Regulation of the RhoA exchange factor GEF-H1 by profibrotic stimuli through a positive feedback loop involving RhoA, MRTF, and Sp1.

RhoA and its effectors, the transcriptional coactivators myocardin-related transcription factor (MRTF) and serum response factor (SRF), control epithelial phenotype and are indispensable for profibrotic epithelial reprogramming during fibrogenesis. Context-dependent control of RhoA and fibrosis-associated changes in its regulators, however, remain incompletely characterized. We previously identified the guanine nucleotide exchange factor GEF-H1 as a central mediator of RhoA activation in renal tubular cells exposed to inflammatory or fibrotic stimuli. Here we found that GEF-H1 expression and phosphorylation were strongly elevated in two animal models of fibrosis. In the Unilateral Ureteral Obstruction mouse kidney fibrosis model, GEF-H1 was upregulated predominantly in the tubular compartment. GEF-H1 was also elevated and phosphorylated in a rat pulmonary artery banding (PAB) model of right ventricular fibrosis. Prolonged stimulation of LLC-PK1 tubular cells with tumor necrosis factor (TNF)-α or transforming growth factor (TGF)-ß1 increased GEF-H1 expression and activated a luciferase-coupled GEF-H1 promoter. Knockdown and overexpression studies revealed that these effects were mediated by RhoA, cytoskeleton remodeling, and MRTF, indicative of a positive feedback cycle. Indeed, silencing endogenous GEF-H1 attenuated activation of the GEF-H1 promoter. Of importance, inhibition of MRTF using CCG-1423 prevented GEF-H1 upregulation in both animal models. MRTF-dependent increase in GEF-H1 was prevented by inhibition of the transcription factor Sp1, and mutating putative Sp1 binding sites in the GEF-H1 promoter eliminated its MRTF-dependent activation. As the GEF-H1/RhoA axis is key for fibrogenesis, this novel MRTF/Sp1-dependent regulation of GEF-H1 abundance represents a potential target for reducing renal and cardiac fibrosis.NEW & NOTEWORTHY We show that expression of the RhoA regulator GEF-H1 is upregulated in tubular cells exposed to fibrogenic cytokines and in animal models of kidney and heart fibrosis. We identify a pathway wherein GEF-H1/RhoA-dependent MRTF activation through its noncanonical partner Sp1 upregulates GEF-H1. Our data reveal the existence of a positive feedback cycle that enhances Rho signaling through control of both GEF-H1 activation and expression. This feedback loop may play an important role in organ fibrosis.

Endothelial progenitor cells for diabetic cardiac and kidney disease.

The management of diabetes mellitus and its resultant end organ dysfunction represents a major challenge to global health-care systems. Diabetic cardiac and kidney disease commonly co-occur and are significant contributors to the morbidity and mortality of patients with diabetes, carrying a poor prognosis. The tight link of these parallel end organ manifestations suggests a deeper common underlying pathology. Here, we outline the mechanistic link between diabetic cardiac and kidney disease, providing evidence for the role of endothelial dysfunction in both processes and the potential for cellular therapy to correct these disorders. Specifically, we review the preclinical and clinical evidence for endothelial progenitor cell therapy in cardiac, kidney, and cardio-renal disease applications. Finally, we outline novel approaches to endothelial progenitor cell therapy through cell enhancement and the use of extracellular vesicles, discussing published and future work.

Prediction of Mortality and Heart Failure Hospitalization After Transcatheter Tricuspid Valve Interventions: Validation of TRISCORE.

