Seiji Takashio

Growth differentiation factor-15 is a useful prognostic marker in patients with heart failure with preserved ejection fraction.

BACKGROUND Circulating growth differentiation factor 15 (GDF-15) levels correlate with heart mass and fibrosis; however, little is known about its value in predicting the prognosis of patients with heart failure with preserved ejection fraction (HFpEF). METHODS We measured serum GDF-15 levels in 149 consecutive patients with left ventricular diastolic dysfunction (LVDD) and normal LV ejection fraction (>50%) and followed them for cardiovascular events. LVDD was defined according to the European Society of Cardiology guidelines. RESULTS The New York Heart Association functional class and circulating B-type natriuretic peptide (BNP) levels were significantly higher in the high-GDF-15 group (n = 75; greater than or equal to the median value [3694 pg/mL]) than in the low-GDF-15 group (n = 74). Patients were divided into HFpEF and LVDD groups according to the presence or absence of HF. Serum GDF-15 levels were significantly higher in the HFpEF group (n = 73) than in the LVDD group (n = 76) (median, 4215 [interquartile range, 3382-5287] vs 3091 [interquartile range, 2487-4217 pg/mL]; P < 0.0001). Kaplan-Meier curve analysis showed a significantly higher probability of cardiovascular events in the high-GDF-15 group than in the low-GDF-15 group for data of all patients (log-rank test P = 0.006) and data of patients in the HFpEF group only (P = 0.014). Multivariate Cox hazard analysis identified age (hazard ratio [HR], 0.92; 95% confidence interval [CI], 0.87-0.98; P = 0.008), atrial fibrillation (HR, 7.95; 95% CI, 1.98-31.85, P = 0.003), lnBNP (HR, 3.37; 95% CI, 1.73-6.55; P < 0.0001), and GDF-15 (ln[GDF-15]) (HR, 4.74; 95% CI, 1.26-17.88, P = 0.022) as independent predictors of primary end points. CONCLUSIONS GDF-15 is a potentially useful prognostic biomarker in patients with HFpEF.

Clinical features and prognosis of patients with coronary spasm-induced non-ST-segment elevation acute coronary syndrome.

Background The prevalence, clinical features, and long‐term outcome of patients with non–ST‐segment elevation acute coronary syndrome (NSTE ACS) associated with coronary spasm are not fully investigated. Methods and Results This observational multicenter study enrolled 1601 consecutive patients with suspected NSTE‐ACS who underwent cardiac catheterization between January 2001 and December 2010. A culprit lesion was found in 1152 (72%) patients. In patients without a culprit lesion, the acetylcholine provocation test was performed in 221 patients and was positive in 175 patients. In the other patients, coronary spasm was verified in 145 patients during spontaneous attack. Spasm‐induced NSTE‐ACS was diagnosed in 320 (20%) patients. Multivariable analysis identified age <70 years (odds ratio [OR] 2.19, 95% CI 1.58 to 3.04), estimated glomerular filtration rate >60 mL/min per 1.73 m2 (OR 1.72, 95% CI 1.16 to 2.56), and lack of hypertension (OR 2.55, 95% CI 1.90 to 3.41), dyslipidemia (OR 2.76, 95% CI 2.05 to 3.73), diabetes mellitus (OR 2.49, 95% CI 1.78 to 3.48), previous myocardial infarction (OR 5.37, 95% CI 2.89 to 10.0), and elevated cardiac biomarkers (OR 2.84, 95% CI 2.11 to 3.83) as significant correlates of spasm‐induced NSTE‐ACS (P<0.01 for all variables). Transient ST‐segment elevation during spontaneous attack (variant angina) was observed in 119 patients with spasm‐induced NSTE‐ACS. Variant angina was more common in nondyslipidemic men among patients with spasm‐induced NSTE‐ACS. Conclusions The study showed frequent involvement of coronary spasm in the pathogenesis of NSTE‐ACS. Variant angina was observed in one third of patients with spasm‐induced NSTE‐ACS. Coronary spasm should be considered even in patients with less coronary risk factors and nonobstructive coronary arteries.

