Major Facilitator Superfamily Domain Containing 5 Inhibition Reduces Lipoprotein(a) Uptake and Calcification in Valvular Heart Disease.

BACKGROUND: High circulating levels of Lp(a) (lipoprotein[a]) increase the risk of atherosclerosis and calcific aortic valve disease, affecting millions of patients worldwide. Although atherosclerosis is commonly treated with low-density lipoprotein-targeting therapies, these do not reduce Lp(a) or risk of calcific aortic valve disease, which has no available drug therapies. Targeting Lp(a) production and catabolism may provide therapeutic benefit, but little is known about Lp(a) cellular uptake. METHODS: Here, unbiased ligand-receptor capture mass spectrometry was used to identify MFSD5 (major facilitator superfamily domain containing 5) as a novel receptor/cofactor involved in Lp(a) uptake. RESULTS: Reducing MFSD5 expression by a computationally identified small molecule or small interfering RNA suppressed Lp(a) uptake and calcification in primary human valvular endothelial and interstitial cells. MFSD5 variants were associated with aortic stenosis (P=0.027 after multiple hypothesis testing) with evidence suggestive of an interaction with plasma Lp(a) levels. CONCLUSIONS: MFSD5 knockdown suppressing human valvular cell Lp(a) uptake and calcification, along with meta-analysis of MFSD5 variants associating with aortic stenosis, supports further preclinical assessment of MFSD5 in cardiovascular diseases, the leading cause of death worldwide.

Pharmacokinetics of pimobendan after oral administration to dogs with myxomatous mitral valve disease.

BACKGROUND: Pimobendan is an important therapy for dogs with myxomatous mitral valve disease (MMVD). The pharmacokinetics are reported in healthy dogs but not in dogs with heart disease. HYPOTHESIS/OBJECTIVES: To determine if dog characteristics such as age, breed, body condition score, ACVIM stage of heart disease or biochemical laboratory value alter the pharmacokinetics of orally administered pimobendan and its metabolite in a cohort of dogs with naturally occurring MMVD. ANIMALS: Fifty-seven client-owned dogs with MMVD ACVIM Stage B2, C, or D and administered pimobendan to steady state blood concentrations. METHODS: Prospective, observational study. Samples were collected using a sparse-sampling protocol at specific intervals after administration of pimobendan. Plasma pimobendan and the active metabolite (O-desmethyl-pimobendan, ODMP) concentrations were determined via high-pressure liquid chromatography and fluorescence detection. Data was analyzed via a population pharmacokinetic approach and nonlinear mixed effects modeling (NLME). Numerous covariates were examined in the NLME model. RESULTS: The absorption and elimination half-lives (t1/2 ) were approximately 1.4 and 1 hour for pimobendan and 1.4 and 1.3 hours for ODMP, respectively. Pharmacokinetic parameters were highly variable, especially the values for pimobendan absorption and elimination rate, and absorption rate of ODMP with coefficients of variation of 147.84%, 64.51% and 64.49%, respectively. No covariate evaluated was a significant source of variability. CONCLUSIONS AND CLINICAL IMPORTANCE: The pharmacokinetic parameters were highly variable among this group of dogs with MMVD. The variability was not associated with the dog's age, body weight or condition score, stage of heart disease, dose, serum creatinine, or alkaline phosphatase.

Atrial Cardiomyopathy in Valvular Heart Disease: From Molecular Biology to Clinical Perspectives.

