Shared and Reciprocal Mechanisms Between Heart Failure and Cancer　- An Emerging Concept of Heart-Cancer Axis.

Epidemiological evidence of increased risks of cancer in heart failure (HF) patients and HF in cancer patients has suggested close relationships between the pathogenesis of both diseases. Indeed, HF and cancer share common risk factors, including aging and unhealthy lifestyles, and underlying mechanisms, including activation of the sympathetic nervous system and renin-angiotensin-aldosterone system, chronic inflammation, and clonal hematopoiesis of indeterminate potential. Mechanistically, HF accelerates cancer development and progression via secreted factors, so-called cardiokines, and epigenetic remodeling of bone marrow cells into an immunosuppressive phenotype. Reciprocally, cancer promotes HF via cachexia-related wasting and metabolic remodeling in the heart, and possibly via cancer-derived extracellular vesicles influencing myocardial structure and function. The novel concept of the "heart-cancer axis" will help in our understanding of the shared and reciprocal relationships between HF and cancer, and provide innovative diagnostic and therapeutic approaches for both diseases.

Forecasting the Acute Heart Failure Admissions: Development of Deep Learning Prediction Model Incorporating the Climate Information.

BACKGROUND: Climate is known to influence the incidence of cardiovascular events. However, their prediction with traditional statistical models remains imprecise. METHODS AND RESULTS: We analyzed 27,799 acute heart failure (AHF) admissions within the Tokyo CCU Network Database from January 2014 to December 2019. High-risk AHF (HR-AHF) day was defined as a day with the upper 10th percentile of AHF admission volume. Deep neural network (DNN) and traditional regression models were developed using the admissions in 2014-2018 and tested in 2019. Explanatory variables included 17 meteorological parameters. Shapley additive explanations were used to evaluate their importance. The median number of incidences of AHF was 12 (9-16) per day in 2014-2018 and 11 (9-15) per day in 2019. The predicted AHF admissions correlated well with the observed numbers (DNN: R2 = 0.413, linear regression: R2 = 0.387). The DNN model was superior in predicting HR-AHF days compared with the logistic regression model [c-statistics: 0.888 (95% CI: 0.818-0.958) vs 0.827 (95% CI: 0.745-0.910): P = .0013]. Notably, the strongest predictive variable was the 7-day moving average of the lowest ambient temperatures. CONCLUSIONS: The DNN model had good prediction ability for incident AHF using climate information. Forecasting AHF admissions could be useful for the effective management of AHF.

Novel AGL variants in a patient with glycogen storage disease type IIIb and pulmonary hypertension caused by pulmonary veno-occlusive disease: A case report.

Glycogen storage disease type III (GSD-III) is an autosomal recessive metabolic disorder caused by mutations in the AGL gene, and may develop various types of pulmonary hypertension (PH). Here, we report a case of 24-year-old man with GSD-IIIb with two novel null variants in AGL (c.2308 + 2T>C and c.3045_3048dupTACC). He developed multi-drug-resistant pulmonary veno-occlusive disease (PVOD) and was registered as a candidate for lung transplantation. No pathogenic variants were detected in previously known causative genes for pulmonary hypertension and the underlying mechanism of coincidence of two rare diseases was unknown. We discuss the association of the loss of glycogen-debranching enzyme with incident PVOD.

Association of ambient temperature and acute heart failure with preserved and reduced ejection fraction.

AIMS: Evidence on the association between ambient temperature and the onset of acute heart failure (AHF) is scarce and mixed. We sought to investigate the incidence of AHF admissions based on ambient temperature change, with particular interest in detecting the difference between AHF with preserved (HFpEF), mildly reduced (HFmrEF), and reduced ejection fraction (HFrEF). METHODS AND RESULTS: Individualized AHF admission data from January 2015 to December 2016 were obtained from a multicentre registry (Tokyo CCU Network Database). The primary event was the daily number of admissions. A linear regression model, using the lowest ambient temperature as the explanatory variable, was selected for the best-estimate model. We also applied the cubic spline model using five knots according to the percentiles of the distribution of the lowest ambient temperature. We divided the entire population into HFpEF + HFmrEF and HFrEF for comparison. In addition, the in-hospital treatment and mortality rates were obtained according to the interquartile ranges (IQRs) of the lowest ambient temperature (IQR1 <5.5°C; IQR25.5-13.3°C; IQR3 13.3-19.7°C; and IQR4 >19.7°C). The number of admissions for HFpEF, HFmrEF and HFrEF were 2736 (36%), 1539 (20%), and 3354 (44%), respectively. The lowest ambient temperature on the admission day was inversely correlated with the admission frequency for both HFpEF + HFmrEF and HFrEF patients, with a stronger correlation in patients with HFpEF + HFmrEF (R2  = 0.25 vs. 0.05, P < 0.001). In the sensitivity analysis, the decrease in the ambient temperature was associated with the greatest incremental increases in HFpEF, followed by HFmrEF and HFrEF patients (3.5% vs. 2.8% vs. 1.5% per -1°C, P < 0.001), with marked increase in admissions of hypertensive patients (systolic blood pressure >140 mmHg vs. 140-100 mmHg vs. <100 mmHg, 3.0% vs. 2.0% vs. 0.8% per -1°C, P for interaction <0.001). A mediator analysis indicated the presence of the mediator effect of systolic blood pressure. The in-hospital mortality rate (7.5%) did not significantly change according to ambient temperature (P = 0.62). CONCLUSIONS: Lower ambient temperature was associated with higher frequency of AHF admissions, and the effect was more pronounced in HFpEF and HFmrEF patients than in those with HFrEF.