BACKGROUND: Data on the prognostic role of the TRI-SCORE in patients undergoing transcatheter tricuspid valve intervention (TTVI) are limited. OBJECTIVES: The aim of this study was to evaluate the performance of the TRI-SCORE in predicting outcomes of patients undergoing TTVI. METHODS: TriValve (Transcatheter Tricuspid Valve Therapies) is a large multicenter multinational registry including patients undergoing TTVI. The TRI-SCORE is a risk model recently proposed to predict in-hospital mortality after tricuspid valve surgery. The TriValve population was stratified based on the TRI-SCORE tertiles. The outcomes of interest were all-cause death and all-cause death or heart failure hospitalization. Procedural complications and changes in NYHA functional class were also reported. RESULTS: Among the 634 patients included, 223 patients (35.2%) had a TRI-SCORE between 0 and 5, 221 (34.8%) had 6 or 7, and 190 (30%) had ≥8 points. Postprocedural blood transfusion, acute kidney injury, new atrial fibrillation, and in-hospital mortality were more frequent in the highest TRI-SCORE tertile. Postprocedure length of stay increased with a TRI-SCORE increase. A TRI-SCORE ≥8 was associated with an increased risk of 30-day all-cause mortality and all-cause mortality and the composite endpoint assessed at a median follow-up of 186 days (OR: 3.00; 95% CI: 1.38-6.55; HR: 2.17; 95% CI: 1.78-4.13; HR: 2.08, 95% CI: 1.57-2.74, respectively) even after adjustment for procedural success and EuroSCORE II or Society of Thoracic Surgeons Predicted Risk of Mortality. The NYHA functional class improved across all TRI-SCORE values. CONCLUSIONS: In the TriValve registry, the TRI-SCORE has a suboptimal performance in predicting clinical outcomes. However, a TRISCORE ≥8 is associated with an increased risk of clinical events and a lack of prognostic benefit after successful TTVI.

Tissue mapping by cardiac magnetic resonance imaging for the prognostication of cardiac amyloidosis: A systematic review and meta-analysis.

BACKGROUND: Cardiac amyloidosis is increasingly recognized as a significant contributor to cardiovascular morbidity and mortality. With the emergence of novel therapies, there is a growing interest in prognostication of patients with cardiac amyloidosis using cardiac magnetic resonance imaging (CMR). In this systematic review and meta-analysis, we aimed to examine the prognostic significance of myocardial native T1 and T2, and extracellular volume (ECV). METHODS: Observational cohort studies or single arms of clinical trials were eligible. MEDLINE, EMBASE and CENTRAL were systematically searched from their respective dates of inception to January 2023. No exclusions were made based on date of publication, study outcomes, or study language. The study populations composed of adult patients (≥18 years old) with amyloid cardiomyopathy. All studies included the use of CMR with and without intravenous gadolinium contrast administration to assess myocardial native T1 mapping, T2 mapping, and ECV in association with the pre-specified primary outcome of all-cause mortality. Data were extracted from eligible primary studies by two independent reviewers and pooled via the inverse variance method using random effects models for meta-analysis. RESULTS: A total of 3852 citations were reviewed. A final nine studies including a total of 955 patients (mean age 65 ± 10 years old, 32% female, mean left ventricular ejection fraction (LVEF) 59 ± 12% and 24% had NYHA class III or IV symptoms) with cardiac amyloidosis [light chain amyloidosis (AL) 50%, transthyretin amyloidosis (ATTR) 49%, other 1%] were eligible for inclusion and suitable for data extraction. All included studies were single centered (seven with 1.5 T MRI scanners, two with 3.0 T MRI scanners) and non-randomized in design, with follow-up spanning from 8 to 64 months (median follow-up = 25 months); 320 patients died during follow-up, rendering a weighted mortality rate of 33% across studies. Compared with patients with AL amyloid, patients with ATTR amyloid had significantly higher mean left ventricular mass index (LVMi) (102 ± 34 g/m2 vs 127 ± 37 g/m2, p = 0.02). N-terminal pro-brain natriuretic peptide (NT-proBNP), troponin T levels, mean native T1 values, ECV and T2 values did not differ between patients with ATTR amyloid and AL amyloid (all p > 0.25). Overall, the hazard ratios for mortality were 1.33 (95% CI = [1.10, 1.60]; p = 0.003; I2 = 29%) for every 60 ms higher T1 time, 1.16 (95% CI = [1.09, 1.23], p < 0.0001; I2 = 76%) for every 3% higher ECV, and 5.23 (95% CI = [2.27, 12.02]; p < 0.0001; I2 = 0%) for myocardial-to-skeletal T2 ratio below the mean (vs above the mean). CONCLUSION: Higher native T1 time and ECV, and lower myocardial to skeletal T2 ratio, on CMR are associated with worse mortality in patients with cardiac amyloidosis. Therefore, tissue mapping using CMR may offer a useful non-invasive technique to monitor disease progression and determine prognosis in patients with cardiac amyloidosis.

Relationship between saxagliptin use and left ventricular diastolic function assessed by cardiac MRI.

