Sex Differences in Cardiac and Clinical Phenotypes and Their Relation to Outcomes in Patients with Heart Failure.

Biological sex is one of the major factors characterizing the heart failure (HF) patient phenotype. Understanding sex-related differences in HF is crucial to implement personalized care for HF patients with various phenotypes. There are sex differences in left ventricular (LV) remodeling patterns in the HF setting, namely, more likely concentric remodeling and diastolic dysfunction in women and eccentric remodeling and systolic dysfunction in men. Recently supra-normal EF (snLVEF) has been recognized as a risk of worse outcome. This pathology might be more relevant in female patients. The possible mechanism may be through coronary microvascular dysfunction and sympathetic nerve overactivation from the findings of previous studies. Further, estrogen deficit might play a significant role in this pathophysiology. The sex difference in body composition may also be related to the difference in LV remodeling and outcome. Lower implementation in guideline-directed medical therapy (GDMT) in female HFrEF patients might also be one of the factors related to sex differences in relation to outcomes. In this review, we will discuss the sex differences in cardiac and clinical phenotypes and their relation to outcomes in HF patients and further discuss how to provide appropriate treatment strategies for female patients.

Supra-normal and mildly reduced ejection fraction in women -An overlooked vulnerable subpopulation in heart failure.

BACKGROUND: Recently, patients with supra-normal left ventricular ejection fraction (snEF) are reported to have high risk of adverse outcomes, especially in women. We sought to evaluate sex-related differences in the association between LVEF and long-term outcomes in heart failure (HF) patients. METHODS: The multicenter WET-HF Registry enrolled all patients hospitalized for acute decompensated HF (ADHF). We analyzed 3943 patients (age 77 years; 40.1% female) registered from 2006 to 2017. According to LVEF the patients were divided into the 3 groups: HF with reduced EF (HFrEF), mildly reduced EF (HFmrEF) and preserved EF. The primary endpoint was defined as the composite of cardiac death and ADHF rehospitalization after discharge. RESULTS: In HFmrEF, implementation of guideline-directed medical therapy (GDMT) such as the combination of renin-angiotensin-system inhibitor (RASi) and ß-blocker at discharge was significantly lower in women than men even after adjustment for covariates (p = 0.007). There were no such sex-related differences in HFrEF. Female sex was associated with higher incidence of the primary endpoint and ADHF rehospitalization after adjustment for covariates exclusively in HFmrEF. Restricted cubic spline analysis demonstrated a U-shaped relationship between LVEF and the hazard ratio of the primary endpoint showing higher event rate in HFmrEF and HFsnEF in women, but such relationship was not observed in men (p for interaction = 0.037). CONCLUSIONS: In women, mrEF and snEF were associated with worse long-term outcomes. Additionally, sex-related differences in the GDMT implementation for HFmrEF highlight the need for further exploration, which might lead to creation of sex-specific guidelines to optimize HF management.

The Safety and Efficacy of Sodium-Glucose Cotransporter-2 Inhibitors for Patients with Sarcopenia or Frailty: Double Edged Sword?

Sodium-glucose cotransporter-2 inhibitors (SGLT-2is) show cardiovascular protective effects, regardless of the patient's history of diabetes mellitus (DM). SGLT2is suppressed cardiovascular adverse events in patients with type 2 DM, and furthermore, SGLT-2is reduced the risk of worsening heart failure (HF) events or cardiovascular death in patients with HF. Along with these research findings, SGLT-2is are recommended for patients with HF in the latest guidelines. Despite these benefits, the concern surrounding the increasing risk of body weight loss and other adverse events has not yet been resolved, especially for patients with sarcopenia or frailty. The DAPA-HF and DELIVER trials consistently showed the efficacy and safety of SGLT-2i for HF patients with frailty. However, the Rockwood frailty index that derived from a cumulative deficit model was employed for frailty assessment in these trials, which might not be suitable for the evaluation of physical frailty or sarcopenia alone. There is no fixed consensus on which evaluation tool to use or its cutoff value for the diagnosis and assessment of frailty in HF patients, or which patients can receive SGLT-2i safely. In this review, we summarize the methodology of frailty assessment and discuss the efficacy and safety of SGLT-2i for HF patients with sarcopenia or frailty.

A Low Arginine/Ornithine Ratio is Associated with Long-Term Cardiovascular Mortality.

