Heart Failure Research Articles

Orthostatic and Standing Hypertension and Risk of Cardiovascular Disease.

Orthostatic hypertension is an emerging risk factor for adverse events. Recent consensus statements combine an increase in blood pressure upon standing with standing hypertension, but whether these 2 components have similar risk associations with cardiovascular disease (CVD) is unknown. The ARIC study (Atherosclerosis Risk in Communities) measured supine and standing blood pressure during visit 1 (1987-1989). We defined systolic orthostatic increase (a rise in systolic blood pressure [SBP] ≥20 mm Hg, standing minus supine blood pressure) and elevated standing SBP (standing SBP ≥140 mm Hg) to examine the new consensus statement definition (rise in SBP ≥20 mm Hg and standing SBP ≥140 mm Hg). We used Cox regression to examine associations with incident coronary heart disease, heart failure, stroke, fatal coronary heart disease, and all-cause mortality. Of 11 369 participants (56% female; 25% Black adults; mean age, 54 years) without CVD at baseline, 1.8% had systolic orthostatic increases, 20.1% had standing SBP ≥140 mm Hg, and 1.3% had systolic orthostatic increases with standing SBP ≥140 mm Hg. During up to 30 years of follow-up, orthostatic increases were not significantly associated with any of the adverse outcomes of interest, while standing SBP ≥140 mm Hg was significantly associated with all end points. In joint models comparing systolic orthostatic increases and standing SBP ≥140 mm Hg, standing SBP ≥140 mm Hg was significantly associated with a higher risk of CVD, and associations differed significantly from systolic orthostatic increases. Unlike systolic orthostatic increases, standing SBP ≥140 mm Hg was strongly associated with CVD outcomes and death. These differences in CVD risk raise important concerns about combining systolic orthostatic increases and standing SBP ≥140 mm Hg in a consensus definition for orthostatic hypertension.

Cardiooncology in the ICU - Cardiac Urgencies in Cancer Care.

Cardiovascular disease is an increasing risk of morbidity and mortality in cancer patients, related to an growing number of aging survivors with pre-existing cardiovascular disease and the use of traditional and novel cancer therapies with cardiotoxic effects. While many cardiac complications are chronic processes that develop over time, there are many acute processes that may arise in hospitalized patients. It is important for hospitalists and critical care physicians to be familiar with the recognition and management of these conditions in this unique population. This article reviews the presentation and management of common cardiac urgencies in critically ill cancer patients including acute decompensated heart failure, acute coronary syndromes, arrhythmias, hypertensive crises, pulmonary embolism, pericardial tamponade and myocarditis.

Diagnosis and management of a more advanced stage of preclinical myxomatous mitral valve disease in dogs without echocardiography.

Myxomatous mitral valve disease (MMVD) is the most common cardiac disease in dogs. Appropriate diagnosis and staging can be performed by means of an echocardiographic examination. Early disease stages might be accompanied by valvular insufficiency and, in more advanced phases, by cardiac dilatation. A correct diagnosis of this preclinical phase and identification of cardiac enlargement should be carried out in order to advise appropriate medical treatment. When echocardiography is not available or declined by the dog's owners, alternative methods to identify the disease and predict clinically relevant cardiomegaly, can be performed. Among these, cardiac auscultation and assessment of heart murmur intensity, cardiac dimensions obtained by thoracic radiography, by means of vertebral heart size, and cardiac biomarkers, in particular N-terminal pro-B-type natriuretic peptide (NT-proBNP), can be carried out as single tests or in combination, in order to identify dogs with increased risk of congestive heart failure, and needing an early treatment with pimobendan. In particular, a heart murmur intensity ≥3/6 (moderate or louder), a vertebral heart size ≥11,5 units obtained from a latero-lateral thoracic radiographic view, and plasma concentrations of N-terminal pro-B-type natriuretic peptide value > 1100 pmol/l, are findings that might suggest presence of clinically relevant cardiomegaly with a good specificity. A practical algorithm to guide clinicians in managing dogs with suspicion of valvular disease has been created, starting from clinical examination, and using the aforementioned additional tests in order to advise the appropriate controls and therapy.