AIMS: Type 2 diabetes mellitus (T2DM) increases the risk of major cardiovascular events. In SAVOR-TIMI53 trial, the excess heart failure (HF) hospitalization among patients with T2DM in the saxagliptin group remains poorly understood. Our aim was to evaluate left ventricular (LV) diastolic function after 6 months of saxagliptin treatment using cardiac magnetic resonance imaging (CMR) in patients with T2DM. METHODS: In this prospective study, 16 T2DM patients without HF were prescribed saxagliptin as part of routine guideline-directed management. CMR performed at baseline and 6 months after initiation of saxagliptin treatment were evaluated in a blinded fashion. We assessed LV diastolic function by measuring LV peak filling rate with correction for end-diastolic volume (PFR/LVEDV), time to peak filling rate with correction for cardiac cycle (TPF/RR), and early diastolic strain rate parameters [global longitudinal diastolic strain rate (GLSR-E), global circumferential diastolic strain rate (GCSR-E)] by feature tracking (FT-CMR). RESULTS: Among the 16 patients (mean age of 59.9, 69% males, mean hemoglobin A1c 8.3%, mean left ventricular ejection fraction 57%), mean PFR was 314 ± 108 ml/s at baseline and did not change over 6 months (- 2.7, 95% CI - 35.6, 30.2, p = 0.86). There were also no significant changes in other diastolic parameters including PFR/EDV, TPF, TPF/RR, and GLSR-E and GCSR-E (all p > 0.50). CONCLUSION: In T2DM patients without HF receiving saxagliptin over 6 months, there were no significant subclinical changes in LV diastolic function as assessed by CMR.

Adherence to oral hormonal therapy in advanced prostate cancer: a scoping review.

Background: Orally administrated agents play a key role in the management of prostate cancer, providing a convenient and cost-effective treatment option for patients. However, they are also associated with adherence issues which can compromise therapeutic outcomes. This scoping review identifies and summarizes data on adherence to oral hormonal therapy in advanced prostate cancer and discusses associated factors and strategies for improving adherence. Methods: PubMed (inception to 27 January 2022) and conference databases (2020-2021) were searched to identify English language reports of real-world and clinical trial data on adherence to oral hormonal therapy in prostate cancer using the key search terms 'prostate cancer' AND 'adherence' AND 'oral therapy' OR respective aliases. Results: Most adherence outcome data were based on the use of androgen receptor pathway inhibitors in metastatic castration-resistant prostate cancer (mCRPC). Self-reported and observer-reported adherence data were used. The most common observer-reported measure, medication possession ratio, showed that the vast majority of patients were in possession of their medication, although proportion of days covered and persistence rates were considerably lower, raising the question whether patients were consistently receiving their treatment. Study follow-up for adherence was generally around 6 months up to 1 year. Studies also indicate that persistence may drop further with longer follow-up, especially in the non-mCRPC setting, which may be a concern when years of therapy are required. Conclusions: Oral hormonal therapy plays an important role in the treatment of advanced prostate cancer. Data on adherence to oral hormonal therapies in prostate cancer were generally of low quality, with high heterogeneity and inconsistent reporting across studies. Short study follow-up for adherence and focus on medication possession rates may further limit relevance of available data, especially in settings that require long-term treatment. Additional research is required to comprehensively assess adherence.

Statins to prevent early cardiac dysfunction in cancer patients at increased cardiotoxicity risk receiving anthracyclines.

BACKGROUND AND AIMS: Anthracyclines can cause cancer therapy-related cardiac dysfunction (CTRCD). We aimed to assess whether statins prevent decline in left ventricular ejection fraction (LVEF) in anthracycline-treated patients at increased risk for CTRCD. METHODS: In this multicenter double-blinded, placebo-controlled trial, patients with cancer at increased risk of anthracycline-related CTRCD (per ASCO guidelines) were randomly assigned to atorvastatin 40 mg or placebo once-daily. Cardiovascular magnetic resonance (CMR) imaging was performed before and within 4 weeks after anthracyclines. Blood biomarkers were measured at every cycle. The primary outcome was post-anthracycline LVEF, adjusted for baseline. CTRCD was defined as a fall in LVEF by >10% to <53%. Secondary endpoints included left ventricular (LV) volumes, CTRCD, CMR tissue characterization, high sensitivity troponin I (hsTnI), and B-type natriuretic peptide (BNP). RESULTS: We randomized 112 patients (56.9 ± 13.6 years, 87 female, and 73 with breast cancer): 54 to atorvastatin and 58 to placebo. Post-anthracycline CMR was performed 22 (13-27) days from last anthracycline dose. Post-anthracycline LVEF did not differ between the atorvastatin and placebo groups (57.3 ± 5.8% and 55.9 ± 7.4%, respectively) when adjusted for baseline LVEF (P = 0.34). There were no significant between-group differences in post-anthracycline LV end-diastolic (P = 0.20) or end-systolic volume (P = 0.12), CMR myocardial edema and/or fibrosis (P = 0.06-0.47), or peak hsTnI (P ≥ 0.99) and BNP (P = 0.23). CTRCD incidence was similar (4% versus 4%, P ≥ 0.99). There was no difference in adverse events. CONCLUSIONS: In patients at increased risk of CTRCD, primary prevention with atorvastatin during anthracycline therapy did not ameliorate early LVEF decline, LV remodeling, CTRCD, change in serum cardiac biomarkers, or CMR myocardial tissue changes. TRIAL REGISTRATION: NCT03186404.