Usefulness of Sum of ST-Segment Elevation on Electrocardiograms (Limb Leads) for Predicting In-Hospital Complications in Patients With Stress (Takotsubo) Cardiomyopathy

Although the prognosis of patients with stress (takotsubo) cardiomyopathy is relatively favorable, serious complications occur in some patients. It is generally accepted that electrocardiography is an essential tool for the diagnosis of stress cardiomyopathy, with findings highly suggestive of the characteristics of myocardial damage. We tested the hypothesis that the quantitative analysis of electrocardiograhic changes can predict complications in stress cardiomyopathy. The study subjects were 85 patients with stress cardiomyopathy. A total of 34 patients developed ≥1 in-hospital complications (heart failure, intraventricular pressure gradient [>30 mm Hg], cardiogenic shock, ventricular tachycardia/fibrillation, and embolism). Patients with complications were likely to have a higher heart rate (96 ± 25 vs 76 ± 17 beats/min, p <0.001), larger sum of ST-segment elevation in 12 leads (median 10.5 mm; interquartile range 5.0 to 17.5 vs 3.0 mm, interquartile range 0 to 7.0; p <0.001) and extension of ST-segment elevation to limb leads (50% vs 12%, p <0.001) than those without complications. Multivariate logistic regression analysis identified heart rate (odds ratio 1.05, 95% confidence interval 1.02 to 1.07, p = 0.001) and sum of ST-segment elevation in 12 leads (odds ratio 1.24, 95% confidence interval 1.11 to 1.39, p <0.001) as significant and independent predictors of complications. Receiver operating characteristic analysis selected 5.5 mm as the best cutoff value of sum of ST-segment elevation in 12 leads for the prediction of complications, with a sensitivity and specificity of 74% and 73%, respectively, and area under the curve of 0.81 (95% confidence interval 0.72 to 0.90, p <0.001). The results suggest that the extent and magnitude of ST-segment elevation on the electrocardiogram are potentially useful predictors of in-hospital complications in patients with stress cardiomyopathy.

Significance of Low Plasma Levels of Brain-Derived Neurotrophic Factor in Patients With Heart Failure

Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family, which regulates neuronal differentiation and functions. Low levels of BDNF are because of psychological stress and potentially play a role in the pathogenesis of depression and cognition disorders. Because psychological stress and depression are associated with increased risk of heart failure (HF), the pathogenic link between HF and psychological status has attracted clinical attention. We hypothesized that plasma BDNF levels might be decreased in patients with HF and that BDNF could be a key factor associated with HF. We evaluated plasma BDNF levels in 242 patients with HF and 80 subjects without HF who are age and gender matched. Plasma BDNF levels were significantly lower in patients with HF (3,712 pg/ml [2,124 to 6,180]) than those without HF (7,247 pg/ml [5,388 to 9,255], p <0.001) and lower in patients with HF with the New York Heart Association functional class III than class I (p = 0.01) and class II (p <0.001). Log BDNF levels correlated negatively with log B-type natriuretic peptide (r = -0.203, p = 0.03) in patients with HF. Of 61 acute decompensated patients with HF, plasma BDNF levels were significantly higher at discharge (4,194 pg/ml [2,356 to 6,916]) compared with those at admission (2,749 pg/ml [1,380 to 4,161], p = 0.003). Multivariate logistic regression analysis identified log BDNF level as a significant correlate with the presence of HF (odds ratio 0.82; 95% confidence interval 0.76 to 0.91, p <0.001). In conclusion, plasma BDNF levels were decreased in patients with HF and associated with HF severity. BDNF could be a potentially clinically useful biomarker of HF reflecting possible cardio-neuronal linkage.

Correlation Between Extent of Myocardial Fibrosis Assessed by Cardiac Magnetic Resonance and Cardiac Troponin T Release in Patients With Nonischemic Heart Failure

Persistently high cardiac troponin T (cTnT) levels reflect myocardial damage in heart failure (HF). The presence and extent of myocardial fibrosis assessed by cardiac magnetic resonance (CMR) and high levels of cTnT predict poor prognosis in various cardiomyopathies. However, the association between myocardial fibrosis and transcardiac cTnT release has not been evaluated. This study investigated the correlation between myocardial fibrosis and transcardiac cTnT release from nonischemic failing myocardium. Serum cTnT levels were measured in aortic root (Ao) and coronary sinus (CS) using highly sensitive assay (detection limit >5 ng/L) in 74 nonischemic patients with HF who underwent CMR. Transcardiac cTnT release (ΔcTnT [CS-Ao]) represented the difference between CS and Ao-cTnT levels. Myocardial fibrosis was quantified by late gadolinium enhancement (LGE) volume and %LGE on CMR. cTnT was detectable in 65 patients (88%), and ΔcTnT (CS-Ao) levels were available (ΔcTnT [CS-Ao] >0 ng/L) in 60 patients (81%). LGE was observed in 42 patients (57%), and ΔcTnT (CS-Ao) levels were available in 41 LGE-positive patients (98%). In patients with available cTnT release, ΔcTnT (CS-Ao) levels were significantly higher in LGE-positive patients than those in LGE-negative patients (4.3 [2.2-5.5] vs 1.5 [0.9-2.6] ng/L; p = 0.001). Log (ΔcTnT [CS-Ao]) levels were correlated with LGE volume (r = 0.460, p = 0.003) and %LGE (r = 0.356, p = 0.03). In conclusion, the amount of transcardiac cTnT release was higher in LGE-positive patients than LGE-negative patients and correlated with the extent of LGE in nonischemic patients with HF. These results suggested that ongoing myocardial damage correlates with the presence and extent of myocardial fibrosis.

