Unraveling the Mechanisms of Valvular Heart Disease to Identify Medical Therapy Targets: A Scientific Statement From the American Heart Association.

Valvular heart disease is a common cause of morbidity and mortality worldwide and has no effective medical therapy. Severe disease is managed with valve replacement procedures, which entail high health care-related costs and postprocedural morbidity and mortality. Robust ongoing research programs have elucidated many important molecular pathways contributing to primary valvular heart disease. However, there remain several key challenges inherent in translating research on valvular heart disease to viable molecular targets that can progress through the clinical trials pathway and effectively prevent or modify the course of these common conditions. In this scientific statement, we review the basic cellular structures of the human heart valves and discuss how these structures change in primary valvular heart disease. We focus on the most common primary valvular heart diseases, including calcific aortic stenosis, bicuspid aortic valves, mitral valve prolapse, and rheumatic heart disease, and outline the fundamental molecular discoveries contributing to each. We further outline potential therapeutic molecular targets for primary valvular heart disease and discuss key knowledge gaps that might serve as future research priorities.

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.

Atorvastatin Effect on Aortic Dilatation and Valvular Calcification Progression in Bicuspid Aortic Valve (BICATOR): A Randomized Clinical Trial.

BACKGROUND: Ascending aorta dilation and aortic valve degeneration are common complications in patients with bicuspid aortic valve. Several retrospective studies have suggested the benefit of statins in reducing these complications. This study aimed to determine whether atorvastatin treatment is effective in reducing the growth of aortic diameters in bicuspid aortic valve and if it slows the progression of valve calcification. METHODS: In a randomized clinical trial, 220 patients with bicuspid aortic valve (43 women; 46±13 years of age) were included and treated with either 20 mg of atorvastatin per day or placebo for 3 years. Inclusion criteria were ≥18 years of age, nonsevere valvular dysfunction, nonsevere valve calcification, and ascending aorta diameter ≤50 mm. Computed tomography and echocardiography studies were performed at baseline and after 3 years of treatment. RESULTS: During follow-up, 28 patients (12.7%) discontinued medical treatment (15 on atorvastatin and 13 taking placebo). Thus, 192 patients completed the 36 months of treatment. Low-density lipoprotein cholesterol levels decreased significantly in the atorvastatin group (median [interquartile range], -30 mg/dL [-51.65 to -1.75 mg/dL] versus 6 mg/dL [-4, 22.5 mg/dL]; P<0.001). The maximum ascending aorta diameter increased with no differences between groups: 0.65 mm (95% CI, 0.45-0.85) in the atorvastatin group and 0.74 mm (95% CI, 0.45-1.04) in the placebo group (P=0.613). Similarly, no significant differences were found for the progression of the aortic valve calcium score (P=0.167) or valvular dysfunction. CONCLUSIONS: Among patients with bicuspid aortic valve without severe valvular dysfunction, atorvastatin treatment was not effective in reducing the progression of ascending aorta dilation and aortic valve calcification during 3 years of treatment despite a significant reduction in low-density lipoprotein cholesterol levels. REGISTRATION: URL: https://www.clinicaltrialsregister.eu; Unique identifier: 2015-001808-57. URL: https://www.clinicaltrials.gov; Unique identifier: NCT02679261.

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.

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.

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.

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.

[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.

Slowing Progression of Cardiovascular Calcification With SNF472 in Patients on Hemodialysis: Results of a Randomized Phase 2b Study.