Is there a role for biomarkers in asymptomatic severe chronic primary mitral regurgitation?

PURPOSE OF REVIEW: Chronic primary mitral regurgitation (MR) is a common heart valve disease with a rising prevalence with the aging populations worldwide. The timing of surgical intervention in patients who have severe MR but remain asymptomatic is often debated. Herein we synthesize the latest American College of Cardiology/American Heart Association (ACC/AHA) and European Society of Cardiology/ European Association for Cardio-Thoracic Surgery (ESC/EACTS) heart valve guidelines in such patients and illustrate how circulating and/or imaging biomarkers can be used to help refine decision making algorithms. RECENT FINDINGS: The approach to decision making and strength of guideline recommendations in patients with asymptomatic stage C1 (left ventricular ejection fraction [LVEF] > 60% and left ventricular end systolic dimension [LVESD] < 40 mm) and stage C2 disease (LVEF ≤ 60% and/or LVESD ≥ 40 mm) are reviewed. While surgical intervention is clearly indicated in patients with stage C2 disease, a multifaceted approach that integrates repairability, expertise, sub-clinical evidence of left ventricular (LV) dysfunction, and patient preferences is required to identify the optimal approach to surveillance vs. surgery. The role of imaging (3D echocardiography, contrast echocardiography, left ventricular global longitudinal strain, and cardiovascular magnetic resonance imaging [CMR]) and circulating (natriuretic peptides) biomarkers in decision making is also reviewed. SUMMARY: The decision making around timing of intervention in chronic primary MR requires a personalized approach that is based on accurate assessments of severity of MR, LV dimensions, LV function, valve morphology/repairability, surgeon and center expertise, and patient wishes. Biomarkers hold promise in refining decision making.

Risk Factors for Postrepair Elevated Mitral Gradient: A Post-hoc Analysis of a Randomized Trial.

BACKGROUND: Predischarge elevated mean mitral gradients (>5 mm Hg) may occur after repair for degenerative mitral regurgitation. We sought to identify risk factors associated with elevated gradients and to evaluate its impact on functional outcomes at 12 months in this subanalysis of the Canadian Mitral Research Alliance CardioLink-2 trial. METHODS: One hundred four patients with degenerative mitral regurgitation undergoing mitral repair were randomized to either a leaflet resection or preservation strategy. Logistic regression was used to identify risk factors associated with an elevated gradient. Functional outcomes at 12 months were compared between participants with and without elevated gradients. RESULTS: Elevated gradients was identified in 15 participants (14.4%), which was not significantly different based on allocation to each repair strategy (P = .10). Patients with elevated gradients were more likely to be women (odds ratio [OR], 4.28; 95% confidence interval [CI], 1.29-14.19; P = .02) and to have a lower preoperative hemoglobin level (OR, 0.93; 95% CI, 0.89-0.98; P = .01) and smaller intercommissural diameter (OR, 0.86; 95% CI, 0.76-0.97; P = .02) and mitral annuloplasty size (OR, 0.71; 95% CI, 0.57-0.87; P = .001). The ratio of intercommissural diameter-to-annuloplasty size was similar between those with and without elevated gradients (both 0.8 ± 0.1, P = .69). At 12 months those with elevated gradients had a worse New York Heart Association functional status (P = .0001), lower peak oxygen saturation in exercise test (P = .01), smaller body weight-walk distance product (P = .02), and higher Borg scale (P = .01) in the 6-minute walk test. CONCLUSIONS: Female gender, smaller mitral anatomy sizes, and lower preoperative hemoglobin levels were associated with postoperative elevated mitral gradients, which was in turn were associated with reduced functional status. Further research is warranted to investigate these potential risk factors.