Long-Term Outcomes in Patients With Chronic Total Occlusion and Left Ventricular Systolic Dysfunction - A Single-Center Inverse Probability of Treatment Weighting Analysis.

The optimal treatment strategy for patients with coronary chronic total occlusion (CTO) and left ventricular systolic dysfunction (LVSD) remains unclear. This study investigated the long-term outcomes of percutaneous coronary intervention (PCI), coronary artery bypass grafting (CABG), and medical therapy (MT) in this specific patient cohort. This retrospective cohort study included 987 consecutive patients with CTO and LVSD who met the inclusion criteria and underwent either CTO-PCI (n=277), CTO-CABG (n=222), or CTO-MT (n=488) between 2014 and 2020. The primary outcome was all-cause mortality during follow-up. Secondary endpoints were major adverse cardiac and cerebrovascular events (MACCE) and their components, including cardiovascular mortality, myocardial infarction (MI), stroke, unplanned revascularization, and hospitalization for heart failure. During a median follow-up of 5.3 years, 232 (23.51%) patients died from any cause. In the unadjusted analysis, CTO-MT was associated with worse long-term survival prospects. After inverse probability of treatment weighting and variable adjustment, CTO-PCI and CTO-CABG demonstrated significant reductions in the long-term risks of all-cause and cardiovascular mortality. Notably, CTO-CABG was associated with the lowest long-term risks of MACCE, MI, unplanned revascularization, and hospitalization for heart failure. For patients with CTO and LVSD, successful CTO revascularization significantly improved long-term survival compared with CTO-MT. CTO-CABG can be regarded as the optimal treatment modality for better long-term prognosis.

Telemonitoring for Chronic Heart Failure: Narrative Review of the 20-Year Journey From Concept to Standard Care in Germany.

Chronic heart failure (CHF) is a major cause of morbidity and mortality worldwide, placing a significant burden on health care systems. The concept of telemedicine for CHF was first introduced in the late 1990s, and since 2010, studies have demonstrated its potential to improve patient outcomes and reduce health care costs. Over the following decade, technological advancements and changes in health care policy led to the development of more sophisticated telemedicine solutions for CHF, including remote patient management through invasive or noninvasive telemonitoring devices, mobile apps, and virtual consultations. Years of public funding in Germany have generated evidence that remote patient management improves outcomes for patients with CHF, such as quality of life, and reduces hospital admissions. Based on these data, the Federal Joint Committee (Gemeinsamer Bundesausschuss; G-BA) decided, independently of the current European Society of Cardiology recommendations, to incorporate telemedicine as a standard digital intervention for high-risk patients with reduced left ventricular ejection fraction in Germany in 2020. This review aims to illustrate the journey from the initial concept through pioneering studies that led to telemedicine's integration into standard care, and to share current experiences that have positioned Germany as a leader in cardiovascular telemedicine. We review and discuss existing literature and evidence on the development and implementation of telemonitoring for CHF in Germany over the past 20 years. Relevant studies, reports, and guidelines were identified through a comprehensive search of electronic databases, including PubMed, Google Scholar, and specialized journals focused on CHF telemonitoring. Pioneering studies, such as the TIM-HF2 (Telemedical Interventional Management in Heart Failure II) and IN-TIME (Influence of Home Monitoring on Mortality and Morbidity in Heart Failure Patients with Impaired Left Ventricular Function) trials, demonstrated the effectiveness of remote patient management applications for patients with CHF in Germany and their applicability to current practices involving both invasive and noninvasive methods. Collaborations between researchers and technology developers overcame barriers, leading to sustainable improvements in patient care. Ongoing research on artificial intelligence applications for prioritizing and interpreting individual health data will continue to transform digital health care. The establishment of telemedical care for patients with HF across Europe is likely to benefit from experiences in Germany, where significant improvements have been achieved in the care of patients with HF.

New and future heart failure drugs.

