Neutrophil Extracellular Traps in Myocardial Tissue Drive Cardiac Dysfunction and Adverse Outcomes in Patients With Heart Failure With Dilated Cardiomyopathy.

BACKGROUND: The immune systems and chronic inflammation are implicated in the pathogenesis of dilated cardiomyopathy (DCM) and heart failure. However, the significance of neutrophil extracellular traps (NETs) in heart failure remains to be elucidated. METHODS: We enrolled consecutive 62 patients with heart failure with idiopathic DCM who underwent endomyocardial biopsy. Biopsy specimens were subjected to fluorescent immunostaining to detect NETs, and clinical and outcome data were collected. Ex vivo and in vivo experiments were conducted. RESULTS: The numbers of NETs per myocardial tissue area and the proportion of NETs per neutrophil were significantly higher in patients with DCM compared with non-DCM control subjects without heart failure, and the numbers of NETs were negatively correlated with left ventricular ejection fraction. Patients with DCM with NETs (n=32) showed lower left ventricular ejection fraction and higher BNP (B-type natriuretic peptide) than those without NETs (n=30). In a multivariable Cox proportional hazard model, the presence of NETs was independently associated with an increased risk of adverse cardiac events in patients with DCM. To understand specific underlying mechanisms, extracellular flux analysis in ex vivo revealed that NETs-containing conditioned medium from wild-type neutrophils or purified NET components led to impaired mitochondrial oxygen consumption of cardiomyocytes, while these effects were abolished when PAD4 (peptidyl arginine deiminase 4) in neutrophils was genetically ablated. In a murine model of pressure overload, NETs in myocardial tissue were predominantly detected in the acute phase and persisted throughout the ongoing stress. Four weeks after transverse aortic constriction, left ventricular ejection fraction was reduced in wild-type mice, whereas PAD4-deficient mice displayed preserved left ventricular ejection fraction without inducing NET formation. CONCLUSIONS: NETs in myocardial tissue contribute to cardiac dysfunction and adverse outcomes in patients with heart failure with DCM, potentially through mitochondrial dysfunction of cardiomyocytes.

Heart Failure Post-Myocardial Infarction Promotes Mammary Tumor Growth Through the NGF-TRKA Pathway.

Background: Epidemiological investigations suggest that patients with heart failure have a higher incidence of cancer; however, the causal role of cardiac disease on cancer progression remains unclear. Objectives: This study aimed to investigate the impact and underlying mechanisms of myocardial infarction (MI)-induced heart failure on tumor cell growth. Methods: We generated a syngeneic mouse model by implanting mammary tumor-derived 4T1 cells into BALB/c mice with MI resulting from ligation of the left anterior descending artery. Results: Mice with MI exhibited increased tumor volume, tumor weight, and Ki67-positive proliferative cells in the tumor tissue compared with the sham-operated mice. Furthermore, RNA sequencing analysis in the tumor tissue revealed significant enrichment of pathways related to tumor progression, particularly the PI3K-AKT pathway in the MI mice. Upregulation of tropomyosin receptor kinase A (TRKA) phosphorylation, an upstream regulator of PI3K-AKT signaling, was observed in the tumor tissue of the MI mice. We also observed elevated levels of circulating nerve growth factor (NGF), a ligand of TRKA, and increased NGF expressions in the myocardium after MI. In in vitro experiments, NGF stimulation led to increased cell proliferation, as well as phosphorylation of TRKA and AKT. Notably, inhibition of TRKA by small interfering RNA or the chemical inhibitor GW441756 effectively blocked these effects. Administration of GW441756 resulted in the suppression of tumor volume and cell proliferation in the MI mice. Conclusions: Our study demonstrates that MI promotes mammary tumor growth through the NGF-TRKA pathway. Consequently, inhibiting TRKA could represent a therapeutic strategy for breast cancer patients concurrently experiencing heart failure after MI.