BACKGROUND: The high cardiovascular morbidity and mortality in patients with end-stage kidney disease could be partially caused by extensive cardiovascular calcification. SNF472, intravenous myo-inositol hexaphosphate, selectively inhibits the formation and growth of hydroxyapatite. METHODS: This double-blind, placebo-controlled phase 2b trial compared progression of coronary artery calcium volume score and other measurements of cardiovascular calcification by computed tomography scan during 52 weeks of treatment with SNF472 or placebo, in addition to standard therapy, in adult patients with end-stage kidney disease receiving hemodialysis. Patients were randomized 1:1:1 to SNF472 300 mg (n=92), SNF472 600 mg (n=91), or placebo (n=91) by infusion in the hemodialysis lines thrice weekly during hemodialysis sessions. The primary end point was change in log coronary artery calcium volume score from baseline to week 52. The primary efficacy analysis combined the SNF472 treatment groups and included all patients who received at least 1 dose of SNF472 or placebo and had an evaluable computed tomography scan after randomization. RESULTS: The mean change in coronary artery calcium volume score was 11% (95% CI, 7-15) for the combined SNF472 dose group and 20% (95% CI, 14-26) for the placebo group (P=0.016). SNF472 compared with placebo attenuated progression of calcium volume score in the aortic valve (14% [95% CI, 5-24] versus 98% [95% CI, 77-123]; P<0.001) but not in the thoracic aorta (23% [95% CI, 16-30] versus 28% [95% CI, 19-38]; P=0.40). Death occurred in 7 patients (4%) who received SNF472 and 5 patients (6%) who received placebo. At least 1 treatment-emergent adverse event occurred in 86%, 92%, and 87% of patients treated with SNF472 300 mg, SNF472 600 mg, and placebo, respectively. Most adverse events were mild. Adverse events resulted in discontinuation of SNF472 300 mg, SNF472 600 mg, and placebo for 14%, 29%, and 20% of patients, respectively. CONCLUSIONS: Compared with placebo, SNF472 significantly attenuated the progression of coronary artery calcium and aortic valve calcification in patients with end-stage kidney disease receiving hemodialysis in addition to standard care. Future studies are needed to determine the effects of SNF472 on cardiovascular events. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02966028.

Therapeutic Controversies in the Medical Management of Valvular Heart Disease.

OBJECTIVE: To evaluate the evidence for common therapeutic controversies in the medical management of valvular heart disease (VHD). DATA SOURCES: A literature search of PubMed (inception to December 2020) was performed using the terms angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) and aortic stenosis (AS); and adrenergic ß-antagonists and aortic valve regurgitation (AR) or mitral stenosis (MS). STUDY SELECTION AND DATA EXTRACTION: Randomized controlled trials (RCTs) and meta-analyses conducted in humans and published in English that reported ≥1 clinical outcome were included. DATA SYNTHESIS: Nine articles were included: 3 RCTs and 1 meta-analysis for ACE inhibitors/ARBs in AS, 1 RCT for ß-blockers in AR, and 4 RCTs for ß-blockers in MS. Evidence suggests that ACE inhibitors/ARBs do not increase the risk of adverse outcomes in patients with AS but may delay valve replacement. ß-Blockers do not appear to worsen outcomes in patients with chronic AR and may improve left-ventricular function in patients with a reduced ejection fraction. ß-Blockers do not improve and may actually worsen exercise tolerance in patients with MS in sinus rhythm. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: ACE inhibitors/ARBs and ß-blockers can likely be safely used in patients with AS or AR, respectively, who have a compelling indication. There is insufficient evidence to recommend routine use of ß-blockers in patients with MS without atrial fibrillation. CONCLUSIONS: Common beliefs about the medical treatment of VHD are not supported by high-quality data. There remains a need for larger-scale RCTs in the medical management of VHD.

The effect of treatment with pimobendan in dogs with preclinical mitral valve disease - a placebo-controlled double-blinded crossover study.

BACKGROUND: Pimobendan is a widely used medication for the treatment of dogs with congestive heart failure (CHF) and preclinical degenerative mitral valve disease (DMVD) with cardiomegaly. The benefit of a treatment in dogs with preclinical DMVD but without cardiomegaly has not yet been elucidated. Some positive effects concerning life quality and a decrease in cardiac biomarkers could be verified. This study aimed to further investigate these results using a placebo-controlled double-blinded crossover design. Out of a total of 15 dogs, eight were allocated to sequence-group AB, in which dogs received pimobendan (A) during the first treatment period and placebo (B) during the second period. Accordingly, sequence-group BA was treated first with placebo followed by pimobendan. Each treatment period lasted six months and included a baseline investigation and follow-ups after 90 and 180 days. The investigations included a questionnaire completed by the owners, echocardiographic examination, and measurements of NT-proBNP, cTnI and lactate before and after a standardised submaximal exercise test. RESULTS: NT-proBNP values decreased significantly during the treatment period with pimobendan, and the post-exercise increase was attenuated at day 180. No significant treatment effects could be verified for cTnI and lactate, neither pre- nor post-exercise. Left ventricular size decreased under treatment, whereas no significant changes in left atrial size were detected. The owners described their dogs under treatment with pimobendan as being more active at day 90 (11/15) and day 180 (12/15). Those animals treated with placebo were described as being more active at day 90 (2/15) and day 180 (5/15). CONCLUSIONS: Pimobendan had reducing effects on the concentrations of pre- and post-exercise cardiac biomarkers and the size of the left ventricle in dogs with DMVD ACVIM B1. Exercise testing in addition to an assessment of cardiac biomarkers might improve the decision when to initiate pimobendan treatment in dogs with DMVD.