In the past decade, our understanding of heart failure pathophysiology has advanced significantly, resulting in the development of new medications such as angiotensin-neprilysin inhibitors, sodium-glucose cotransporter-2 inhibitors and oral soluble guanylate cyclase stimulators. Backed by positive findings from large randomized controlled trials, recommendations for their use were recently included in the 2022 AHA/ACC/HFSA guidelines and 2023 ESC guidelines for management of heart failure. Promising drugs for future heart failure treatment include agents that modulate the neurohormonal system, vasodilators, anti-inflammatory drugs, mitotropes, which improve deranged energy metabolism of the failing heart, and myotropes, which increase cardiac contractility by affecting cardiac sarcomere function. Here, we discuss these new and future heart failure drugs. We explain their mechanisms of action, critically evaluate their performance in clinical trials and summarize the clinical scenarios in which the latest guidelines recommend their use. This Review aims to offer clinicians and researchers a comprehensive overview of novel therapeutic classes in heart failure treatment.

Oral Health, Inflammation, and Cardiometabolic Factors in the VA Million Veteran Program.

Associations between cardiometabolic comorbidities and self-reported oral health (OH) are often underexplored in large biobank datasets. While these associations are unaffected by dental care access, they could be mediated by immune responses and inflammation. This study assessed the associations between cardiometabolic comorbidities and self-reported OH, periodontitis, and tooth loss using the International Classification of Diseases (ICD) codes in participants from the U.S. Veterans Affairs Million Veteran Program (MVP), adjusting for immune and inflammatory covariates. Data from 154,167 MVP participants were extracted from January 2011 to September 2021, including lifetime cardiometabolic comorbidities, self-reported OH, ICD-coded periodontitis and tooth loss, and laboratory measurements. Multivariate logistic regression analysis was used to calculate the odds ratios of cardiometabolic comorbidities for self-reported OH, periodontitis, and tooth loss, adjusting for demographic, socioeconomic, cardiovascular, and inflammatory (neutrophil and lymphocyte cell counts) risk factors. A separate dataset was used for additional sensitivity analyses, adjusting for serum levels of C-reactive protein and albumin. Complete data were analyzed for 154,167 participants (19%). Most participants (92%) were male and from European ancestry (94%). The mean age was 65.5 y (SD 11.4 y). Ten percent of participants had excellent self-reported OH. Fourteen percent had any periodontitis, and 17% had any tooth loss. Significant associations were found between tooth loss and congestive heart failure (odds ratio [OR], 1.74, P < 0.001) and peripheral vascular diseases (OR, 1.82, P < 0.001). There were also significant associations between congestive heart failure and self-reported OH (excellent versus "poor/fair/good/very good"), with increasing odds as self-reported OH declined (P < 0.001 for trend). These associations remained significant even after sensitivity analyses, albeit with slight attenuation. This study of veterans underscores the important cardiometabolic links of self-reported poor OH and tooth loss, akin to those observed with periodontitis, even after adjusting for potential confounders related to demographics, lifestyle, and inflammation. Exploring cardiometabolic associations with self-reported OH, clinically diagnosed periodontitis, and tooth loss using the ICD in the Veterans Affairs Million Veteran Program, we found significant associations. These associations persisted after adjustment for inflammatory confounders. These findings emphasized the benefit of assessing OH as a vital indicator of overall cardiometabolic health in large-scale biobank studies.

Association among diabetes, cardiovascular disease and mortality in patients hospitalised for COVID-19: an analysis of the American Heart Association COVID-19 CVD Registry

ObjectiveTo examine inpatient COVID-19-related outcomes among patients with and without diabetes alone or with a history of established heart failure (HF) or established atherosclerotic cardiovascular disease (ASCVD).DesignObservational study; longitudinal analysis...