Predictive Value of Aortic Valve Calcium Volume Measured by Computed Tomography for Paravalvular Leakage After Transcatheter Aortic Valve Implantation.

Paravalvular leakage (PVL) is a complication of transcatheter aortic valve implantation (TAVI) for aortic stenosis, leading to an adverse prognosis. We investigated whether aortic valve calcium volume (Ca-Vol) measured by preoperative cardiac computed tomography had a predictive value for PVL after TAVI using a third-generation self-expandable valve.We retrospectively analyzed 59 consecutive patients who underwent TAVI using a third-generation self-expandable valve. We measured Ca-Vol in the aortic valve and each cusp (non-coronary cusp [NCC], right-coronary cusp [RCC], and left-coronary cusp [LCC]). We divided the patients into 2 groups: a PVL group (32.2%) and a non-PVL group (67.8%). Total Ca-Vol was significantly higher in the PVL group than in the non-PVL group (P < 0.001). Ca-Vol in each cusp was also significantly higher in the PVL group ([NCC] P < 0.001, [RCC] P = 0.001, [LCC] P < 0.001). Univariate logistic regression analysis for PVL indicated that the total and per-cusp Ca-Vols were predictors for PVL (total, odds ratio [OR] 4.0, P < 0.001; NCC, OR 12.5, P = 0.002; RCC, OR 16.0, P = 0.008; LCC, OR 44.5, P < 0.001).Receiver operating characteristic curve analysis of Ca-Vol for predicting PVL revealed the optimal cut-off values of Ca-Vol were 2.4 cm3 for the total, 0.74 cm3 for NCC, 0.73 cm3 for RCC, and 0.56 cm3 for LCC (area under the curve, 0.85, 0.79, 0.76, and 0.83, respectively).Preoperative total, NCC, RCC, and LCC calcium volumes were significant predictors for PVL after TAVI using third-generation self-expandable valves.

Acute coronary syndrome with severe coronary calcification in a patient with pseudo-pseudohypoparathyroidism.

A 40-year-old female with a history of steroid therapy for juvenile rheumatoid arthritis was brought to our hospital because of chest pain. A diagnosis of non-ST elevation myocardial infarction was made, and emergency coronary angiography revealed stenotic lesions with severe calcification in the left anterior descending artery and the right coronary artery. Percutaneous coronary intervention with rotational atherectomy followed by a drug-coated balloon was performed to the lesion in the left anterior descending artery. The patient had characteristic physical findings including short stature, a round face, and 'knuckle-dimple sign'. Whole-body computed tomography showed many ectopic calcifications, indicating Albright's hereditary osteodystrophy. Ellsworth-Howard test revealed that urinary cyclic adenosine monophosphate response was positive, thus a diagnosis of pseudo-pseudohypoparathyroidism (PPHP) was made. Here, we describe a rare case of PPHP complicated by acute coronary syndrome with severely calcified coronary arteries. Learning objective: Pseudo-pseudohypoparathyroidism (PPHP) presents with several characteristic physical findings and ectopic calcifications. Since PPHP involves coronary artery calcification as in the present case, it may be considered as a cause of coronary artery disease.

Prognostic Role of Circulating LTBP-2 in Patients With Dilated Cardiomyopathy: A Novel Biomarker Reflecting Extracellular Matrix LTBP-2 Accumulation.