Oral Administration of Euglena Gracilis Z Alleviates Constipation and Cardiac Dysfunction in a Mouse Model of Isoproterenol-Induced Heart Failure.

Background: Patients with heart failure (HF) often experience gastrointestinal problems such as constipation, diarrhea, and disturbances to drug absorption. In HF, hypoperfusion and congestion cause structural and functional changes in the gut, which, in turn, lead to impaired cardiac function. Euglena gracilis Z (hereafter "Euglena"), called Midorimushi in Japanese, is a microalga that is used as a food or nutritional supplement. It is unclear whether Euglena is beneficial for bowel habitus and cardiac function in subjects with HF. Methods and Results: We injected C57BL/6 male mice subcutaneously with isoproterenol (ISO) (20 mg/kg/day) for 7 days to examine bowel movement in HF. Euglena was orally administered to mice on an ad libitum-feeding to a normal chow containing 2% dietary mixture. ISO induced a decrease in bowel movement and an increase in fecal retention in the cecum, as well as a decrease in left ventricular (LV) contraction. Euglena accelerated intestinal transit, relieved fecal retention, and prevented the alterations in gut pathology in ISO-treated mice. Euglena also suppressed ISO-induced decreases in LV contraction, although it had no significant effect on LV hypertrophy. Conclusions: The results suggested that oral administration of Euglena alleviated constipation and cardiac dysfunction in a mouse model of ISO-induced HF, and highlight the potential clinical benefit of Euglena in patients with HF in preventing constipation and contractile deterioration.

Asymptomatic Myocarditis with Mild Cardiac Marker Elevation Following Nivolumab-Induced Myositis.

Although myocarditis following immune checkpoint inhibitor (ICI) therapy is rarely reported, it is considered clinically important because of its high mortality rate. Although various tests may be used for early diagnosis, abnormalities suggestive of myocarditis may not be detected. We report a case of ICI-induced myositis and concurrent asymptomatic myocarditis with mild cardiac marker elevation following nivolumab therapy in a 79-year-old man with metastatic gastric cancer. In this case, cardiac magnetic resonance imaging was useful for diagnosis. Treatment with oral prednisolone rapidly improved the patient's symptoms and creatine kinase levels. Follow-up examination revealed no flare-up of myositis and exacerbation of myocarditis. Since ICI-induced myositis is often complicated by myocarditis, this case report highlights the importance of detecting concurrent myocarditis in patients with ICI-induced myositis through intensive cardiac assessments to improve clinical outcomes.

Empagliflozin attenuates neointimal hyperplasia after drug-eluting-stent implantation in patients with type 2 diabetes.

The effects of empagliflozin, a sodium-glucose co-transporter 2 inhibitor, on neointimal response after drug-eluting-stent (DES) implantation remains unknown. Insufficiently controlled diabetes patients with coronary artery disease planned for DES stenting were consecutively enrolled. The patients were assigned to receive empagliflozin in addition to standard therapy or intensive therapy using other glucose-lowering drugs (oGLD). The primary endpoint was thickness of neointimal hyperplasia (NIH) 12 months after stenting assessed by optical coherence tomography (OCT). A total of 28 patients were analyzed (n = 15 in the empagliflozin group, n = 13 in the oGLD group). The levels of glucose profile were not significantly different between both groups at follow-up [HbA1c; 7.2 ± 0.8 vs 7.3 ± 0.9%, p = 0.46]. In OCT analysis, neointima was significantly less in the empagliflozin group than the oGLD group [mean NIH thickness: 137 ± 32 vs 168 ± 39 µm, p = 0.02]. Changes of systolic and diastolic blood pressure (BP), changes of body mass index, and changes of hematocrit after additional treatment were significantly associated with NIH attenuation, whereas no correlation was observed in changes in blood glucose parameters. Multivariate logistic regression analysis revealed that changes in systolic BP was the strongest predictor for NIH attenuation, followed by changes in diastolic BP. In patients with type 2 diabetes, standard plus empagliflozin attenuated neointimal progression as compared with intensive standard therapy after DES implantation. Our data possibly support a beneficial effect of empagliflozin in type 2 diabetes required for coronary revascularization therapy.