Association of potassium disorders with the mode of death and etiology in patients with chronic heart failure: the INCOR-HF study

Observational studies suggest a U-shaped association between serum potassium (K⁺) levels and mortality in patients with chronic heart failure (CHF). However, the mode of death in patients with HF and K⁺ disorders remains speculative. To investigate the association between potassium disorders and the mode of death in patients with CHF. A retrospective cohort of 10,378 CHF outpatients was analyzed over an average of 3.28 ± 2.5 years. Kaplan-Meier method, Cox proportional hazards regression models, Poisson regression models adjusting for confounders, and e-value determination (e' > 1.6) were used to observe associations between potassium disorders and outcomes. Chagas etiology (p < 0.01) and triple HF therapy (p < 0.01) were associated with hyperkalemia. Atrial fibrillation was associated with hypokalemia (p < 0.01). Chronic kidney disease (CKD) (p < 0.01) and diabetes (p = 0.03) were associated with both. Hypertension was inversely related to hyperkalemia (p < 0.01); age was inversely related to hypokalemia. Associations with mortality were significant for Chagas (p < 0.01, e-value 2.16), stroke (p < 0.01, e-value 1.85), hypokalemia (p = 0.02, e-value 1.94), severe hyperkalemia (p = 0.08, e-value 1.93), and CKD (p < 0.01, e-value > 1.63). Decompensated HF or cardiogenic shock was the cause of death in 54% of patients with normokalemia, 67.8% with hypokalemia, 44.9% with mild hyperkalemia, 57.8% with moderate hyperkalemia, and 69% with severe hyperkalemia. Most patients with hypokalemia and severe hyperkalemia died from decompensated HF (p = 0.007). Data suggest hypokalemia and severe hyperkalemia, along with Chagas and CKD, are associated with death. Unexpectedly, progressive HF was the most frequent mode of death rather than arrhythmias. Further studies are needed to confirm these findings and explore the underlying mechanisms.

Pain Outcomes Among Medical Centers With High vs Low Specialist Palliative Care Reach Among People With Heart Failure.

Background: Pain affects more than 60% of people with heart failure (HF), with increasing frequency and severity towards the end of life (EOL). We examined if family-rated pain near EOL was associated with rates of specialist palliative care (SPC) among patients with HF. Methods: We conducted a retrospective cohort study among 1095 decedents with advanced HF (aHF = ≥2 hospitalizations) from 83 Veterans Affairs Medical Centers (VAMCs) between 2018-2020. We used multilevel logistic regression to derive facility rates of predicted SPC for each VAMC adjusting for demographic and clinical characteristics. We examined associations between VAMCs in the top 20% (vs bottom 80%) of SPC rates and family-reported pain at the EOL from the Bereaved Family Survey and the interaction between receiving SPC and VAMC-level SPC rates on study outcomes. Analyses were conducted using generalized linear models, adjusting for demographic, clinical, and facility covariates. Results: The sample was 98% male, 73% White, and 20% Black, with a mean age of 79.7+/-10.3years. Over 77% of the sample had uncontrolled pain at the EOL. In adjusted models, there was no association between family-reported pain and VAMC rates of SPC (Odds Ratio = 1.082, 95% Confidence Interval = 0.706-1.659). Receipt of SPC did not change this relationship (p-interaction = .405). Conclusion: Families of people with aHF cared for in VAMCs with high rates of SPC were as likely to report uncontrolled pain relative to people cared for in VAMCs with lower SPC rates. Research is needed to identify delivery and organizational features associated with improved pain control at the EOL among this symptomatic population.

Effect of traditional Chinese medicine on cardiovascular death and all-cause death among patients with heart failure and/or atrial fibrillation.

We tried to define the association of adverse cardiovascular (CV) events, such as CV death and all-cause death among patients with heart failure (HF) and/or atrial fibrillation (AF) receiving traditional Chinese medicine (TCM) or not. We used data from the Taiwan National Health Insurance Research Database in a retrospective cohort study using propensity scoring (PS) matching. We matched 54,859 and 18,307 patients each to the treatment vs. non-treatment group and found a significantly decreased risk of adverse CV events after PS score matching, suggesting that TCM reduces the risk of these adverse outcomes. Compared to HF patients without AF in non-TCM user, HF patients without AF in TCM user and HF patients with AF in TCM user had decreased risk of CV death by 0.50 times (95% CI 0.49, 0.52) and 0.84 times (95% CI 0.49,0.52), respectively. HF patients without AF in TCM user and HF patients with AF in TCM user had decreased risk of all-cause death relative to HF patients without AF in non-TCM user by 0.53 times (95% CI 0.52, 0.54) and 0.74 times (95% CI 0.72,0.76), respectively. The results said that there is significant reduction of decrease in risk of CV death and all death among the patients receiving TCM, especially those without AF.