BACKGROUND: Dilated cardiomyopathy (DCM) is a life-threatening disease related to heart failure. Extracellular matrix proteins have an important role in the pathogenesis of DCM. Latent transforming growth factor beta-binding protein 2 (LTBP-2), a type of extracellular matrix protein, has not been investigated in DCM. METHODS: First, we compared plasma LTBP-2 levels in 131 patients with DCM who underwent endomyocardial biopsy and 44 controls who were matched for age and sex and had no cardiac abnormalities. Next, we performed immunohistochemistry for LTBP-2 on endomyocardial biopsy specimens and followed the DCM patients for ventricular assist device (VAD) implantation, cardiac death, and all-cause death. RESULTS: Patients with DCM had elevated plasma LTBP-2 levels compared with controls (P < 0.001). Plasma LTBP-2 levels were positively correlated with LTBP-2-positive fraction in the myocardium from the biopsy specimen. When patients with DCM were divided into 2 groups according to LTBP-2 levels, Kaplan-Meier analysis demonstrated that patients with high plasma LTBP-2 were associated with increased incidences of cardiac death/VAD and all-cause death/VAD. In addition, patients with high myocardial LTBP-2-positive fractions were associated with increased incidences of these adverse outcomes. Multivariable Cox proportional hazard analysis showed that plasma LTBP-2 and myocardial LTBP-2-positive fraction were independently associated with adverse outcomes. CONCLUSIONS: Circulating LTBP-2 can serve as a biomarker to predict adverse outcomes, reflecting extracellular matrix LTBP-2 accumulation in the myocardium in DCM.

A case of COVID-19-associated fulminant myocarditis due to SARS-CoV-2 omicron BA.2 sub-lineage in an unvaccinated female.

COVID-19-associated myocarditis can be a lethal complication in previous variants, but it is not well understood in the Omicron variant. We present an unvaccinated case of COVID-19-associated fulminant myocarditis due to the Omicron BA.2 sub-lineage requiring mechanical circulatory support (MCS). A 66-year-old female without vaccination against SARS-CoV-2 was hospitalized due to COVID-19. On the next day, she was transferred to our hospital due to the development of fulminant myocarditis. After arrival, she was treated with Impella CP and venoarterial extracorporeal membrane oxygenation due to unstable hemodynamics. In addition to MCS, we treated her with inotropes, methylprednisolone, tocilizumab, and remdesivir. Left ventricular contraction gradually improved, and MCS was removed on day 8. Endomyocardial biopsy showed mild interstitial infiltration of CD3+-T lymphocytes and CD68+-macrophages with no remarkable necrosis or fibrosis. This case showed similar histological characteristics to COVID-19-associated myocarditis before the Omicron variant. The vaccination against the Omicron variant should be considered to prevent the development of severe illness, including fulminant myocarditis. Learning objective: Although the Omicron variant is thought to be generally less severe, COVID-19-associated fulminant myocarditis, as in this case, can occur. The vaccination against the Omicron variant should be considered to prevent from developing severe illness.

Cancer therapeutics-related cardiovascular dysfunction: Basic mechanisms and clinical manifestation.

Although recent advances in cancer treatment improve cancer prognosis, cancer therapeutics-related cardiovascular dysfunction (CTRCD) significantly contributes to the global burden of cardiovascular disease. CTRCD causes two crucial issues: first, premature treatment interruption or discontinuation of chemotherapy; second, the development of congestive heart failure during and after cancer treatment. Thus, early detection and prompt treatment of CTRCD may improve the prognosis in cancer patients. This review covers representative anticancer drugs, including anthracyclines, human epidermal growth factor 2 inhibitors, tyrosine kinase inhibitors, proteasome inhibitors, and immune checkpoint inhibitors. We focus on the molecular mechanisms of CTRCD and various approaches to diagnosis, prevention, monitoring, and treatment.

A retrospective investigation to establish new screening approach for the detection of patients at high risk of Fabry disease in male left ventricular hypertrophy patients.

