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.

Outcomes and predictors of periprocedural stroke after transcatheter aortic valve implantation.

BACKGROUND: Risk factors for stroke after transcatheter aortic valve implantation (TAVI) are currently incompletely understood. PURPOSE: To identify possible predictors of early post-TAVI stroke and explore its short-term outcomes. METHODS: Retrospective analysis of consecutive patients (pts) submitted to TAVI between 2009 and 2020 in a tertiary center. Baseline characteristics, procedural information and stroke in first 30 days after TAVI were collected. In-hospital and 12 months outcomes were analyzed. RESULTS: A total of 512pts (56,1% female, mean age of 82 ± 6years.) were included. In the first 30 days after TAVI 19pts (3,7%) had a stroke. In univariate analysis stroke was associated with higher body mass index (29 vs 27kg/m2, p=0.035), higher triglyceridemia (> 117,5mg/dL, p=0,002), lower high-density lipoprotein (< 38,5mg/dL, p=0,009) and porcelain aorta (36,8% vs 15,5%, p=0,014) and more frequent use of post-dilatation (58,8% vs 32%, p=0,021). In multivariate analysis, triglycerides > 117,5mg/dL (p=0,032, OR = 3,751) and post-dilatation (p=0,019, OR = 3,694) were the independent predictors. Stroke after TAVI was associated with longer intensive care unit stay (12 vs 4 days, p<0,001) and post-TAVI hospital stay (25 vs 10 days, p<0,0001), higher intra-hospital mortality (21,1% vs 4,3%, p=0,003), cardiovascular 30-day mortality (15,8% vs 4,1%, p=0,026) and 1-year stroke (13,2% vs 1,1%, p=0,003). CONCLUSION: Periprocedural and 30-day stroke is a relatively uncommon but potentially devastating complication after TAVI. In this cohort, 30-day stroke rate after TAVI was 3.7%. Hypertriglyceridemia and post-dilatation were found to be the only independent risk predictors. Outcomes after stroke, including 30-day mortality, were significantly worse.

Gender differences in bicuspid aortic valve Sievers types, valvulopathy, aortopathy, and outcome of aortic valve replacement.

BACKGROUND: The gender difference of the bicuspid aortic valve (BAV) is not well understood. OBJECTIVES: We evaluated the impact of gender on the Sievers types, valvulopathy, aortopathy, and outcomes of aortic valve replacement (AVR) of BAV patients in a cohort of Chinese patients. METHODS: Among 992 BAV patients without aortic dissection nor congenital heart disease, 658 underwent AVR. The demography, Sievers types, valvulopathy, aortopathy, and outcomes of AVR were compared between genders. RESULTS: Aortic regurgitation (AR ≥ 2+) (39.0% vs. 12.8%, p < .001), aortic root dilation only (3.8% vs. .8%, p = .014), and diffuse dilation (25.3% vs. 4.3%, p < .001) were more common in men, while moderate to severe aortic stenosis (AS) (21.3% vs. 45.7%, p < .001) and ascending dilation only (46.2% vs. 61.2%, p < .001) were more common in women. Men were more prone to develop preoperative AR ≥ 2+ (OR = 5.15, p < .001), moderate to severe AS + AR ≥ 2 + (OR = 2.95, p = .001), and Diffuse aortic dilation (OR = 3.91, p < .001). Sievers types did not have a significant effect on valvular dysfunction. Gender didn't predict early adverse events after AVR (n = 90) (HR = 1.21, p = .44), but male gender predicted a left ventricular ejection fraction <50% after AVR (OR = 3.07, p = .03). CONCLUSIONS: In this BAV series of Chinese patients, gender didn't differ significantly in Sievers types of BAV but showed significant differences in valvulopathy, aortopathy, and LV function after AVR. In addition, the male patients developed more severe conditions at a younger age.

Percutaneous tricuspid valve implantation: an alternative in critically ill patients.

Tricuspid valvulopathy has gained a lot of attention in recent years, especially due to the advances in percutaneous management. CHD can present with primary or secondary malfunction of the tricuspid valve, often not addressed due to high surgical risk after several interventions. We present two cases of adults with complex congenital heart malformations and borderline clinical situations who successfully underwent percutaneous tricuspid replacement.

[Dynamic mitral regurgitation and acute pulmonary edema]. / Insuffisance mitrale dynamique et œdème pulmonaire aigu.

