether TTE-LAWV can predict long-term cerebrovascular events in patients with ischemic stroke with AF. METHODS TTE imaging and transesophageal echocardiographic imaging were performed <7 days after onset in 179 consecutive patients with stroke with AF. TTE-LAWV was measured using Doppler tissue imaging at the LAA tip from the parasternal short-axis view on TTE imaging, as previously reported. All patients were followed up prospectively. RESULTS Cerebrovascular events were defined as cerebrovascular death and/or recurrent ischemic stroke requiring hospitalization. There were 32 cerebrovascular events during a median follow-up period of 397 days. TTE-LAWV was significantly lower in patients with cerebrovascular events than in patients without (8.3 ± 2.8 vs 11.3 ± 4.0 cm/sec, P < .01). Cox multivariate hazard analysis showed that low TTE-LAWV (<8.7 cm/sec) was an independent predictor of cerebrovascular events (hazard ratio, 3.460; P < .05). Kaplan-Meier analysis showed that cerebrovascular event rates were significantly higher in patients with low TTE-LAWV (<8.7 cm/sec) compared with those with high TTE-LAWV (34% vs 7%, P < .01). CONCLUSIONS Impaired LAA function was associated with long-term cerebrovascular events in patients with stroke with AF. TTE-LAWV may be a feasible parameter for risk stratification in patients with AF.

Serum Midkine as a Predictor of Cardiac Events in Patients With Chronic Heart Failure

BACKGROUND Midkine, a heparin-binding growth factor, has various functions such as migration of inflammatory cell and anti-apoptotic effect. Invasion of inflammatory cell and cardiomyocyte apoptosis are involved in development and progression of heart failure (HF). However, the relationship between midkine and HF has not been previously examined. Therefore, we examined clinical significance of serum midkine levels to determine the prognosis of HF patients. METHODS AND RESULTS Serum levels of midkine were measured at admission in 216 consecutive patients hospitalized for HF and 60 control subjects. Patients were prospectively followed during a mean follow-up period of 653 +/- 375 days with the end points of cardiac death and progressive HF requiring rehospitalization. Serum concentrations of midkine were significantly higher in patients with HF than in controls. Patients with cardiac events had significantly higher concentrations of midkine than those without cardiac events. Kaplan-Meier analysis revealed that cardiac event rates increased markedly as midkine levels rose. Furthermore in the multivariate analysis, after adjustment for age, gender ,and complications, midkine was the independent predictor of cardiac events. CONCLUSION Serum midkine levels are increased in HF patients, and midkine is a novel marker for risk stratifying HF patients.

Ongoing myocardial damage relates to cardiac sympathetic nervous disintegrity in patients with heart failure

Iodine-123-metaiodobenzylguanidine (123I-MIBG) has been used to assess the integrity and function of the cardiac sympathetic nervous system in patients with heart failure. Heart-type fatty acid binding protein (H-FABP) is released into the circulation when the myocardium is injured, and H-FABP has been recently used as a novel marker for the diagnosis of ongoing myocardial damage.ObjectiveThe aim of the present study was to compare cardiac sympathetic nervous activity assessed by123I-MIBG imaging with serum levels of H-FABP in patients with heart failure.MethodsFifty patients with chronic heart failure were studied.123I-MIBG imaging was carried out at 30 min (early) and 240 min (delayed) after the tracer injection. We measured serum levels of H-FABP using a sandwich enzyme linked immunosorbent assay.ResultsHeart to mediastinum (H/M) ratios of123I-MIBG decreased and washout rate increased with higher New York Heart Association (NYHA) functional class. H-FABP, norepinephrine and brain natriuretic peptide (BNP) levels increased as the severity of NYHA class advanced. Delayed H/M ratio was significantly correlated with H-FABP (r = -0.296, p = 0.029) and BNP (r = -0.335, p = 0.0213). Myocardial washout rate of123I-MIBG was also correlated with H-FABP (r = 0.469, p < 0.001), norepinephrine (r = 0.433, p = 0.005), and BNP (r = 0.465, p = 0.001).ConclusionsThese data suggest that cardiac sympathetic nervous activation was associated with ongoing cardiomyocyte damage characterized by an elevated serum level of H-FABP in patients with heart failure.123I-MIBG imaging is an appropriate approach to evaluate non-invasively not only cardiac sympathetic nervous activity, but also latent ongoing myocardial damage in the failing heart.

Ongoing myocardial damage in patients with heart failure and preserved ejection fraction

BACKGROUND The relationship between ongoing myocardial damage and heart failure with preserved left ventricular systolic function (HF-PEF) is still unclear. To investigate this relationship, we measured the cardiac-specific cytosolic marker, heart-type fatty acid binding protein (H-FABP), and a myofibrillar component (troponin T), and analyzed clinical outcomes. METHODS AND RESULTS Consecutive heart failure patients (n=151) with echocardiographic left ventricular ejection fraction >50% were prospectively enrolled. The cut-off values for myocardial membrane injury (H-FABP >4.3 ng/mL) and myofibrillar injury (troponin T >0.01 ng/mL) were defined using receiver operating characteristic curves. Myocardial membrane injury was observed more frequently than myofibrillar injury (41% vs. 26% of patients, p<0.05). Patients were followed up for a median of 694 days, with the end-points being cardiovascular death or re-hospitalization. By multivariate analysis, the serum H-FABP level was an independent predictor of cardiovascular events (hazard ratio 1.165 per 1 ng/mL increase, 95% confidence interval 1.034-1.314, p=0.012). CONCLUSIONS Latent myocardial injury was frequently observed in patients with HF-PEF. The circulating H-FABP level was an independent predictor of subsequent cardiovascular events.