This review discusses the evolving topic of atrial cardiomyopathy concerning valvular heart disease. The pathogenesis of atrial cardiomyopathy involves multiple factors, such as valvular disease leading to atrial structural and functional remodeling due to pressure and volume overload. Atrial enlargement and dysfunction can trigger atrial tachyarrhythmia. The complex interaction between valvular disease and atrial cardiomyopathy creates a vicious cycle of aggravating atrial enlargement, dysfunction, and valvular disease severity. Furthermore, atrial remodeling and arrhythmia can predispose to atrial thrombus formation and stroke. The underlying pathomechanism of atrial myopathy involves molecular, cellular, and subcellular alterations resulting in chronic inflammation, atrial fibrosis, and electrophysiological changes. Atrial dysfunction has emerged as an essential determinant of outcomes in valvular disease and heart failure. Despite its predictive value, the detection of atrial fibrosis and dysfunction is challenging and is not included in the clinical routine. Transthoracic echocardiography and cardiac magnetic resonance imaging are the main diagnostic tools for atrial cardiomyopathy. Recently published data have revealed that both left atrial volumes and functional parameters are independent predictors of cardiovascular events in valvular disease. The integration of atrial function assessment in clinical practice might help in early cardiovascular risk estimation, promoting early therapeutic intervention in valvular disease.

Treatment outcome of patients with prosthetic stuck valves at the Cardiac Center of Ethiopia.

BACKGROUND: Prosthetic Valve Thrombosis (PVT) is rare but life threatening condition which requires urgent intervention. Patient treatment outcome is not well studied in resource limited settings and the current study aims to explore the treatment outcome of patients with PVT at the Cardiac Center of Ethiopia. METHODS: The study was conducted at the Cardiac Center of Ethiopia which provides heart valve surgery. All patients who were diagnosed and managed for PVT in the center during the period July 2017 to March 2022 were included in the study. Data were collected through chart abstraction by using a structured questionnaire. Data analysis was done using SPSS version 20.0 for windows software. RESULT: Eleven patients (13 episodes of stuck valve) with PVT were included in the study and nine of them were female. The median age was 28 years old (IQR 22.5-34.0) with the youngest and oldest patients being 18 and 46 years old respectively. All the patients had bi-leaflet prosthetic mechanical valves (10 at mitral valve, two at aortic and mitral and one at aortic positions). The median duration of valve replacement before having PVT was 36 months (IQR 5-72). All patients reported good adherence to anticoagulant therapy; yet only five had optimal INR value. Nine patients presented with failure symptoms. Eleven patients received thrombolytic therapy and nine of them responded to it. One patient operated for failed thrombolytic therapy. Two patients responded to heparinization and optimization of anticoagulant therapy. Of the ten patients who received streptokinase, two of them developed fever and one patient developed bleeding as a complication of the treatment. All the patients survived hospital discharge. CONCLUSION: Prosthetic valve thrombosis was accompanied by sub-optimal anticoagulant therapy. Most patients responded to medical therapy alone.

Thromboembolism and Major Bleeding in Patients with Atrial Fibrillation and EHRA Type 2 Valvular Heart Disease: The Jordan Atrial Fibrillation (JoFib) Study.

Aim: The risks of thromboembolism and major bleeding in atrial fibrillation (AF) patients were assessed according to the "Evaluated Heartvalves, Rheumatic or Artificial" (EHRA) classification. Additionally, the safety and efficacy of vitamin K antagonists (VKAs) and non-VKA oral anticoagulants (NOACs) were compared in AF patients with EHRA type 2 valvular heart disease (VHD) versus those with no VHD. Methods: AF patients enrolled in the "Jordan Atrial Fibrillation (JoFib)" study were followed up for thromboembolic events and major bleeding at 30, 180, and 365 days. Patients in the EHRA type 2 VHD and non-VHD groups were sub-grouped to compare different OACs. Results: 2020 AF patients were recruited. The thromboembolic risk was higher in EHRA type 2 VHD patients compared to non-VHD controls. Major bleeding also occurred at higher rates in EHRA type 2 patients. In addition, NOACs were more effective in preventing thromboembolic events than VKAs and non-anticoagulation in EHRA type 2 VHD patients. Furthermore, EHRA type 2 VHD patients taking rivaroxaban had significantly less thromboembolic risk than their non-anticoagulated counterparts. At the same time, apixaban and warfarin did not significantly lower the risk of thromboembolism compared to non-anticoagulation. Conclusion: AF patients with EHRA type 2 VHD are at significant risk of thromboembolism and major bleeding. Furthermore, NOACs were more effective than VKAs in preventing thromboembolic events in this group of patients without conferring an added risk of major bleeding. Moreover, rivaroxaban appears to be particularly efficacious.