BACKGROUND: The prevalence of Fabry disease (FD) in male patients with left ventricular hypertrophy (LVH) is about 1%. From the perspective of performing more efficient screening with measurement of α-galactosidase (α-Gal) activity, it is important to raise the pretest probability. METHODS: We retrospectively investigated the prevalence of FD in 701 male patients with LVH who already had been screened by measurement of α-Gal activity in eight hospitals. From the viewpoint of enzymatic screening, we validated previously reported clinical features of FD including the electrocardiographic and echocardiographic characteristics with comparing each clinical determinant between patients with FD and non-FD patients. We finally aimed to establish a new screening approach for the detection of patients at high risk of FD. RESULTS: There were five FD patients (0.7%) in the 701 male patients with LVH. Those five patients with FD all had the cardiac variant type and age at detection of LVH was ≥35 years in all patients. In LVH patients with LV ejection fraction (EF) ≥ 50%, Pend-Q interval < 40 msec, SV1 + RV5 > 4.0 mV, and diffuse LVH were important determinants of FD. In LVH patients with LVEF < 50%, asymmetric septal hypertrophy and posterior wall motion abnormality seemed to be associated with FD. CONCLUSIONS: In our retrospective study, the prevalence of FD in male patients with LVH was found to be 0.7%. We established the efficient combinations of clinical determinants using age at detection of LVH, Pend-Q interval, high voltage, and LVH pattern in an echocardiogram.

Validation of Japanese Bleeding Risk Criteria in Patients After Percutaneous Coronary Intervention and Comparison With Contemporary Bleeding Risk Criteria.

Background: The utility of the Japanese version of high bleeding risk (J-HBR) criteria compared with contemporary bleeding risk criteria, including Academic Research Consortium for High Bleeding Risk criteria, has not been fully investigated. Methods and Results: This study included patients who underwent percutaneous coronary intervention between 2010 and 2019. The J-HBR score was calculated by assigning 1 point for each major criterion and 0.5 points for each minor criterion in the J-HBR criteria. Among 1,643 patients, 1,143 (69.6%) met the J-HBR criteria. Accumulated major bleeding event rates at 1 year were higher among those who met the J-HBR criteria (4.8% vs. 0.6%; P<0.001). J-HBR criteria had higher sensitivity (94.8%) and lower specificity (31.4%) than contemporary bleeding risk criteria in predicting major bleeding. Bleeding events increased with increasing J-HBR score. The C statistic for the J-HBR score for predicting major bleeding at 1 year was 0.75 (95% confidence interval 0.69-0.81), and is comparable to that of other risk scores. In multivariate analysis, of the factors included in J-HBR criteria, chronic kidney disease, heart failure, and active malignancy were associated with major bleeding. Conclusions: J-HBR criteria identified patients at high bleeding risk with high sensitivity and low specificity. Bleeding risk was closely related to J-HBR score and its individual components. The discriminative ability of the J-HBR score was comparable to that of contemporary bleeding risk scores.

D-Dimer Is a Predictive Factor of Cancer Therapeutics-Related Cardiac Dysfunction in Patients Treated With Cardiotoxic Chemotherapy.

BACKGROUND: D-dimer is a sensitive biomarker for cancer-associated thrombosis, but little is known about its significance on cancer therapeutics-related cardiac dysfunction (CTRCD). METHODS: Consecutive 169 patients planned for cardiotoxic chemotherapy were enrolled and followed up for 12 months. All patients underwent echocardiography and blood test at baseline and at 3-, 6-, and 12 months. RESULTS: The patients were divided into two groups based on the level of D-dimer (>1.65 µg/ml or ≦ 1.65 µg/ml) at baseline before chemotherapy: high D-dimer group (n = 37) and low D-dimer group (n = 132). Left ventricular ejection fraction (LVEF) decreased at 3- and 6 months after chemotherapy in high D-dimer group [baseline, 65.2% (62.8-71.4%); 3 months, 62.9% (59.0-67.7%); 6 months, 63.1% (60.0-67.1%); 12 months, 63.3% (58.8-66.0%), p = 0.03], but no change was observed in low D-dimer group. The occurrence of CTRCD within the 12-month follow-up period was higher in the high D-dimer group than in the low D-dimer group (16.2 vs. 4.5%, p = 0.0146). Multivariable logistic regression analysis revealed that high D-dimer level at baseline was an independent predictor of the development of CTRCD [odds ratio 3.93, 95% CI (1.00-15.82), p = 0.047]. CONCLUSION: We should pay more attention to elevated D-dimer levels not only as a sign of cancer-associated thrombosis but also the future occurrence of CTRCD.