Mitral repair with leaflet preservation versus leaflet resection and ventricular reverse remodeling from a randomized trial.

OBJECTIVES: In the Canadian Mitral Research Alliance (CAMRA) Trial CardioLink-2 leaflet resection versus preservation techniques for posterior leaflet prolapse was investigated and no difference was shown in their effect on mean mitral gradient at peak exercise at 12 months postoperatively. The purpose of this subanalysis was to evaluate the effect of the 2 strategies on left ventricular (LV) reverse remodeling after repair. METHODS: A total of 104 patients were randomized to either a leaflet resection or leaflet preservation strategy. Echocardiograms, performed at baseline (preoperative), predischarge, and 12 months postoperatively, were analyzed in a blinded fashion at a core laboratory. RESULTS: All patients underwent successful mitral repair. At discharge, 3 patients showed moderate mitral regurgitation, whereas the remainder showed mild or less regurgitation. Compared with the baseline echocardiogram, the indexed end diastolic volume was reduced at the discharge echocardiogram (P < .0001) and was further reduced at the 12-month echocardiogram (P = .01). In contrast, the indexed end systolic volume did not significantly change from baseline assessed at the predischarge echocardiogram (P = .32) but improved at 12 months postoperatively (P < .0001), resulting in a corresponding improvement in ejection fraction at 12 months (P < .0001). The type of mitral repair strategy had no significant effect on LV reverse remodeling trends. CONCLUSIONS: The mitral repair strategies used did not influence postoperative LV reverse remodeling, which occurred in stages. Although LV end diastolic dimensions recovered before discharge, improvements in LV end systolic dimension were evident 12 months after repair.

Restoring myocardial infarction-induced long-term memory impairment by targeting the cystic fibrosis transmembrane regulator.

BACKGROUND: Cognitive impairment is a serious comorbidity in heart failure patients, but effective therapies are lacking. We investigated the mechanisms that alter hippocampal neurons following myocardial infarction (MI). METHODS: MI was induced in male C57Bl/6 mice by left anterior descending coronary artery ligation. We utilised standard procedures to measure cystic fibrosis transmembrane regulator (CFTR) protein levels, inflammatory mediator expression, neuronal structure, and hippocampal memory. Using in vitro and in vivo approaches, we assessed the role of neuroinflammation in hippocampal neuron degradation and the therapeutic potential of CFTR correction as an intervention. FINDINGS: Hippocampal dendrite length and spine density are reduced after MI, effects that associate with decreased neuronal CFTR expression and concomitant microglia activation and inflammatory cytokine expression. Conditioned medium from lipopolysaccharide-stimulated microglia (LCM) reduces neuronal cell CFTR protein expression and the mRNA expression of the synaptic regulator post-synaptic density protein 95 (PSD-95) in vitro. Blocking CFTR activity also down-regulates PSD-95 in neurons, indicating a relationship between CFTR expression and neuronal health. Pharmacologically correcting CFTR expression in vitro rescues the LCM-mediated down-regulation of PSD-95. In vivo, pharmacologically increasing hippocampal neuron CFTR expression improves MI-associated alterations in neuronal arborisation, spine density, and memory function, with a wide therapeutic time window. INTERPRETATION: Our results indicate that CFTR therapeutics improve inflammation-induced alterations in hippocampal neuronal structure and attenuate memory dysfunction following MI. FUNDING: Knut and Alice Wallenberg Foundation [F 2015/2112]; Swedish Research Council [VR; 2017-01243]; the German Research Foundation [DFG; ME 4667/2-1]; Hjärnfonden [FO2021-0112]; The Crafoord Foundation; Åke Wibergs Stiftelse [M19-0380], NMMP 2021 [V2021-2102]; the Albert Påhlsson Research Foundation; STINT [MG19-8469], Lund University; Canadian Institutes of Health Research [PJT-153269] and a Heart and Stroke Foundation of Ontario Mid-Career Investigator Award.

The SGLT2i Dapagliflozin Reduces RV Mass Independent of Changes in RV Pressure Induced by Pulmonary Artery Banding.