Prognostic Value of Prothrombin Time International Normalized Ratio in Acute Decompensated Heart Failure – A Combined Marker of Hepatic Insufficiency and Hemostatic Abnormality –

BACKGROUND There are limited studies regarding the prognostic value of coagulation abnormalities in heart failure patients. The clinical significance of prothrombin time international normalized ratio (INR), a widely accepted marker assessing coagulation abnormalities, in acute decompensated heart failure (ADHF) remains unclear. METHODSANDRESULTS Among 561 consecutive patients admitted for ADHF, INR was assessed in 294 patients without prior anticoagulation therapy, acute coronary syndrome, liver disease, or overt disseminated intravascular coagulation. Increased INR on admission was positively associated with increased levels of thrombin-antithrombin complex, C-reactive protein, total bilirubin, γ-glutamyl transpeptidase, inferior vena cava diameter, tricuspid regurgitation severity, markers of neurohormonal activation, and also negatively associated with decreased albumin, cholinesterase, and total cholesterol. In contrast, there was no significant association with left ventricular ejection fraction, serum sodium or blood urea nitrogen. Multivariate analysis showed that increased INR was independently associated with increased all-cause mortality (hazard ratio 1.89 per 0.1 increase, 95% confidence interval 1.14-3.13, P=0.013) during the median follow up of 284 days. Increased INR also had a higher prognostic value compared to risk score models including the Model for End-Stage Liver Disease (MELD) score or the MELD excluding INR (MELD-XI) score. CONCLUSIONS Increased INR is an independent predictor of all-cause mortality in ADHF patients without anticoagulation, reflecting coagulation abnormalities and hepatic insufficiency, possibly through systemic inflammation, neurohormonal activation and venous congestion.

Diagnostic and Prognostic Value of Subcutaneous Tissue Biopsy in Patients With Cardiac Amyloidosis

Cardiac involvement in systemic amyloidosis causes detrimental prognosis; therefore, early detection and classification are important to develop appropriate therapeutic strategies. Subcutaneous tissue biopsy is a useful screening procedure for systemic amyloidosis; however, its diagnostic and prognostic value in patients with cardiac amyloidosis remains elusive. Thus, we investigated the value of subcutaneous tissue biopsy in cardiac amyloidosis. In 22 patients with cardiac amyloidosis, we retrospectively analyzed 14 consecutive patients with cardiac amyloidosis who underwent subcutaneous tissue biopsy. Amyloid deposition was observed in 11 patients (79%). Histopathologic analysis demonstrated that acquired monoclonal immunoglobulin light-chain amyloidosis could be predicted when the degree of amyloid deposition was greater in blood vessels than adipose tissue compared to senile systemic amyloidosis and familial amyloidosis (60% vs 0%, p = 0.03). During the follow-up period (median 297 days, range 3 to 761), 7 patients (5 with monoclonal immunoglobulin light-chain amyloidosis and 2 with senile systemic amyloidosis) died or were admitted to the hospital because of worsening heart failure. Of them, 6 patients (86%) were positive for amyloid deposition in blood vessels in subcutaneous tissue biopsy. Incidence of death and composite outcome including heart failure hospitalization and death was significantly higher in patients positive for amyloid deposition in blood vessels than in those without (p = 0.03, p = 0.006, respectively). These results suggest that amyloid subtype could be diagnosed by assessing the degree of amyloid deposition in blood vessels and adipose tissue in subcutaneous tissue biopsy samples from patients with cardiac amyloidosis. Amyloid deposition in blood vessels suggests poor prognosis of these patients.