Prospective validation of the International Warfarin Pharmacogenetics Consortium algorithm in high-risk elderly people (VIALE study).

We assessed the predictive accuracy of the Warfarin Pharmacogenetics Consortium (IWPC) algorithm in a prospective cohort of 376 high-risk elderly patients (≥65 years) who required new treatment with warfarin for either medical (non valvular atrial fibrillation) or surgical conditions (heart valve replacement), had ≥1 comorbid conditions, and regularly used ≥2 other drugs. Follow-up visits were performed according to clinical practice and lasted for a maximum of 1 year. Two hundred and eighty-three (75%) patients achieved a stable maintenance dose. Warfarin maintenance doses were low on average (median 20.3 mg/week, interquartile range, 14.1-27.7 mg/week) and were substantially overestimated by the IWPC algorithm. Overall the percentage of patients whose predicted dose of warfarin was within 20% of the actual stable dose was equal to 37.5%, (95% CI 32.0-43.3%). IWPC algorithm explained only 31% of the actual warfarin dose variability. Modifications of the IWPC algorithm are needed in high-risk elderly people.

Thromboembolic and bleeding outcomes in patients with atrial fibrillation and valvular heart disease: A descriptive nationwide cohort study.

AIMS: The risks of thromboembolism and bleeding in patients with atrial fibrillation (AF) and valvular heart disease (VHD) are sparsely described. We described the risk of events in non-anticoagulated and anticoagulated patients with AF and VHD according to the evaluated heart valves, rheumatic or artificial valve classification (EHRA classification), EHRA Type 1 and Type 2 VHD, and within subgroups of EHRA Type 1 and Type 2 VHD. METHODS AND RESULTS: Cohort study of AF patients with coexisting VHD, identified in nationwide Danish registries from 2000 to 2018. Risk of thromboembolism and bleeding after 1 year of follow-up were calculated in each group. We identified 28 770 incident AF patients with VHD. Not surprisingly, we observed the highest risks of thromboembolism in the non-anticoagulated AF patients with EHRA Type 1 and Type 2 VHD (4.9% vs 2.6% and 3.2% vs 1.9%) and the highest risks of bleeding in the anticoagulated AF patients with EHRA Type 1 and Type 2 VHD (6.6% vs 4.3% and 6.1% vs 4.9%). However, within the subgroups of AF patients with EHRA Type 1 and Type 2 VHD, we observed a large proportion of non-anticoagulated patients (32.9%-49.2%), despite a CHA2 DS2 -VASc score of 2≤ in the majority of these patients (81.9%-95.6%). CONCLUSIONS: When using data reflecting contemporary clinical practice, we observed markedly different risks of thromboembolism and bleeding in EHRA Type 1 and Type 2 VHD. Additionally, we observed a potential underuse of oral anticoagulation within the subgroups of AF patients with EHRA Type 1 and Type 2 VHD, underlining need for further attention on this patient group.

Regulation of calcific vascular and valvular disease by nuclear receptors.

PURPOSE OF REVIEW: This review addresses recent developments in studies of lipid regulation of calcific disease of arteries and cardiac valves, including the role of nuclear receptors. The role of lipid-soluble signals and their receptors is timely given the recent evidence and concerns that lipid-lowering treatment may increase the rate of progression of coronary artery calcification, which has been long associated with increased cardiovascular risk. Understanding the mechanisms will be important for interpreting such clinical information. RECENT FINDINGS: New findings support regulation of calcific vascular and valvular disease by nuclear receptors, including the vitamin D receptor, glucocorticoid receptor, nutrient-sensing nuclear receptors (liver X receptor, farnesoid X receptor, and peroxisome proliferator-activated receptors), and sex hormone (estrogen and androgen) receptors. There were two major unexpected findings: first, vitamin D supplementation, which was previously believed to prevent or reduce vascular calcification, showed no cardiovascular benefit in large randomized, controlled trials. Second, both epidemiological studies and coronary intravascular ultrasound studies suggest that treatment with HMG-CoA reductase inhibitors increases progression of coronary artery calcification, raising a question of whether there are mechanically stable and unstable forms of coronary calcification. SUMMARY: For clinical practice and research, these new findings offer new fundamental mechanisms for vascular calcification and provide new cautionary insights for therapeutic avenues.