BACKGROUND: Sodium glucose linked transporter 2 (SGLT2) inhibition not only reduces morbidity and mortality in patients with diagnosed heart failure but also prevents the development of heart failure hospitalization in those at risk. While studies to date have focused on the role of SGLT2 inhibition in left ventricular failure, whether this drug class is efficacious in the treatment and prevention of right heart failure has not been explored. HYPOTHESIS: We hypothesized that SGLT2 inhibition would reduce the structural, functional, and molecular responses to pressure overload of the right ventricle. METHODS: Thirteen-week-old Fischer F344 rats underwent pulmonary artery banding (PAB) or sham surgery prior to being randomized to receive either the SGLT2 inhibitor: dapagliflozin (0.5 mg/kg/day) or vehicle by oral gavage. After 6 weeks of treatment, animals underwent transthoracic echocardiography and invasive hemodynamic studies. Animals were then terminated, and their hearts harvested for structural and molecular analyses. RESULTS: PAB induced features consistent with a compensatory response to increased right ventricular (RV) afterload with elevated mass, end systolic pressure, collagen content, and alteration in calcium handling protein expression (all p < 0.05 when compared to sham + vehicle). Dapagliflozin reduced RV mass, including both wet and dry weight as well as normalizing the protein expression of SERCA 2A, phospho-AMPK and LC3I/II ratio expression (all p < 0.05). SIGNIFICANCE: Dapagliflozin reduces the structural, functional, and molecular manifestations of right ventricular pressure overload. Whether amelioration of these early changes in the RV may ultimately lead to a reduction in RV failure remains to be determined.

Automated in vivo compound screening with zebrafish and the discovery and validation of PD 81,723 as a novel angiogenesis inhibitor.

Angiogenesis is a critical process in tumor progression. Inhibition of angiogenesis by blocking VEGF signaling can impair existing tumor vessels and halt tumor progression. However, the benefits are transient, and most patients who initially respond to these therapies develop resistance. Accordingly, there is a need for new anti-angiogenesis therapeutics to delay the processes of resistance or eliminate the resistive effects entirely. This manuscript presents the results of a screen of the National Institutes of Health Clinical Collections Libraries I & II (NIHCCLI&II) for novel angiogenesis inhibitors. The 727 compounds of the NIHCCLI&II library were screened with a high-throughput drug discovery platform (HTP) developed previously with angiogenesis-specific protocols utilizing zebrafish. The screen resulted in 14 hit compounds that were subsequently narrowed down to one, with PD 81,723 chosen as the lead compound. PD 81,723 was validated as an inhibitor of angiogenesis in vivo in zebrafish and in vitro in human umbilical vein endothelial cells (HUVECs). Zebrafish exposed to PD 81,723 exhibited several signs of a diminished endothelial network due to the inhibition of angiogenesis. Immunochemical analysis did not reveal any significant apoptotic or mitotic activity in the zebrafish. Assays with cultured HUVECs elucidated the ability of PD 81,723 to inhibit capillary tube formation, migration, and proliferation of endothelial cells. In addition, PD 81,723 did not induce apoptosis while significantly down regulating p21, AKT, VEGFR-2, p-VEGFR-2, eNOS, and p-eNOS, with no notable change in endogenous VEGF-A in cultured HUVECs.

Stage-based approach to predict left ventricular reverse remodeling after mitral repair.

BACKGROUND: Although predictors of reverse left ventricular (LV) remodeling postmitral valve repair are critical for guiding perioperative decision-making, there remains a paucity of randomized, prospective data to support the criteria that potential predictor variables must meet. METHODS AND RESULTS: The CAMRA CardioLink-2 randomized trial allocated 104 patients to either leaflet resection or preservation strategies for mitral repair. The correlation of indexed left ventricular end-systolic volume (LVESVI), indexed left ventricular end-diastolic volume (LVEDVI), and left ventricular ejection fraction (LVEF) were tested with univariate analysis and subsequently with multivariate analysis to determine independent predictors of reverse remodeling at discharge and at 12 months postoperatively. At discharge, both LVESVI and LVEDVI were independently associated with their preoperative values (p < .001 for both) and LVEF by preoperative LVESVI (p < .001). Mitral ring size was favorably associated with the change in LVESVI (p < .05) and LVEF (p < .01) from predischarge to 12 months, while the mean mitral valve gradient after repair was adversely associated with the change in LVESVI (p < .05) and LVEDVI (p < .05). No significant associations were found between reverse remodeling and coaptation height nor mitral repair technique. CONCLUSIONS: Beyond confirming the lack of impact of mitral repair technique on reverse remodeling, this investigation suggests that recommending surgery before significant LV dilatation or dysfunction, as well as higher postoperative mitral valve hemodynamic performance, may enhance remodeling capacity following mitral repair.