Comparison of the Recent Updates to the ACC/AHA and ESC Guidelines for the Management of Valvular Heart Disease: Similarities and Differences.

PURPOSE OF REVIEW: There have been several advances in the diagnosis and management of valvular heart disease (VHD) over the last decade. These have been reflected in the latest European and North American guidelines, although both contain significant similarities and differences. In this review, we highlight the important overlaps and variations between the updated guidelines and their previous versions to help guide the general cardiologist. RECENT FINDINGS: There has been extensive revision on the use of percutaneous treatments, the indications for intervention in asymptomatic VHD, and perioperative bridging therapies. The updated guidelines provide new recommendations in many aspects of VHD; however, there remain significant gaps in the role of biomarkers in VHD and the long-term outcomes of novel oral anticoagulants (NOACs) and transcatheter therapies.

Long-term low-dose cabergoline usage: Another association with cardiac valvulopathy.

A 60-year-old patient, professor of physics, presented in 1999 with sudden-onset vitiligo associated with hyperprolactinemia and a prolactinoma. Fearful of potential surgical complications at the peak of his career, the patient declined surgery and opted for medical management with bromocriptine. The decreasing effectiveness of bromocriptine after 5 years required a switch to cabergoline. After a 15-year-course of cabergoline therapy with a cumulative dose of 572 mg, echocardiographic monitoring demonstrated aortic and mitral valve thickening and regurgitation. An additional 3 years of cabergoline treatment (cumulative dose: 649 mg) resulted in worsening valve thickening and regurgitation. It is well-recognized that such valvular changes may occur with high-dose cabergoline treatment. We report a case of mitral and aortic vavulopathy in a patient who was treated with long-term (18 years) low-dosage (.5-1 mg weekly) cabergoline. cabergoline, echocardiography, valvulopathy.

Apixaban Versus Rivaroxaban in Patients With Atrial Fibrillation and Valvular Heart Disease : A Population-Based Study.

BACKGROUND: Although apixaban and rivaroxaban are commonly used in patients with atrial fibrillation (AF) and valvular heart disease (VHD), there is limited evidence comparing the 2 drugs in these patients. OBJECTIVE: To emulate a target trial of effectiveness and safety of apixaban and rivaroxaban in patients with AF and VHD. DESIGN: New-user, active comparator, cohort study design. SETTING: Commercial health insurance database from 1 January 2013 to 31 December 2020. PATIENTS: New users of apixaban or rivaroxaban who had a diagnosis of AF and VHD before initiation of anticoagulant therapy. MEASUREMENTS: The primary effectiveness outcome was a composite of ischemic stroke or systemic embolism. The primary safety outcome was a composite of gastrointestinal or intracranial bleeding. Cox proportional hazards regression with a robust variance estimator was used to estimate hazard ratios (HRs) and 95% CIs. RESULTS: When compared with rivaroxaban in a propensity score-matched cohort of 19 894 patients (9947 receiving each drug), apixaban was associated with a lower rate of ischemic stroke or systemic embolism (HR, 0.57 [95% CI, 0.40 to 0.80]) and bleeding (HR, 0.51 [CI, 0.41 to 0.62]). The absolute reduction in the probability of stroke or systemic embolism with apixaban compared with rivaroxaban was 0.0026 within 6 months and 0.011 within 1 year of treatment initiation. The absolute reduction in the probability of bleeding events with apixaban compared with rivaroxaban was 0.012 within 6 months and 0.019 within 1 year of treatment initiation. LIMITATION: Short follow-up time and inability to ascertain some types of VHD. CONCLUSION: In this study of patients with AF and VHD, patients receiving apixaban had a lower risk for ischemic stroke or systemic embolism and for bleeding when compared with those receiving rivaroxaban. PRIMARY FUNDING SOURCE: National Institutes of Health.

Effect of standard-dose and high-dose pimobendan on select indices of renal and cardiac function in dogs with American College of Veterinary Internal Medicine stage B2 myxomatous mitral valve disease.