Autoimmune-Like Mechanism in Heart Failure Enables Preventive Vaccine Therapy.

Heart failure (HF) is strongly associated with inflammation. In pressure overload (PO)-induced HF, cardiac stress triggers adaptive immunity, ablation, or inhibition, which blocks disease progression. We hypothesized that PO-HF might fulfill the often-used criteria of autoimmunity: if so, the associated adaptive immune response would be not only necessary but also sufficient to induce HF; it should also be possible to identify self-antigens driving the autoimmune response. Finally, we hypothesized that such an antigen-specific response can be manipulated to preventively reduce the severity of PO-HF in a tolerizing vaccine. We used the transfer of lymphocytes or serum from PO-HF mice into healthy recipients to assess whether the adaptive response is sufficient to induce disease. We devised a novel pipeline to identify self-antigens driving the response. We immunized healthy mice with novel antigens to assess whether they induce disease. To determine whether these antigens could be present in human patients, we sought to detect existing responses against these antigens in patients with HF. Finally, we used the antigens in an oral tolerance protocol to preventively protect mice from subsequently induced PO-HF, analyzing the results with next-generation sequencing. We found that PO-HF fulfills the criteria of an autoimmune disease, albeit partially, and identified novel cardiac self-antigens, capable of inducing cardiac dysfunction. The novel antigens in a tolerizing vaccine formulation preemptively reduced the severity of disease triggered by subsequent application of PO, via induction of effector regulatory T cells, enabling a potent reduction of PO-driven loss of systolic function, cardiac inflammation, and proinflammatory CD4+ T-cell clonal expansion. We demonstrate that PO-HF is triggered by hemodynamic stress and then sets off an autoimmune-like response against cardiac self-antigens. The antigens can be used to reduce the severity of future-onset disease, via oral tolerization, effectively acting as a protective vaccine.

Identifying Patients with Heart Failure Eligible for Guideline-Directed Medical Therapy.

A majority of patients with heart failure (HF) do not receive adequate medical therapy as recommended by clinical guidelines. One major obstacle encountered by population health management (PHM) programs to improve medication usage is the substantial burden placed on clinical staff who must manually sift through electronic health records (EHRs) to ascertain patients' eligibility for the guidelines. As a potential solution, the study team developed a rule-based system (RBS) that automatically parses the EHR for identifying patients with HF who may be eligible for guideline-directed therapy. The RBS was deployed to streamline a PHM program at Brigham and Women's Hospital wherein the RBS was executed every other month to identify potentially eligible patients for further screening by the program staff. The study team evaluated the performance of the system and performed an error analysis to identify areas for improving the system. Of approximately 161,000 patients who have an echocardiogram in the health system, each execution of the RBS typically identified around 4200 patients. A total 5460 patients were manually screened, of which 1754 were found to be truly eligible with an accuracy of 32.1%. An analysis of the false-positive cases showed that over 38% of the false positives were due to incorrect determination of symptomatic HF and medication history of the patients. The system's performance can be potentially improved by integrating information from clinical notes. The RBS provided a systematic way to narrow down the patient population to a subset that is enriched for eligible patients. However, there is a need to further optimize the system by integrating processing of clinical notes. This study highlights the practical challenges of implementing automated tools to facilitate guideline-directed care.