Optimizing Foundational Therapies in Patients With HFrEF: How Do We Translate These Findings Into Clinical Care?

Given the high risk of adverse outcomes in patients with heart failure and reduced ejection fraction (HFrEF), there is an urgent need for the initiation and titration of guideline-directed medical therapy (GDMT) that can reduce the risk of morbidity and mortality. Clinical practice guidelines are now emphasizing the need for early and rapid initiation of therapies that have cardiovascular benefit. Recognizing that there are many barriers to GDMT initiation and optimization, health care providers should aim to introduce the 4 pillars of quadruple therapy now recommended by most clinical practice guidelines: angiotensin receptor-neprilysin inhibitors, beta-blockers, mineralocorticoid receptor antagonists, and sodium-glucose co-transporter 2 inhibitors. A large proportion of patients with HFrEF do not have clinical contraindications to GDMT but are not treated with these therapies. Early initiation of low-dose combination therapy should be tolerated by most patients. However, patient-related factors such as hemodynamics, frailty, and laboratory values will need consideration for maximum tolerated GDMT. GDMT initiation in acute heart failure hospitalization represents another important avenue to improve use of GDMT. Finally, removal of therapies that do not have clear cardiovascular benefit should be considered to lower polypharmacy and reduce the risk of adverse side effects. Future prospective studies aimed at guiding optimal implementation of quadruple therapy are warranted to reduce morbidity and mortality in patients with HFrEF.

Dealing With the Epidemic of Endocarditis in People Who Inject Drugs.

North America is facing an opioid epidemic and growing illicit drug supply, contributing to growing numbers of injection drug use-related infective endocarditis (IDU-IE). Patients with IDU-IE have high early and late mortality. Patients with IDU-IE more commonly present with right-side IE compared with those with non-IDU IE, and a majority are a result of Streptococcus aureus. Although most patients can be successfully managed with intravenous antibiotic treatment, surgery is often required in part owing to high relapse rates, potential treatment biases, and more aggressive pathophysiology in some. Multidisciplinary management as endocarditis teams, including not only cardiologists and cardiac surgeons, but also infectious disease specialists, drug addiction experts, social workers, neurologists, and neurosurgeons, is essential to best manage substance use disorder and facilitate safe discharge to home and society. Structural and population-level interventions, such as harm-reduction programs, are necessary to reduce IDU-IE relapse rates in the community and other IDU-related health concerns, such as overdoses. In this review, we describe the pathophysiologic, clinical, surgical, social, and ethical characteristics of IDU-IE and their management. We present the most recent clinical guidelines for this condition and discuss existing gaps in knowledge to guide future research, practice changes, and policy interventions.

Repeated endo-tracheal tube disconnection generates pulmonary edema in a model of volume overload: an experimental study.

BACKGROUND: An abrupt lung deflation in rodents results in lung injury through vascular mechanisms. Ventilator disconnections during endo-tracheal suctioning in humans often cause cardio-respiratory instability. Whether repeated disconnections or lung deflations cause lung injury or oedema is not known and was tested here in a porcine large animal model. METHODS: Yorkshire pigs (~ 12 weeks) were studied in three series. First, we compared PEEP abruptly deflated from 26 cmH2O or from PEEP 5 cmH2O to zero. Second, pigs were randomly crossed over to receive rapid versus gradual PEEP removal from 20 cmH2O. Third, pigs with relative volume overload, were ventilated with PEEP 15 cmH2O and randomized to repeated ETT disconnections (15 s every 15 min) or no disconnection for 3 h. Hemodynamics, pulmonary variables were monitored, and lung histology and bronchoalveolar lavage studied. RESULTS: As compared to PEEP 5 cmH2O, abrupt deflation from PEEP 26 cmH2O increased PVR, lowered oxygenation, and increased lung wet-to-dry ratio. From PEEP 20 cmH2O, gradual versus abrupt deflation mitigated the changes in oxygenation and vascular resistance. From PEEP 15, repeated disconnections in presence of fluid loading led to reduced compliance, lower oxygenation, higher pulmonary artery pressure, higher lung wet-to-dry ratio, higher lung injury score and increased oedema on morphometry, compared to no disconnects. CONCLUSION: Single abrupt deflation from high PEEP, and repeated short deflations from moderate PEEP cause pulmonary oedema, impaired oxygenation, and increased PVR, in this large animal model, thus replicating our previous finding from rodents. Rapid deflation may thus be a clinically relevant cause of impaired lung function, which may be attenuated by gradual pressure release.