BACKGROUND: Pimobendan might have favorable effects on renal function but this has not been well-studied in dogs with myxomatous mitral valve disease (MMVD). OBJECTIVES: Determine the effects of standard-dose (SD_pimo) and high-dose pimobendan (HD_pimo) on glomerular filtration rate (GFR) and cardiac size and function in dogs with preclinical MMVD. ANIMALS: Thirty nonazotemic dogs with stage B2 MMVD. METHODS: Prospective, randomized, double-blinded, placebo-controlled clinical study. Dogs had an echocardiographic examination, assessment of GFR (iohexol clearance), N-terminal probrain natriuretic peptide (NT-proBNP), and quality of life (QOL) score at baseline and 7 to 10 days after placebo (n = 6), SD_pimo 0.2 to 0.3 mg/kg q12 (n = 12), or HD_pimo 0.5 to 0.6 mg/kg q12h (n = 12). RESULTS: No significant differences in GFR or QOL scores were detected between groups (P ≥ .07). After HD_pimo, the mean [SD] percent change of NT_proBNP (-46.1 [20.2]%), left atrial volume (LAV; -27.1 [16.9]%), left ventricular end-diastolic volume (EDV; -21.8 [15.0]%), and end-systolic volume (ESV; -55.0 [20.7]%) were significantly different (P ≤ .004) from placebo (0.5 [19.9]%, 1.3 [15.6]%, -0.2 [8.2]%, -7.3 [35.6]%, respectively) but not the percent change after SD_pimo (-36.6 [16.1]%, -22.7 [14.9]%, -16.7 [12.5]%, -41.6 [14.8]%, respectively; P > .05). After SD_pimo, percent change of NT_proBNP, LAV, EDV, and ESV were significantly different from placebo (P < .05). CONCLUSIONS AND CLINICAL IMPORTANCE: Results suggest that pimobendan (SD_pimo or HD_pimo) might not affect renal function in nonazotemic dogs with stage B2 MMVD. High-dose pimobendan did not demonstrate advantages over SD_pimo within the constraints of our study.

[Infective endocarditis in pregnancy: A case report].

Infective endocarditis in pregnancy is extremely rare in clinical practice. Guidelines addressing prophylaxis and management of infective endocarditis do not extensively deal with concomitant pregnancy, and case reports on infective endocarditis are scarce. Due to increased blood volume and hemodynamic changes in late pregnancy, endocardial neoplasms are easy to fall off and cause systemic or pulmonary embolism, respiratory, cardiac arrest and sudden death may occur in pregnant women, the fetus can suffer from intrauterine distress and stillbirth at any time, leading to adverse outcomes for pregnant women and fetuses. The disease is dangerous and difficult to treat, which seriously threatens the lives of mothers and babies. Early diagnosis and reasonable treatment can effectively improve the prognosis of patients. The most important method for the treatment of infective endocarditis requires early, adequate, long-term and combined antibiotic therapy. Moreover, surgical controversies regarding indication and timing of treatment exist, especially in pregnancy. In terms of the timing of termination of pregnancy, the timing of cardiac surgery, and the method of surgery, individualized programs must be adopted. A pregnant woman with 30+5 weeks of gestation is reported. She was admitted to hospital due to intermittent chest tightness, suffocation and fever, with grade Ⅲ cardiac insufficiency. Imaging revealed large mitral valve vegetation, 22.0 mm×4.1 mm and 22.0 mm×5.1 mm, respectively, and severe valve regurgitation. Mitral valve perforation was more likely, blood culture suggested Staphylococcus epidermidis infection, after antibiotic conservative treatment, the effect was poor. After the joint consultation including cardiology, neonatology, interventional vascular surgery, anesthesiology, and obstetrics, the combined operation of obstetrics and cardiac surgery was performed in time. The heart was blocked for 60 minutes, the bleeding was 1 200 mL, the newborn was mildly asphyxiated after birth, and the birth weight was 1 890 g. Nine days after the operation, the patient was discharged from the hospital, and the newborn was discharged with the weight of 2 020 g. Critical cases like this require a thorough weighing of risks and benefits followed by swift action to protect the mother and her unborn child. An optimal outcome in a challenging case like this greatly depends on effective interdisciplinary communication, informed consent of the patient, and concerted action among the specialists involved.