AIMS: The long-term prognostic value of the bioavailability of L-arginine, an important source of nitric oxide for the maintenance of vascular endothelial function, has not been investigated fully. We therefore investigated the relationship between amino acid profile and long-term prognosis in patients with a history of standby coronary angiography. METHODS: We measured the serum concentrations of L-arginine, L-citrulline, and L-ornithine by high-speed liquid chromatography. We examined the relationship between the L-arginine/L-ornithine ratio and the incidence of all-cause death, cardiovascular death, and major adverse cardiovascular events (MACEs) in 262 patients (202 men and 60 women, age 65±13 years) who underwent coronary angiography over a period of ≤ 10 years. RESULTS: During the observation period of 5.5±3.2 years, 31 (12%) patients died, including 20 (8%) of cardiovascular death, while 32 (12%) had MACEs. Cox regression analysis revealed that L-arginine/L-ornithine ratio was associated with an increased risk for all-cause death (unadjusted hazard ratio, 95% confidence interval) (0.940, 0.888-0.995) and cardiovascular death (0.895, 0.821-0.965) (p＜0.05 for all). In a model adjusted for age, sex, hypertension, hyperlipidemia, diabetes, current smoking, renal function, and log10-transformed brain natriuretic peptide level, cardiovascular death (0.911, 0.839-0.990, p=0.028) retained an association with a low L-arginine/ L-ornithine ratio. When the patients were grouped according to an L-arginine/L-ornithine ratio of 1.16, the lower L-arginine/L-ornithine ratio group had significantly higher incidence of all-cause death, cardiovascular death, and MACEs. CONCLUSION: A low L-arginine/L-ornithine ratio may be associated with increased 10-year cardiac mortality.

D-Dimer beyond Diagnosis of Pulmonary Embolism: Its Implication for Long-Term Prognosis in Cardio-Oncology Era.

Venous thromboembolism (VTE) is a common comorbidity of cancer, often referred to as cancer-associated thrombosis (CAT). Even though its prevalence has been increasing, its clinical picture has not been thoroughly investigated. In this single-center retrospective observational study, 259 patients who were treated for pulmonary embolism (PE) between January 2015 and December 2020 were available for analysis. The patients were divided by the presence or absence of concomitant malignancy, and those with malignancy (N = 120, 46%) were further classified into active (N = 40, 15%) and inactive groups according to the treatment status of malignancy. In patients with malignancy, PE was more often diagnosed incidentally by computed tomography or D-dimer testing, and the proportion of massive PE was lower. Although D-dimer levels overall decreased after the initiation of anticoagulation therapy, concomitant malignancy was independently associated with higher D-dimer at discharge despite the lower severity of PE at onset. The patients with malignancy had a poor prognosis during post-discharge follow-up. Active malignancy was independently associated with major adverse cardiovascular events (MACE) and major bleeding. D-dimer at discharge was an independent predictor of mortality even after adjustment for malignancy. This study's findings suggest that CAT-PE patients might have hypercoagulable states, which can potentially lead to a poorer prognosis.

ß1 Adrenergic Receptor Autoantibodies and IgG Subclasses: Current Status and Unsolved Issues.

A wide range of anti-myocardial autoantibodies have been reported since the 1970s. Among them, autoantibodies against the ß1-adrenergic receptor (ß1AR-AAb) have been the most thoroughly investigated, especially in dilated cardiomyopathy (DCM). Β1AR-Aabs have agonist effects inducing desensitization of ß1AR, cardiomyocyte apoptosis, and sustained calcium influx which lead to cardiac dysfunction and arrhythmias. Β1AR-Aab has been reported to be detected in approximately 40% of patients with DCM, and the presence of the antibody has been associated with worse clinical outcomes. The removal of anti-myocardial autoantibodies including ß1AR-AAb by immunoadsorption is beneficial for the improvement of cardiac function for DCM patients. However, several studies have suggested that its efficacy depended on the removal of AAbs belonging to the IgG3 subclass, not total IgG. IgG subclasses differ in the structure of the Fc region, suggesting that the mechanism of action of ß1AR-AAb differs depending on the IgG subclasses. Our previous clinical research demonstrated that the patients with ß1AR-AAb better responded to ß-blocker therapy, but the following studies found that its response also differed among IgG subclasses. Further studies are needed to elucidate the possible pathogenic role of IgG subclasses of ß1AR-AAbs in DCM, and the broad spectrum of cardiovascular diseases including HF with preserved ejection fraction.

The target ablation index values for electrical isolation of the superior vena cava.