Strategies to reduce 28-day mortality in adult patients with bacteremia in the emergency department

BackgroundBacteremia, a common emergency department presentation, has a high burden of mortality, cost and morbidity. We aimed to identify areas for potential improvement in emergency department bacteremia management.MethodsThis retrospective cohort study included adults with bacteremia in an emergency department in 2019 and 2022. The primary outcome was 28-day mortality. Descriptive analyses evaluated demographics, comorbidities and clinical characteristics. Univariate and multivariate analyses identified mortality predictors.ResultsOverall, 433 patients were included [217 males (50.1%), mean ± SD age: 74.1 ± 15.2 years]. The 28-day mortality rate was 15.2% (n = 66). In univariate analysis, age ≥ 70 years, arrival by ambulance, arrhythmia, congestive heart failure, recent steroid use, hypotension (< 90/60 mmHg), mechanical ventilation, cardiac arrest, intensive care unit (ICU) admission, intravenous antibiotics, pneumonia as bacteremia source, non-urinary tract infections, no infectious disease consultation, no antibiotic adjustment and no control blood cultures were significantly associated with 28-day mortality (p < 0.05). Malignancy showed a statistical trend (0.05 < p < 0.15). The above-stated sixteen variables, identified in univariate analysis, were assessed via multivariate analysis. Primarily, clinical relevance and, secondarily, statistical significance were used for multivariate model creation to prioritize pertinent variables. Five risk factors, significantly associated with mortality (p < 0.05), were included in the model: ICU admission [adjusted OR (95% CI): 6.03 (3.08–11.81)], pneumonia as bacteremia source [4.94 (2.62–9.32)], age ≥ 70 [3.16 (1.39–7.17)], hypotension [2.12 (1.02–4.40)], and no infectious disease consultation [2.02 (1.08–3.78)]). Surprisingly, initial antibiotic administration within 6 h, inappropriate initial antibiotic regimen and type of bacteria (Gram-negative, Gram-positive) were non-significant (p > 0.05).ConclusionsWe identified significant mortality predictors among emergency department patients presenting with bacteremia. Referral to an infectious disease physician is the only modifiable strategy to decrease 28-day mortality with long-term effect and should be prioritized.

Preoperative risk factors for venous thromboembolism in major urologic cancer surgeries.

Venous thromboembolism (VTE) is a serious complication of urologic cancer surgeries. Incidence varies by procedure, with cystectomy carrying the highest risk. Our study aims to explore the preoperative risk factors for VTE development in major urologic cancer surgeries. Using the ACS-NSQIP database, cystectomy, prostatectomy or nephrectomy cases between 2011 and 2020 were identified. Patient characteristics and pre-operative variables were compared using χ2 test. Multivariate logistic regression was used to control for confounding variables. 207,861 patients were included. 2484 (1.2%) patients experienced VTE post-operatively, with a rate of 3.16% among cystectomy patients. The incidence of pulmonary embolism (PE) peaked at day 2, while that of deep venous thrombosis (DVT) peaked at days 2 and 8. On multivariate analysis, blood transfusion and cystectomy were associated with the highest risk of VTE (OR = 2.29 [1.64, 3.18], P = < 0.001 and OR = 2.96, 95%CI [2.62, 3.37], P < 0.0001; respectively). Other important risk factors included advanced age ≥ 80 years (OR = 1.98 [1.65, 2.40], P = 0.001), BMI ≥ 40kg/m2 (OR = 1.82 [1.43, 2.24], P = 0.001), congestive heart failure (OR = 1.75 [1.15, 2.66], P = 0.008), steroid use (OR = 1.55 [1.26, 1.94], P = < 0.001), thrombocytosis OR = 1.43 [1.16, 1.76], P = 0.001) and leukocytosis (OR = 1.41 [1.11, 1.54], P = < 0.001). Our study highlights important pre-operative risk factors for the development of VTE after urologic cancer surgeries. This stresses the importance of pre-operative risk assessment to guide counseling and thromboprophylaxis strategies especially among cystectomy patients who are older, obese, and requiring blood transfusion.

The Role of Exosomes in Myocardial Ischemia-Reperfusion Injury.

Acute myocardial infarction (AMI) is one of the critical and serious diseases in the cardiovascular system, and reperfusion therapy is the preferred treatment for AMI, but it often worsens cardiac injury and leads to myocardial ischemia reperfusion injury (MIRI), which can further result in arrhythmia, heart failure, and death. More and more studies have found that mesenchymal stem cells (MSCs)-derived exosomes play an important role in improving the cardiac injury after MIRI, and can exert anti-apoptosis, anti-inflammation, anti-fibrosis, and promotion of endothelial cells and angiogenesis functions. This review summarizes the mechanisms of action of exosomes in the treatment of MIRI and discusses exosomes as a new approach for the treatment of MIRI. 1) Exosomes play a variety of protective roles in MIRI by carrying miRNAs and other bioactive substances. 2) Exosomes can be used as carriers of drugs or active substances for the treatment of cardiovascular diseases.