Pannexin 1: a novel regulator of acute hypoxic pulmonary vasoconstriction.

AIMS: Hypoxic pulmonary vasoconstriction (HPV) is a physiological response to alveolar hypoxia that diverts blood flow from poorly ventilated to better aerated lung areas to optimize ventilation-perfusion matching. Yet, the exact sensory and signalling mechanisms by which hypoxia triggers pulmonary vasoconstriction remain incompletely understood. Recently, ATP release via pannexin 1 (Panx1) and subsequent signalling via purinergic P2Y receptors has been identified as regulator of vasoconstriction in systemic arterioles. Here, we probed for the role of Panx1-mediated ATP release in HPV and chronic hypoxic pulmonary hypertension (PH). METHODS AND RESULTS: Pharmacological inhibition of Panx1 by probenecid, spironolactone, the Panx1 specific inhibitory peptide (10Panx1), and genetic deletion of Panx1 specifically in smooth muscle attenuated HPV in isolated perfused mouse lungs. In pulmonary artery smooth muscle cells (PASMCs), both spironolactone and 10Panx1 attenuated the increase in intracellular Ca2+ concentration ([Ca2+]i) in response to hypoxia. Yet, genetic deletion of Panx1 in either endothelial or smooth muscle cells did not prevent the development of PH in mice. Unexpectedly, ATP release in response to hypoxia was not detectable in PASMC, and inhibition of purinergic receptors or ATP degradation by ATPase failed to attenuate HPV. Rather, transient receptor potential vanilloid 4 (TRPV4) antagonism and Panx1 inhibition inhibited the hypoxia-induced [Ca2+]i increase in PASMC in an additive manner, suggesting that Panx1 regulates [Ca2+]i independently of the ATP-P2Y-TRPV4 pathway. In line with this notion, Panx1 overexpression increased the [Ca2+]i response to hypoxia in HeLa cells. CONCLUSION: In the present study, we identify Panx1 as novel regulator of HPV. Yet, the role of Panx1 in HPV was not attributable to ATP release and downstream signalling via P2Y receptors or TRPV4 activation, but relates to a role of Panx1 as direct or indirect modulator of the PASMC Ca2+ response to hypoxia. Panx1 did not affect the development of chronic hypoxic PH.

Empagliflozin Disrupts a Tnfrsf12a-Mediated Feed Forward Loop That Promotes Left Ventricular Hypertrophy.

PURPOSE: Although the cardioprotective benefits of sodium-glucose cotransporter 2 (SGLT2) inhibitors are now widely appreciated, the mechanisms underlying these benefits remain unresolved. Tumor necrosis factor receptor superfamily member 12a (Tnfrsf12a) is a receptor for tumor necrosis factor superfamily member 12 (Tnfsf12). Tnfrsf12a is highly inducible and plays a key role in the development of cardiac hypertrophy and heart failure. Here we set out to determine if SGLT2 inhibition affects the Tnfsf12/Tnfrsf12a system in the stressed myocardium. METHODS: C57BL/6N mice that had undergone sham or transverse aortic constriction (TAC) surgery were treated with either the SGLT2 inhibitor empagliflozin (400 mg/kg diet; 60-65 mg/kg/day) or standard chow alone and were followed for 8 weeks. Tnfrsf12a expression in mouse hearts was assessed by in situ hybridization, qRT-PCR, and immunoblotting. RESULTS: Left ventricular (LV) mass, end-systolic volume, and end-diastolic volume were all increased in TAC mice and were significantly lower with empagliflozin. Myocyte hypertrophy and interstitial fibrosis in TAC hearts were similarly attenuated with empagliflozin. Tnfrsf12a expression was upregulated in mouse hearts following TAC surgery but not in the hearts of empagliflozin-treated mice. In cultured cardiomyocytes, Tnfrsf12a antagonism attenuated the increase in cardiomyocyte size that was induced by phenylephrine. CONCLUSION: Empagliflozin attenuates LV enlargement in mice with hypertrophic heart failure. This effect may be mediated, at least in part, by a reduction in loading conditions which limits upregulation of the inducible, proinflammatory, and prohypertrophic TNF superfamily receptor, Tnfrsf12a. Disruption of the Tnfsf12/Tnfrsf12a feed forward system may contribute to the cardioprotective benefits of SGLT2 inhibition.