Red Blood Cell Distribution Width Is a Predictive Factor of Anthracycline-Induced Cardiotoxicity.

Background: Red blood cell distribution width (RDW) is associated with prognosis in widespread cardiovascular fields, but little is known about relationship with the onset of cancer therapeutics-related cardiac dysfunction (CTRCD). Objectives: The purpose of this study was to assess whether RDW could predict the onset of CTRCD by anthracycline. Methods: Consequential 202 cancer patients planed for anthracycline treatment were enrolled and followed up for 12 months. The patients were divided into 2 groups based on the median value of baseline RDW before chemotherapy [low RDW group, n = 98, 13.0 [12.6-13.2]; high RDW group, n = 104, 14.9 [13.9-17.0]]. Cardiac function was assessed serially by echocardiography at baseline (before chemotherapy), as well as at 3, 6, and 12 months after chemotherapy with anthracycline. Results: Baseline left ventricular end systolic volume index and ejection fraction (EF) were similar between two groups. After chemotherapy, EF decreased at 3- and 6-month in the high RDW group [baseline, 64.5% [61.9-68.9%]; 3-month, 62.6% [60.4-66.9%]; 6-month, 63.9% [60.0-67.9%]; 12-month, 64.7% [60.8-67.0%], P = 0.04], but no change was observed in low RDW group. The occurrence of CTRCD was higher in high RDW group than in low RDW group (11.5 vs. 2.0%, P = 0.008). When we set the cut-off value of RDW at 13.8, sensitivity and specificity to predict CTRCD were 84.6 and 62.0%, respectively. Multivariable logistic regression analysis revealed that baseline RDW value was an independent predictor of the development of CTRCD [odds ratio 1.390, 95% CI [1.09-1.78], P = 0.008]. The value of net reclassification index (NRI) and integrated discrimination improvement (IDI) for detecting CTRCD reached statistical significance when baseline RDW value was added to the regression model including known risk factors such as cumulative anthracycline dose, EF, albumin, and the presence of hypertension; 0.9252 (95%CI 0.4103-1.4402, P < 0.001) for NRI and 0.1125 (95%CI 0.0078-0.2171, P = 0.035) for IDI. Conclusions: Baseline RDW is a novel parameter to predict anthracycline-induced CTRCD.

Glasgow-Blatchford Score Predicts Post-Discharge Gastrointestinal Bleeding in Hospitalized Patients with Heart Failure.

BACKGROUND: The Glasgow-Blatchford Score (GBS) is one of the most widely used scoring systems for predicting clinical outcomes for gastrointestinal bleeding (GIB). However, the clinical significance of the GBS in predicting GIB in patients with heart failure (HF) remains unclear. METHODS AND RESULTS: We conducted a prospective observational study in which we collected the clinical data of a total of 2236 patients (1130 men, median 70 years old) who were admitted to Fukushima Medical University Hospital for acute decompensated HF. During the post-discharge follow-up period of a median of 1235 days, seventy-eight (3.5%) patients experienced GIB. The GBS was calculated based on blood urea nitrogen, hemoglobin, systolic blood pressure, heart rate, and history of hepatic disease. The survival classification and regression tree analysis revealed that the accurate cut-off point of the GBS in predicting post-discharge GIB was six points. The patients were divided into two groups: the high GBS group (GBS > 6, n = 702, 31.4%) and the low GBS group (GBS ≤ 6, n = 1534, 68.6%). The Kaplan-Meier analysis showed that GIB rates were higher in the high GBS group than in the low GBS group. Multivariate Cox proportional hazards analysis adjusted for age, malignant tumor, and albumin indicated that a high GBS was an independent predictor of GIB (hazards ratio 2.258, 95% confidence interval 1.326-3.845, p = 0.003). CONCLUSIONS: A high GBS is an independent predictor and useful risk stratification score of post-discharge GIB in patients with HF.