Identification and Assessment of Cardiac Amyloidosis by Myocardial Strain Analysis of Cardiac Magnetic Resonance Imaging

BACKGROUND We explored the usefulness of myocardial strain analysis on cardiac magnetic resonance imaging (CMR) scans for the identification of cardiac amyloidosis.Methods and Results:The 61 patients with systemic amyloidosis underwent 3.0-T CMR, including CMR tagging and late-gadolinium enhanced (LGE) imaging. The circumferential strain (CS) of LGE-positive and LGE-negative patients was measured on midventricular short-axis images and compared. Logistic regression modeling of CMR parameters was performed to detect patients with LGE-positive cardiac amyloidosis. Of the 61 patients with systemic amyloidosis 48 were LGE-positive and 13 were LGE-negative. The peak CS was significantly lower in the LGE-positive than in the LGE-negative patients (-9.5±2.3 vs. -13.3±1.4%, P<0.01). The variability in the peak CS time was significantly greater in the LGE-positive than in the LGE-negative patients (46.1±24.5 vs. 21.2±20.1 ms, P<0.01). The peak CS significantly correlated with clinical biomarkers. The sensitivity, specificity, and accuracy of the diagnostic model using CS parameters for the identification of LGE-positive amyloidosis were 93.8%, 76.9%, and 90.2%, respectively. CONCLUSIONS Myocardial strain analysis by CMR helped detect LGE-positive amyloidosis without the need for contrast medium. The peak CS and variability in the peak CS time may correlate with the severity of cardiac amyloid deposition and may be more sensitive than LGE imaging for the detection of early cardiac disease in patients with amyloidosis.

Direct Oral Anticoagulants Form Thrombus Different From Warfarin in a Microchip Flow Chamber System

Direct oral anticoagulants (DOACs) have low risk of intracranial hemorrhage compared to warfarin. We sought to clarify the different mechanisms responsible for suppression of bleeding events using the Total Thrombus-formation Analysis System (T-TAS), a flow-microchip chamber with thrombogenic surfaces. Blood samples were obtained at Off- and On-anticoagulant (trough) from 120 consecutive patients with atrial fibrillation (warfarin; n = 29, dabigatran; n = 19, rivaroxaban; n = 47, apixaban; n = 25), which were used for T-TAS to compute the area under the curve (AUC) (AR10-AUC30) in the AR chip, and to measure plasma concentrations of DOACs at On-anticoagulant. In addition, the two-dimensional area covered by thrombi (%) in the capillary was analyzed every 3 minutes after sample applications. The AR10-AUC30 correlated weakly and negatively with plasma concentrations of DOACs, and the levels at On-anticoagulant were lower in all groups than at Off-anticoagulant. AR10-AUC30 levels at Off- and On-anticoagulant were identical among the groups. The thrombi areas in early phase were significantly larger in rivaroxaban and apixaban than warfarin and dabigatran groups. The findings suggested that visual analysis of the AR-chip can identify the differential inhibitory patterns of warfarin and DOACs on thrombus formation under flow condition.

Association of CYP2C19 variants and epoxyeicosatrienoic acids on patients with microvascular angina.

Categorization as a cytochrome P450 (CYP) 2C19 poor metabolizer (PM) is reported to be an independent risk factor for cardiovascular disease. Epoxyeicosatrienoic acids (EETs) are metabolites of arachidonic acid by CYP2C19 epoxygenases and anti-inflammatory properties, especially in microvascular tissues. We examined the association of CYP2C19 polymorphisms and EETs on microvascular angina (MVA) caused by coronary microvascular dysfunction. We examined CYP2C19 genotypes in patients with MVA (n = 71) and healthy subjects as control (n = 71). MVA was defined as the absence of coronary artery stenosis and epicardial spasms and the presence of inversion of lactic acid levels between intracoronary and coronary sinuses in acetylcholine-provocation test or the adenosine-triphosphate-induced coronary flow reserve ratio was below 2.5. CYP2C19 PM have two loss-of-functon alleles (*2, *3). We measured serum dihydroxyeicosatrienoic acid (DHET) as representative EET metabolite. MVA group showed significantly higher CYP2C19 PM incidence (35% vs. 16%; P = 0.007) and high sense C-reactive protein (hs-CRP) levels (0.127 ± 0.142 vs. 0.086 ± 0.097 mg/dl; P = 0.043) than those of controls. Moreover, in MVA group, hs-CRP levels in CYP2C19 PM were significantly higher than that of non-PM (0.180 ± 0.107 vs. 0.106 ± 0.149 mg/dl, P = 0.045). Multivariate analysis indicated that smoking, hypertension, high hs-CRP, and CYP2C19 PM are predictive factors for MVA. In MVA group, DHET levels for CYP2C19 PM were significantly lower than that of non-PM [10.9 ± 1.64 vs. 14.2 ± 5.39 ng/ml, P = 0.019 (11,12-DHET); 15.2 ± 4.39 vs. 17.9 ± 4.73 ng/ml, P = 0.025 (14,15-DHET)]. CYP2C19 variants are associated with MVA. The decline of EET-based defensive mechanisms owing to CYP2C19 variants may affect coronary microvascular dysfunction.