Combination drug therapy in pulmonary hypertension: switch from selexipaq to intravenous trepostinil

A wide range of substances is currently available for the treatment of patients with pulmonary arterial hypertension. The current recommendations for initial drug therapy are based on the patient's risk profile. For patients at high risk, an initial triple combination therapy with different substances including prostanoids is recommended. The aim of the prospective, single-arm, unblinded study was to clarify whether PAH patients on triple therapy benefit from switching from selexipag to intravenous treprostinil. The primary endpoint was the achievement of a "low-risk" status after 6 (12) months. 27 PAH patients (45 (37; 61) years, 77.8% women) were included. At study entry they were assigned to low-risk (n=1), intermediate (n=12) or high-risk status (n=14). On average, 22 patients were followed for 8 (range 5-11) months. One patient was successfully transplanted after four months, another four patients died (in one case septic complications of unknown origin; in three cases progressive right heart failure). The primary endpoint (reaching "low-risk" status) was achieved in 12/21 (57.1%) patients (one further patient remained in "low-risk" status). These data indicate (despite the small number of patients) that even with established triple therapy, clinical improvement in individual patients is possible by switching from selexipag to intravenous treprostinil.

Mitral valve transcatheter edge-to-edge repair in the elderly-A safe and effective therapy.

Prevalence of mitral regurgitation (MR) and comorbidity burden rise with age. Mitral valve transcatheter edge-to-edge repair (M-TEER) is increasingly performed in elderly patients, but only limited data are available for this specific subgroup. In this study, outcomes of octogenarians and nonagenarians undergoing M-TEER were analysed using a large real-world dataset. This retrospective study included consecutive patients undergoing M-TEER at the Ulm University Heart Center between January 2010 and December 2021. The cohort was divided into an elderly group and a younger group based on the cohorts' median age. Group differences regarding 1 and 3year mortality and heart failure hospitalization rates were assessed using Kaplan-Meier survival analysis and Cox proportional hazard models. A total of 1118 patients [median age 79 (inter-quartile range 74-83) years; 42% female] were included and divided into 513 elderly (≥80years) and 605 younger (<80years) patients. Primary MR was more frequent in the elderly group (56% vs. 27%, P<0.001). Pre-procedural and post-procedural MR grades were comparable between groups (pre-procedural MR grade 4: 69% in the elderly group vs. 71% in the younger group, P=0.67; post-procedural MR grade 1: 60% in the elderly group vs. 58% in the younger group, P=0.77) as well as in-hospital mortality rates (0.2% vs. 0.3%, P=0.66). Three-year heart failure hospitalization rates did not differ significantly between both groups (30.7% in the older age cohort vs. 36.0% in the younger cohort, P=0.191). While 1year all-cause mortality rates were comparable (18% vs. 16.4%, P=0.577), 3year all-cause mortality was significantly higher in the elderly [43.1% vs. 33.0%; hazard ratio (HR) 1.29 (95% confidence interval 1.02-1.65), P=0.035]. Pre-procedural N-terminal pro-brain natriuretic peptide (NT-proBNP) ≥3402pg/mL [HR 2.29 (95% CI 1.34-3.90), P=0.002], pre-interventional MR grade [HR 1.79 (95% CI 1.01-3.17), P=0.045] and European System for Cardiac Operative Risk Evaluation (EuroSCORE) II [HR 1.06 (95% CI 1.03-1.08), P<0.001] were identified as independent predictors of 3year mortality in the elderly. M-TEER displays a safe and effective treatment option for elderly patients with symptomatic MR, offering symptom relief and comparable 1year outcomes to younger patients. Elderly patients with elevated EuroSCORE II and advanced heart failure might benefit from additional care to further reduce 3year mortality.