Cardiac Troponin I Predicts Elevated B-type Natriuretic Peptide in Patients Treated with Anthracycline-Containing Chemotherapy.

BACKGROUND: Anthracycline is used to treat various types of cancer; however, cardiotoxicity negatively affects patient prognosis. OBJECTIVES: The aim of the present study was to investigate serial changes in levels of cardiac troponin I (TnI) and B-type natriuretic peptide (BNP) in patients treated with anthracycline-containing therapy. METHODS: 91 consecutive cancer patients planned for anthracycline treatment were enrolled and followed up for 12 months. All patients underwent echocardiography and blood sampling at baseline, 3, 6, and 12 months. RESULTS: The patients were divided into two groups based on their TnI level during the follow-up period: the elevated TnI group (TnI ≥0.03 ng/mL; n = 37) and the normal TnI group (n = 54). In the elevated TnI group, the TnI levels increased at 3 and 6 months, but they returned to within normal range at 12 months after anthracycline administration. Unlike TnI, the BNP levels began to increase after 6 months, and remained increased at 12 months. The occurrence of cancer therapeutics-related cardiac dysfunction was higher in the elevated TnI group than in the normal TnI group. When we set the cut-off value of TnI at 0.029 ng/mL, sensitivity and specificity to predict an elevated BNP level of more than 100 pg/mL were 90 and 63%, respectively. Multivariate logistic regression analysis revealed that elevated TnI was an independent predictor of elevated BNP levels. CONCLUSION: Elevated TnI was an independent predictor for the development of BNP increase. The different characteristics of TnI and BNP should be considered when managing patients treated with anthracycline-containing therapy.

Prognostic factors in heart failure patients with cardiac cachexia.

OBJECTIVE: To clarify whether cardiac cachexia (CC) alters the prognostic impact of other general risk factors in patients with heart failure (HF). METHODS: This was an observational study. CC was defined as the combination of a body mass index of < 20 kg/m2 and at least one of the following biochemical abnormalities: C-reactive protein > 5 mg/L; hemoglobin < 12 g/dL; and/or albumin < 3.2 g/dL. We divided 1608 hospitalized HF patients into a CC group (n = 176, 10.9%) and a non-CC group (n = 1432, 89.1%). The primary endpoints were cardiac event and all-cause death. RESULTS: The presence of CC showed significant interactions with other risk factors including cancer, estimated glomerular filtration rate (eGFR), and sodium in predicting these endpoints. Multiple Cox proportional analysis revealed that use of â blockers [hazard ratio (HR) = 1.900, 95% confidence interval (CI): 1.045-3.455, P = 0.035) and eGFR (HR = 0.989, 95% CI: 0.980-0.998, P = 0.018) were independent predictors of cardiac event in the CC group, while age (HR = 1.020, 95% CI: 1.002-1.039, P = 0.029) and hemoglobin (HR = 0.844, 95% CI: 0.734-0.970, P = 0.017) were independent predictors of all-cause death. The survival classification and regression tree analysis showed the optimal cut-off points for cardiac event (eGFR: 59.9 mL/min per 1.73 m2) and all-cause death (age, 83 years old; hemoglobin, 10.1 g/dL) in the CC group. CONCLUSIONS: In predicting prognosis, CC showed interactions with several risk factors. Renal function, age, and hemoglobin were pivotal markers in HF patients with CC.

Sporadic Cardiac Amyloidosis by Amyloidogenic Transthyretin V122I Variant.

Hereditary ATTR amyloid cardiomyopathy is defined as the intramyocardial deposition of amyloid fibrils derived from the mutation of transthyretin (TTR). A 51-year-old man was referred to our hospital for congestive heart failure. He and his family had no past history of heart diseases. Echocardiography showed remarkable left ventricular hypertrophy and reduced ejection fraction. Endomyocardial biopsy specimens presented positive staining of Congo-Red and transthyretin. A genetic test showed heterozygous V122I TTR gene mutation, which is very rare in Japan. We diagnosed him as with sporadic ATTR amyloidosis with mutation, and tafamidis was administered to stabilize TTR tetramer. Since the phenotype of ATTR amyloidosis varies depending on its penetration rate, it is crucial to always keep in mind the possibility of hereditary ATTR amyloidosis even in the case of amyloidosis with no clear family history.