Serotonin contribution to cardiac valve degeneration: new insights for novel therapies?

Heart valve disease (HVD) is a complex entity made by different pathological processes that ultimately lead to the abnormal structure and disorganization of extracellular matrix proteins resulting to dysfunction of the leaflets. At its final evolutionary step, treatments are limited to the percutaneous or surgical valve replacement, whatever the original cause of the degeneration. Understanding early molecular mechanisms that regulate valve interstitial cells remodeling and disease progression is challenging and could pave the way for future drugs aiming to prevent and/or reverse the process. Some valve degenerative processes such as the carcinoid heart disease, drug-induced valvulopathy and degenerative mitral valve disease in small-breed dogs are clearly linked to serotonin. The carcinoid heart is typically characterized by a right-sided valve dysfunction, observed in patients with carcinoid tumors developed from serotonin-producing gut enterochromaffin cells. Fenfluramine or ergot derivatives were linked to mitral and aortic valve dysfunction and share in common the pharmacological property of being 5-HT2B receptor agonists. Finally, some small-breed dogs, such as the Cavalier King Charles Spaniel are highly prone to degenerative mitral valve disease with a prevalence of 40% at 4 years-old, 70% at 7 years-old and 100% in 10-year-old animals. This degeneration has been linked to high serum serotonin, 5-HT2B receptor overexpression and SERT downregulation. Through the comprehension of serotonergic mechanisms involved into these specific situations, new therapeutic approaches could be extended to HVD in general. More recently, a serotonin dependent/ receptor independent mechanism has been suggested in congenital mitral valve prolapse through the filamin-A serotonylation. This review summarizes clinical and molecular mechanisms linking the serotonergic system and heart valve disease, opening the way for future pharmacological research in the field.

Stroke and bleeding risk scores in patients with atrial fibrillation and valvular heart disease: evaluating 'valvular heart disease' in a nationwide cohort study.

AIMS: Substantial interest has been directed towards stroke risk stratification in patients with atrial fibrillation (AF) but prior studies have focused on AF without significant valvular heart disease (VHD), so-called 'non-valvular AF'. A formal validation exercise addressing stroke risks in relation to the CHA2DS2-VASc risk factor(s) in AF patients with VHD is lacking. Also, the use of the HAS-BLED score in anticoagulated patients with VHD has not been previously studied. The aim of this study was to investigate stroke and bleeding rates in AF patients with VHD in relation to the CHA2DS2-VASc and HAS-BLED scores. METHODS AND RESULTS: We conducted a nationwide cohort study. VHD were categorized based on the 2017 joint European consensus document definition, i.e. Evaluated Heartvalves, Rheumatic or Artificial (EHRA) categorization, as follows: (i) EHRA Type 1 VHD, which refers to AF patients with 'VHD needing therapy with a Vitamin K antagonist (VKA)', thus including severe native mitral stenosis and prosthetic mechanical heart valves and (ii) EHRA Type 2 VHD, which refers to AF patients with 'VHD needing therapy with a VKA or a non-VKA oral anticoagulant (NOAC)', thus including all other forms of VHD. We identified 25 818 AF patients with VHD with EHRA Type 2 in 90% (n = 23 253). Thromboembolism and bleeding events increased with increasing CHA2DS2-VASc and HAS-BLED scores, whether with 1 or 2.5 years follow-up. EHRA Type 1 outcomes: The predictive value of CHA2DS2-VASc score for thromboembolism was modest, c-indexes 0.62 (0.55-0.70) at 1 year. The predictive value of the HAS-BLED score for bleeding was also modest being 0.59 (0.53-0.65) at 1 year. EHRA Type 2 outcomes: The predictive value of CHA2DS2-VASc score for thromboembolism was modest, c-indexes 0.63 (0.60-0.65) at 1 year. The predictive value of the HAS-BLED score for bleeding was also modest being 0.59 (0.53-0.65) at 1 year. CONCLUSION: This is the first validation of CHA2DS2-VASc and HAS-BLED scores in AF patients with VHD (so-called 'valvular AF') using the new EHRA classification. Both scores are modestly predictive of thromboembolism and bleeding events in VHD, respectively. Event rates increased with increasing risk factors as evident by increasing CHA2DS2-VASc and HAS-BLED score points, consistent with performance of these clinical scores in 'non-valvular AF' patients.