TRPC6 Channel Regulates Airway Remodeling in Chronic Obstructive Pulmonary Disease Causing Right Heart Failure.

The role of the canonical transient receptor potential 6 (TRPC6) channel in chronic obstructive pulmonary disease (COPD) remains poorly understood at the mechanistic level. Objects: This study aims to investigate the involvement of TRPC6 in COPD and its signaling mechanisms in human airway smooth muscle cells (HASMCs). Methods and Results: The study found that mRNA and protein expression of TRPC6 increased in cultured HASMCs that were incubated with nicotine, as measured by reverse transcription quantitative polymerase chain reaction and Western blot analysis. Nicotine treatment significantly enhanced TRPC6 transcriptional activity in HASMCs through nuclear factor (NF)-κB, as demonstrated by co-immunoprecipitation and electrophoretic mobility shift assays. Furthermore, miR-135a/b-5p was shown to downregulate TRPC6 expression in HASMCs at the mRNA and protein levels, as confirmed by luciferase reporter assays. Immunohistochemistry assays in a mouse model of cigarette-induced airway remodeling revealed a significant increase in smooth muscle (SM) cell proliferation and SM layer mass. Conclusion: These findings suggest that nicotine exposure increases HASMC proliferation and migration through NF-κB signaling, and that cigarette smoke inhalation causes airway SM layer remodeling via altered TRPC6-induced Ca2+ influx, which is abolished by miR-135a/b-5p both in vitro and invivo. Antioxid. Redox Signal. 00, 000-000.

T follicular helper cell is essential for M2 macrophage polarization and pulmonary vascular remodeling in hypoxia-induced pulmonary hypertension

BackgroundHypoxia-induced pulmonary hypertension (HPH) is a subgroup of type 3 pulmonary hypertension that may cause early right ventricular failure and eventual cardiac failure, which lacks potential therapeutic targets. Our previous research demonstrated that T follicular helper (TFH) cells that produce IL-21 were involved in HPH. However, the molecular mechanisms of TFH/IL-21-mediated pathogenesis of HPH have been elusive. Here we investigate the role of TFH cells and IL-21 in HPH.MethodsStudies were performed in C57BL/6 mice or IL-21 knockout mice exposed to chronic hypoxia to induce PH, and examined by hemodynamics. Molecular and cellular studies were performed in mouse lung and pulmonary arterial smooth muscle cells (PASMCs). M2 signature gene (Fizz1), M1 signature genes (iNos, IL-12β and MMP9), GC B cell and its marker GL-7, caspase-1, M2 macrophages, TFH cells, Bcl-6 and IL-21 level were measured. Proliferation rate of PASMCs was measured by EdU. Pyroptosis was assessed using Hoechst 33,342/PI double fluorescent staining.ResultsIn response to chronic hypoxia exposure-induced pulmonary hypertension, IL-21−/− mice or downregulation of TFH cells in WT mice developed blunted pulmonary hypertension, attenuated pulmonary vascular remodelling. Furthermore, chronic hypoxia exposure significantly increased the germinal center (GC) B cell responses, which were not present in IL-21−/− mice or downregulation of TFH cells in WT mice. Importantly, IL-21 promoted the polarization of primary alveolar macrophages toward the M2 phenotype. Consistently, significantly enhanced expression of M2 macrophage marker Fizz1 were detected in the bronchoalveolar lavage fluid of HPH mice. Moreover, alveolar macrophages that had been cultivated with IL-21 promoted PASMCs proliferation and pyroptosis in vitro, while a selective CX3CR1 antagonist, AZD8797 (AZD), significantly attenuated the proliferation and pyroptosis of the PASMCs. Finally, ECM1 knockdown promoted IL-2–STAT5 signaling and inhibited Bcl-6 signaling to inhibit TFH differentiation in HPH.ConclusionsTFH/IL-21 axis amplified pulmonary vascular remodelling in HPH. This involved M2 macrophage polarization, PASMCs proliferation and pyroptosis. These data suggested that TFH/IL-21 axis may be a novel therapeutic target for the treatment of HPH.