Utility of B-Type Natriuretic Peptide for Detecting Cardiac Involvement in Immunoglobulin Amyloidosis.

A useful biomarker for detecting cardiac amyloidosis (CA) has not been fully established. We aimed to investigate the utility of several biomarkers to detect CA in patients with amyloid light-chain (AL) amyloidosis.We examined the plasma levels of B-type natriuretic peptide (BNP), N-terminal fragment of the pro-brain natriuretic peptide (NT-proBNP), high-sensitivity cardiac troponin T (hs-cTnT), serum amyloid A, and the difference between kappa and lambda free light chain (dFLC) between CA patients (n = 30, 47.6%) and non-CA patients (n = 33, 52.4%). Levels of BNP were significantly higher in the CA group compared to the non-CA group (1200.0 versus 224.0 pg/mL, P = 0.001). From the ROC analysis, the sensitivity and specificity of BNP for detecting CA (with a cut-off value of 412 pg/mL) were 83% and 70%, respectively, and the area under the receiver operating curve was 0.75 (95% CI 0.61-0.90, P < 0.001) in all AL amyloidosis patients (n = 63). In contrast, other markers such as NT-proBNP, hs-cTnT, serum amyloid A, and dFLC were not useful for detecting CA in AL amyloidosis patients. Additionally, in the Cox proportional hazard analysis, BNP was a predictor of all-cause mortality (hazard ratio 3.266, 95% confidence interval 1.498-7.119, P = 0.003).BNP is a useful biomarker for detecting cardiac involvement and predicting prognosis in AL amyloidosis patients.

Prior History and Incidence of Cancer Impacts on Cardiac Prognosis in Hospitalized Patients With Heart Failure.

BACKGROUND: Heart failure (HF) and cancer (CA) are becoming increasingly prevalent as the population ages. We aimed to evaluate prior history and occurrence of CA and its prognostic impact on HF.Methods and Results:Consecutive hospitalized HF patients (n=2,103) were divided into 2 groups according to prior history of CA: non-prior-CA group (n=1,828) and prior-CA group (n=275). Compared with the non-prior-CA group, the prior-CA group were older, and had higher prevalence of chronic kidney disease, anemia, and atrial fibrillation (P<0.05). In contrast, sex, other comorbidities, levels of natriuretic peptide and ejection fraction were comparable between groups. We focused on newly diagnosed CA after discharge for HF. In the follow-up period (median 623 days), 114 (6.2%) patients in the non-prior-CA and 17 (6.2%) patients in the prior-CA groups were newly diagnosed as having CA. Additionally, 83 (3.9%) CA-related patient deaths occurred (median 776 days). In the Kaplan-Meier analysis (median 1,037 days), not only all-cause death but also cardiac event rate was significantly higher in the prior-CA group than in the non-prior-CA group (log-rank P<0.01). In the Cox proportional hazard analysis, CA history was a predictor of cardiac event rate (HR 1.450, 95% CI 1.134-1.822), as well as all-cause death (HR 2.483, 95% CI 2.034-3.030). CONCLUSIONS: Prior-CA history was associated with high cardiac event and mortality rates. CA is notable comorbidity in HF patients.

Prognostic impact of chronic obstructive pulmonary disease on adverse prognosis in hospitalized heart failure patients with preserved ejection fraction - A report from the JASPER registry.