Another Whipple's triad? Pericardial, myocardial and valvular disease in an unusual case presentation from a Canadian perspective.

BACKGROUND: Whipple's disease is a clinically relevant multi-system disorder that is often undiagnosed given its elusive nature. We present an atypical case of Whipple's disease involving pan-valvular endocarditis and constrictive pericarditis, requiring cardiac intervention. A literature review was also performed assessing the prevalence of atypical cases of Whipple's disease. CASE PRESENTATION: A previously healthy 56-year-old male presented with a four-year history of congestive heart failure with weight loss and fatigue. Notably, he had absent gastrointestinal symptoms. He went on to develop pan-valvular endocarditis and constrictive pericarditis requiring urgent cardiac surgery. A clinical diagnosis of Whipple's disease was suspected, prompting duodenal biopsy sampling which was unremarkable, Subsequently, Tropheryma whipplei was identified by 16S rDNA PCR on the cardiac valvular tissue. He underwent prolonged antibiotic therapy with recovery of symptoms. CONCLUSIONS: Our study reports the first known case of Whipple's disease involving pan-valvular endocarditis and constrictive pericarditis. A literature review also highlights this presentation of atypical Whipple's with limited gastrointestinal manifestations. Duodenal involvement was limited and the gold standard of biopsy was not contributory. We also highlight the Canadian epidemiology of the disease from 2012 to 2016 with an approximate 4% prevalence rate amongst submitted samples. Routine investigations for Whipple's disease, including duodenal biopsy, in this case may have missed the diagnosis. A high degree of suspicion was critical for diagnosis of unusual manifestations of Whipple's disease.

Effect of Pimobendan on NT-proBNP and c troponin I before and after a submaximal exercise test in dogs with preclinical mitral valve disease without cardiomegaly - a randomised, double-blinded trial.

BACKGROUND: Exercise testing in conjunction with measurement of cardiac biomarkers NT-proBNP and cTnI is a useful tool for monitoring the effect of treatment on cardiac patients. Administering Pimobendan in dogs with degenerative mitral valve disease (DMVD) and cardiomegaly results in delaying the onset of clinical symptoms and prolonging life. Its effect in dogs with DMVD without cardiomegaly has not been well examined. The aim of the current study was to investigate the effect of administering Pimobendan in dogs with DMVD without cardiomegaly using exercise testing in conjunction with measuring cardiac biomarkers in addition to echocardiography. Twenty-one dogs with asymptomatic DMVD without echocardiographic signs of cardiomegaly participated in a randomised, double-blinded trial. Dogs were divided into a Pimobendan-group (n = 11) and a placebo-group (n = 10) in a double-blinded study design and underwent a standardised submaximal exercise test (SSET). One dog in the Pimobendan-group was retrospectively removed from the study after being diagnosed with Leishmaniosis. Cardiac biomarkers NT-proBNP and cTnI were measured before and after exercise. Follow-up appointments were performed at days 90 and 180. RESULTS: Dogs in the Pimobendan-group had significantly lower post-exercise NT-proBNP-levels after being administered Pimobendan than at the beginning of the study. They also had lower pre- and post-exercise-NT-proBNP-levels than those dogs in the placebo-group. There was neither a significant difference regarding the measured cTnI levels nor an increase in cTnI between the groups at any time. CONCLUSIONS: Pimobendan lowers NT-proBNP in dogs with presymptomatic mitral valve disease without cardiomegaly before and after submaximal exercise. This indicates a reduction in cardiac wall stress. If dogs with asymptomatic DMVD without cardiomegaly benefit from treatment with Pimobendan (for example, through a longer survival time) warrants further investigation.

Valvular heart disease in Antiphospholipid antibody syndrome: Isolated Tricuspid stenosis.

Antiphospholipid antibody syndrome (APLS) is a rare disorder characterized by a hypercoagulable state. Manifestations include arterial or venous thrombosis, recurrent fetal wastage, coronary artery disease, valvular heart disease, dilated cardiomyopathy, pulmonary artery hypertension, and intracardiac thrombus. Most commonly mitral valve is affected followed by aortic and then tricuspid valve. In this report, a rare case of spontaneous aortic thrombosis with tricuspid stenosis uncomplicated by other valve lesions is presented with clinical and echocardiographic studies and computed tomographic images.