Comparison of Dabigatran Versus Warfarin Treatment for Prevention of New Cerebral Lesions in Valvular Atrial Fibrillation.

Warfarin is the standard anticoagulation therapy for valvular atrial fibrillation (AF); however, new oral anticoagulants have emerged as an alternative. We compared the efficacy and safety of dabigatran with conventional treatment in AF associated with left-sided valvular heart disease (VHD), including mitral stenosis (MS). Patients with AF and left-sided VHD were randomly assigned to receive dabigatran or conventional treatment. The primary end point was the occurrence of clinical stroke or a new brain lesion (silent brain infarct and microbleed) on 1-year follow-up brain magnetic resonance imaging. Patients in the dabigatran group were switched from warfarin (n = 52), antiplatelets alone (n = 5), or no therapy (n = 2) to dabigatran. In the conventional group, 53 used warfarin (including 42 MS patients), and 7 used antiplatelets. No death or clinical stroke event occurred in either group during follow-up. Silent brain infarct and microbleed occurred in 20 and 2 patients in the dabigatran group and 20 and 4 patients in the conventional treatment group. The incidence rate of the primary end point did not significantly differ between groups (34% vs 40%, relative risk 0.87, 95% confidence interval 0.59 to 1.29, p = 0.491). The primary end point rate was similar between groups in 82 patients (40 in the dabigatran group and 42 in the conventional group) with MS (32% vs 34%, relative risk 0.93, 95% confidence interval: 0.57 to 1.50, p = 0.759). In conclusion, primary end point rates after treatment with dabigatran were similar to conventional treatment in patients with significant VHD and AF. New oral anticoagulants could be a reasonable alternative to warfarin in patients with AF and VHD, which should be confirmed in future large-scale studies.

Long-term cardiovascular safety of fenfluramine in patients with Dravet syndrome treated for up to 3 years: Findings from serial echocardiographic assessments.

OBJECTIVE: To assess the cardiovascular safety of fenfluramine when used to treat children and young adults with Dravet syndrome. METHODS: Patients with Dravet syndrome who completed one of three phase 3 clinical trials of fenfluramine could enroll in the open-label extension (OLE) study (NCT02823145). All patients started fenfluramine treatment at an oral dose of 0.2 mg/kg/day. The dose was titrated based on efficacy and tolerability to a maximum of 0.7 mg/kg/day (absolute maximum 26 mg/day) or 0.4 mg/kg/day (absolute maximum 17 mg/day) in patients concomitantly receiving stiripentol. Serial transthoracic echocardiography was performed using standardized methods and blinded readings at OLE entry, after 4-6 weeks, and every 3 months thereafter. Valvular heart disease (VHD) was defined as ≥ moderate mitral regurgitation or ≥ mild aortic regurgitation combined with physical signs or symptoms attributable to valve dysfunction. Pulmonary artery hypertension (PAH) was defined as systolic pulmonary artery pressure >35 mmHg. RESULTS: A total of 327 patients (median age, 9.0 years; range, 2-19 years) have enrolled in the OLE and received ≥1 dose of fenfluramine. The median duration of treatment was 23.9 months (range, 0.2-42.6 months) and the median dose of fenfluramine was 0.44 mg/kg/day. No patient demonstrated VHD or PAH at any time during the OLE. SIGNIFICANCE/INTERPRETATION: This study, which represents the largest, longest, and most rigorous examination of cardiovascular safety of fenfluramine yet reported, found no cases of VHD or PAH. These results, combined with fenfluramine's substantial antiseizure efficacy, support a strong positive benefit-risk profile for fenfluramine in the treatment of Dravet syndrome.

Outcomes of Direct Oral Anticoagulants in Patients with Atrial Fibrillation and Valvular Heart Disease.