BACKGROUND: The prognostic impact of chronic obstructive pulmonary disease (COPD) on heart failure (HF) with preserved ejection fraction (HFpEF) patients and its clinical characteristics have not yet been fully examined. METHODS: The Japanese Heart Failure Syndrome with Preserved Ejection Fraction (JASPER) registry is a nationwide, observational, prospective registration of consecutive Japanese hospitalized HFpEF patients with left ventricular ejection fraction (LVEF) of ≥50%. Among 535 patients enrolled in the registry, 10 lacking COPD data, and seven who died during the first hospitalization, were excluded. Finally, 518 patients were enrolled in this analysis. We divided these patients into two groups: the COPD group (n=40, 7.7%) and the non-COPD group (n=478, 92.3%). This analysis had two primary endpoints: (1) all-cause death and (2) all-cause death or rehospitalization for HF. RESULTS: The COPD group showed a higher prevalence of male sex (70.0% vs. 48.1%, p=0.008), history of prior hospitalization for HF (63.2% vs. 35.1%, p=0.001), smoking history (71.8% vs. 43.3%, p=0.001), and a higher usage of loop diuretics (70.0% vs. 50.0%, p=0.015). In the follow-up period after discharge (median 733 days), there were 82 all-cause deaths and 127 rehospitalizations for HF. In the Kaplan-Meier analysis, the COPD group showed higher all-cause death and reached the composite endpoint more often than in the non-COPD group (all-cause death, log-rank 0.035; all-cause death or rehospitalization for HF, log-rank 0.025). In the Cox proportional hazard analysis, COPD was a predictor of all-cause death (hazard ratio 1.957, 95% confidence interval 1.037-3.694, p=0.038) and the composite endpoint (hazard ratio 1.694, 95% confidence interval 1.064-2.697, p=0.026). CONCLUSIONS: COPD is associated with adverse prognosis in hospitalized patients with HFpEF.

Soluble neprilysin does not correlate with prognosis in pulmonary hypertension.

AIMS: It has been reported that circulating soluble neprilysin (sNEP), which catalyses the degradation of several vasodilator peptides such as natriuretic peptides, predicts prognosis in heart failure patients with reduced ejection fraction. Hypoxia-induced decrease in NEP expression in lungs has been reported. However, the associations between sNEP and haemodynamic parameters, as well as the prognostic impact of sNEP in pulmonary hypertension (PH), remain unclear. We aimed to clarify the relationships between sNEP and natriuretic peptide, haemodynamics (e.g. parameters of echocardiography and right heart catheter) or prognosis in PH patients. METHODS AND RESULTS: First, we examined the associations between sNEP levels and natriuretic peptide, echocardiography, or right heart catheter in PH patients (mean pulmonary artery pressure ≥ 25 mmHg and pulmonary artery wedge pressure ≤ 15 mm Hg on the basis of right heart catheterization, n = 79). Next, we followed up the patients for all-cause mortality. Laboratory data revealed no significant correlations between sNEP and B-type natriuretic peptide (R = 0.022, P = 0.872), N-terminal proBNP (R = -0.018, P = 0.872), and high-sensitivity troponin I (R = 0.206, P = 0.107). Regarding the parameters of echocardiography and right heart catheter, there were no significant correlations between sNEP and left ventricular ejection fraction (R = -0.036, P = 0.764), right ventricular fractional area change (R = -0.259, P = 0.064), tricuspid valve pressure gradient (R = -0.037, P = 0.767), and any of the right heart catheter parameters. In the Kaplan-Meier analysis (mean follow-up, 1284 days, log-rank P = 0.531), all-cause mortality rates were comparable between the higher NEP group (sNEP ≥ median levels of 1.45 ng/mL, n = 39) and the lower NEP group (sNEP < 1.45 ng/mL, n = 40). In the Cox proportional hazard analysis, sNEP was not a predictor of all-cause mortality (hazard ratio 0.902, 95% CI 0.674-1.207, P = 0.487) in PH patients. CONCLUSIONS: Circulating sNEP does not correlate with natriuretic peptide, haemodynamic parameters, or prognosis in patients with PH.