PURPOSE: The ablation index (AI), developed as a radiofrequency (RF) catheter ablation composite component endpoint, which incorporates contact force (CF), time, and power in a weighted formula, has been reported to be useful for a durable pulmonary vein isolation (PVI) to treat atrial fibrillation (AF). No study has reported the target AI value for the SVC isolation (SVCI). In this study, we aimed to investigate the target AI for the SVCI. METHODS: Thirty-six AF patients who underwent an initial SVCI were enrolled. Ablation was performed at 556 points. The sites where dormant conduction was induced or additional ablation was needed were defined as touch up sites (n = 36). We compared the energy deliver time, power, generator impedance (GI) drop, local bipolar voltage, contact force (CF), force-time integral (FTI), and AI between the touch up sites and the no touch up sites (n = 520). RESULTS: The FTI and AI were significantly lower at the touch up sites (touch up sites vs. no touch up sites; FTI, 126.5 [99.3-208.8] vs. 244 [184-340.8], p < 0.0001; AI, 350.1 ± 43.6 vs. 277.2 ± 21.8, p < 0.0001). The median value of the AI at the no touch up sites was 350, and no reconnections were seen where the minimum AI value was more than 308. Most of the touch up sites were located in the anterior wall and lateral wall (anterior wall, 20/36 sites [55.6%]; lateral wall, 10/36 sites [27.8%]; septal wall, 6/36 sites [16.7%]; posterior wall, 0/36sites [0.0%]). CONCLUSION: The target AI value for the SVCI should be 350, and at least 308 would be needed.

Effects of uninterrupted dabigatran on the intensity of anticoagulation during atrial fibrillation ablation.

BACKGROUND: Uninterrupted dabigatran during atrial fibrillation (AF) ablation is now established as the standard therapy. However, there are few reports on the effects of uninterrupted dabigatran on the intensity of anticoagulation during AF ablation. METHODS: We retrospectively analyzed 247 consecutive patients who underwent AF ablation in our hospital from January 2017 to December 2018. Patients who took warfarin or uninterrupted direct oral anticoagulants (DOACs) except for dabigatran were excluded. 89 patients underwent ablation with uninterrupted dabigatran (uninterrupted group, male 71, mean age 59.6 ± 14.0) and 124 with interrupted DOACs (interrupted group, male 105, mean age 56.9 ± 12.9) during AF ablation. The initial ACT level, proportion of ACT levels of more than 300 s, and total amount of heparin were compared. Furthermore, the incidence of procedure complications was also evaluated. RESULTS: The initial ACT levels were significantly higher in the uninterrupted group, and the total number of ACTs of more than 300 s was significantly higher in the uninterrupted group (uninterrupted vs. interrupted; initial ACT level, 315.6 ± 59.8 vs. 264.5 ± 48.6, p < .001; total number of ACTs ≧300, n [%], 304/ 484 [62.8 %] vs. 372/745 [49.9%], p < .001). The total amount of heparin during procedure was significantly lower in the uninterrupted group (uninterrupted group vs. interrupted group; 12966 ± 4773 vs. 16371 ± 5212, p < .001). There was no significant difference in the incidence of complications between the two groups. CONCLUSIONS: In the catheter ablation of AF, uninterrupted dabigatran would be useful to obtain a stable anticoagulation status during the entire procedure.

Short-Chain Fatty Acids in Gut-Heart Axis: Their Role in the Pathology of Heart Failure.

Heart failure (HF) is a syndrome with global clinical and socioeconomic burden worldwide owing to its poor prognosis. Accumulating evidence has implicated the possible contribution of gut microbiota-derived metabolites, short-chain fatty acids (SCFAs), on the pathology of a variety of diseases. The changes of SCFA concentration were reported to be observed in various cardiovascular diseases including HF in experimental animals and humans. HF causes hypoperfusion and/or congestion in the gut, which may lead to lowered production of SCFAs, possibly through the pathological changes of the gut microenvironment including microbiota composition. Recent studies suggest that SCFAs may play a significant role in the pathology of HF, possibly through an agonistic effect on G-protein-coupled receptors, histone deacetylases (HDACs) inhibition, restoration of mitochondrial function, amelioration of cardiac inflammatory response, its utilization as an energy source, and remote effect attributable to a protective effect on the other organs. Collectively, in the pathology of HF, SCFAs might play a significant role as a key mediator in the gut-heart axis. However, these possible mechanisms have not been entirely clarified and need further investigation.