PURPOSE OF REVIEW: Direct oral anticoagulants (DOACs) are increasingly used for the treatment and prevention of thromboembolic events in patients with non-valvular atrial fibrillation (AF). Evidence regarding their role in patients with AF and concurrent valvular heart disease (VHD) continues to evolve. RECENT FINDINGS: Post hoc analyses of randomized clinical trials suggest that DOACs are non-inferior to warfarin for the prevention of stroke or systemic embolism in patients with AF and VHD. Emerging evidence from observational data showed a favorable benefit-risk profile for DOACs compared to warfarin in patients with AF and VHD. DOACs are an attractive option for the treatment of patients with AF and VHD who cannot tolerate or have contraindications to warfarin therapy. Future studies are needed to evaluate their effectiveness, safety, and examine variability in the direction and magnitude of treatment effects in selected VHD subgroups.

Poly-2-methyl-2-oxazoline-modified bioprosthetic heart valve leaflets have enhanced biocompatibility and resist structural degeneration.

Bioprosthetic heart valves (BHV) fabricated from glutaraldehyde-fixed heterograft tissue, such as bovine pericardium (BP), are widely used for treating heart valve disease, a group of disorders that affects millions. Structural valve degeneration (SVD) of BHV due to both calcification and the accumulation of advanced glycation end products (AGE) with associated serum proteins limits durability. We hypothesized that BP modified with poly-2-methyl-2-oxazoline (POZ) to inhibit protein entry would demonstrate reduced accumulation of AGE and serum proteins, mitigating SVD. In vitro studies of POZ-modified BP demonstrated reduced accumulation of serum albumin and AGE. BP-POZ in vitro maintained collagen microarchitecture per two-photon microscopy despite AGE incubation, and in cell culture studies was associated with no change in tumor necrosis factor-α after exposure to AGE and activated macrophages. Comparing POZ and polyethylene glycol (PEG)-modified BP in vitro, BP-POZ was minimally affected by oxidative conditions, whereas BP-PEG was susceptible to oxidative deterioration. In juvenile rat subdermal implants, BP-POZ demonstrated reduced AGE formation and serum albumin infiltration, while calcification was not inhibited. However, BP-POZ rat subdermal implants with ethanol pretreatment demonstrated inhibition of both AGE accumulation and calcification. Ex vivo laminar flow studies with human blood demonstrated BP-POZ enhanced thromboresistance with reduced white blood cell accumulation. We conclude that SVD associated with AGE and serum protein accumulation can be mitigated through POZ functionalization that both enhances biocompatibility and facilitates ethanol pretreatment inhibition of BP calcification.

Care of the patient after valve intervention.

This review aims to outline the current evidence base and guidance for care of patients post-valve intervention. Careful follow-up, optimisation of medical therapy, antithrombotics, reduction of cardiovascular risk factors and patient education can help improve patient outcomes and quality of life. Those with mechanical valves should receive lifelong anticoagulation with a vitamin K antagonist but in certain circumstances may benefit from additional antiplatelet therapy. Patients with surgical bioprosthetic valves, valve repairs and transcatheter aortic valve implantation also benefit from antithrombotic therapy. Additionally, guideline-directed medical therapy for coexistent heart failure should be optimised. Cardiovascular risk factors such as hyperlipidaemia, hypertension and diabetes should be treated in the same way as those without valve intervention. Patients should also be encouraged to exercise regularly, eat healthily and maintain a healthy weight. Currently, there is not enough evidence to support routine cardiac rehabilitation in individuals post-valve surgery or intervention but this may be considered on a case-by-case basis. Women of childbearing age should be counselled regarding future pregnancy and the optimal management of their valve disease in this context. Patients should be educated regarding meticulous oral health, be encouraged to see their dentist regularly and antibiotics should be considered for high-risk dental procedures. Evidence shows that patients post-valve intervention or surgery are best treated in a dedicated valve clinic where they can undergo clinical review and surveillance echocardiography, be provided with heart valve education and have access to the multidisciplinary valve team if needed.