Benefit and harm of intravenous vasodilators across the clinical profile spectrum in acute cardiogenic pulmonary oedema patients.

BACKGROUND: The absence of high quality, large-scale data that indicates definitive mortality benefits does not allow for firm conclusions on the role of intravenous vasodilators in acute heart failure. We aimed to investigate the associations between intravenous vasodilators and clinical outcomes in acute heart failure patients, with a specific focus on patient profiles and type of vasodilators. METHODS: Data of 26,212 consecutive patients urgently hospitalised for a primary diagnosis of acute heart failure between 2009 and 2015 were extracted from a government-funded multicentre data registration system. Propensity scores were calculated with multiple imputations and 1:1 matching performed between patients with and without vasodilator use. The primary endpoint was inhospital mortality. RESULTS: On direct comparison of the vasodilator and non-vasodilator groups after propensity score matching, there were no significant differences in the inhospital mortality rates (7.5% vs. 8.8%, respectively; P=0.098) or length of intensive/cardiovascular care unit stay and hospital stay between the two groups. However, there was a substantial difference in baseline systolic blood pressure by vasodilator type; favourable impacts of vasodilator use on inhospital mortality were observed among patients who had higher systolic blood pressures and those who had no atrial fibrillation on admission. Furthermore, when compared to nitrates, the use of carperitide (natriuretic peptide agent) was significantly associated with worse outcomes, especially in patients with intermediate systolic blood pressures. CONCLUSIONS: In acute heart failure patients, vasodilator use was not universally associated with improved inhospital outcomes; rather, its effect depended on individual clinical presentation: patients with higher systolic blood pressure and no atrial fibrillation seemed to benefit maximally from vasodilators. TRIAL REGISTRATION: UMIN-CTR identifier, UMIN000013128.

Stent Recoil in Overlapping Stent 18 Years After Wiktor Stent Implantation.

In this paper, we look at the case of a 79 years old male who received a Wiktor stent (WS) implantation for myocardial infarction in proximal left anterior descending artery 18 years ago. Eleven years later, an Everolimus eluting stent (EES; Xience V™) was implanted for the proximal edge restenosis of WS from mid left main trunk to the middle part of WS. Seven years after EES implantation, the angiography and optical coherence tomography revealed in-stent restenosis with severe stent recoil just distal to the overlapping zone of WS. In the present case, stent recoil seems to have occurred due to different radial stiffness and flexibility between the two stents.

Eosinophilic Myocarditis With Hypersegmented Granulocytes and Neutrophilia Without Eosinophilia: A Case Mimicking Neutrophilic Myocarditis.

We report a case of a 78-year-old woman with neutrophilia without eosinophilia who was pathologically diagnosed with eosinophilic myocarditis by myocardial biopsy. The biopsy specimen showed infiltrating granulocytes with hypersegmentation, mimicking neutrophils; however, they were confirmed to be eosinophils by Giemsa staining.

Indications for suboptimal low-dose direct oral anticoagulants for non-valvular atrial fibrillation patients.

BACKGROUND: Direct oral anticoagulants (DOACs) have been developed for stroke prevention in patients with non-valvular atrial fibrillation (NVAF). We conducted a retrospective cohort study of patients with NVAF who were newly treated with DOACs in a real-world clinical setting. METHODS: We retrospectively analyzed patients with NVAF newly treated with one of three DOACs-dabigatran, rivaroxaban, or apixaban-between January 1, 2013, and December 31, 2015. RESULTS: A total of 670 patients with NVAF who were newly prescribed one of the three DOACs were analyzed; 74 patients (10.9%) received dabigatran, 290 (43.3%) received rivaroxaban, and 306 (45.8%) received apixaban. Fifteen patients had thromboembolic events, almost half of which were due to discontinuation of DOACs. Six patients had major bleeding, although almost all were discharged with good neurological prognoses. A total of 129 patients were treated with a suboptimal low-dose DOAC; none experienced a thromboembolic event as long as the DOAC was taken regularly, and none of the patients in any of the three DOAC groups had major bleeding events. CONCLUSIONS: With good adherence, the clinical course associated with DOACs is comparatively good. In the future, suboptimal low-dose DOAC therapy may serve as an appropriate choice for some patients with a high risk of stroke and bleeding.