We report the case of a 61-year old patient with signs and symptoms of heart failure with mid-range left ventricular ejection fraction and moderate mitral regurgitation of mixed etiology (rheumatic heart disease, toxic and ischemic). The dynamic behaviour of the mitral regurgitation was revealed by an acute episode of pulmonary edema in the context of an abrupt elevation of blood pressure inducing an increase in left ventricular afterload. Dynamic mitral regurgitation must be considered in any patient with exercise dyspnea who has a moderate mitral regurgitation in resting conditions or in patients with repeated acute pulmonary edema without an obvious cause. Exercise stress echocardiography is the best diagnostic test to explore the dynamic behaviour of the mitral regurgitation. Surgery or percutaneous treatment may be proposed in severe cases.

Nous rapportons le cas d'une patiente de 61 ans présentant une insuffisance cardiaque à fraction d'éjection moyennement altérée et une insuffisance mitrale modérée d'étiologie mixte (rhumatismale, toxique et ischémique). Le caractère dynamique de cette insuffisance mitrale s'est manifesté par une aggravation brutale de celle-ci lors d'un à-coup hypertensif, avec élévation de la post-charge ventriculaire gauche, menant au développement d'un œdème pulmonaire aigu. L'insuffisance mitrale dynamique est à considérer chez tout patient souffrant de dyspnée d'effort et qui présente une insuffisance mitrale considérée comme modérée dans les conditions de repos ou chez les patients présentant des œdèmes aigus du poumon à répétition sans cause évidente. L'examen de référence pour explorer le caractère dynamique d'une insuffisance mitrale est l'échographie d'effort. La prise en charge de l'insuffisance mitrale sévère peut être chirurgicale ou percutanée pour les cas à haut risque chirurgical.

Long noncoding RNA MEG3 deteriorates inflammatory damage by downregulating microRNA-101a.

Valvulopathy is a familiar heart disease, which fearfully harms the health of the body. We studied the effects and mechanism of long noncoding RNA maternally expressed gene 3 (lncMEG3) on MVICs cell in inflammatory damage. Cell Counting Kit-8 and flow cytometry were respectively used to detect the effect of tumor necrosis factor α (TNF-α), MEG3 and microRNA (miR)-101a on cell viability and apoptosis. Moreover, MEG3 and miR-101a expression were changed by cell transfection and investigated by reverse transcription-quantitative polymerase chain reaction. Furthermore, Western blot was used to investigate the levels of Bax, pro-caspase-3, cleaved-caspase-3, pro-caspase-9, cleaved-caspase-9, interleukin (IL)-1ß, IL-6 and related-proteins of cell pathways. Otherwise, the levels of IL-1ß and IL-6 were also investigated by enzyme-linked immunosorbent assay kit. Reactive oxygen species (ROS) was examined by ROS assay. We found TNF-α caused inflammatory damage and upregulated MEG3. MEG3 was overexpressed and silenced in cells. Besides, MEG3 deteriorated inflammatory damage. Furthermore, MEG3 negatively regulated miR-101a and miR-101a mimic could reverse the effect of pc-MEG3. Besides, MEG3 enhanced the JNK and NF-κB pathways by downregulating miR-101a. In conclusion, MEG3 deteriorated cell inflammatory damage by downregulating miR-101a via JNK and NF-κB pathways.

Intermittent dosing of the transforming growth factor beta receptor 1 inhibitor, BMS-986260, mitigates class-based cardiovascular toxicity in dogs but not rats.

Small-molecule inhibitors of transforming growth factor beta receptor 1 (TGFßRI) have a history of significant class-based toxicities (eg, cardiac valvulopathy) in preclinical species that have limited their development as new medicines. Nevertheless, some TGFßRI inhibitors have entered into clinical trials using intermittent-dosing schedules and exposure limits in an attempt to avoid these toxicities. This report describes the toxicity profile of the small-molecule TGFßRI inhibitor, BMS-986260, in rats and dogs. Daily oral dosing for 10 days resulted in valvulopathy and/or aortic pathology at systemic exposures that would have been targeted clinically, preventing further development with this dosing schedule. These toxicities were not observed in either species in 1-month studies using the same doses on an intermittent-dosing schedule of 3 days on and 4 days off (QDx3 once weekly). Subsequently, 3-month studies were conducted (QDx3 once weekly), and while there were no cardiovascular findings in dogs, valvulopathy and mortality occurred early in rats. The only difference compared to the 1-month study was that the rats in the 3-month study were 2 weeks younger at the start of dosing. Therefore, a follow-up 1-month study was conducted to evaluate whether the age of rats influences sensitivity to target-mediated toxicity. Using the same dosing schedule and similar doses as in the 3-month study, there was no difference in the toxicity of BMS-986260 in young (8 weeks) or adult (8 months) rats. In summary, an intermittent-dosing schedule mitigated target-based cardiovascular toxicity in dogs but did not prevent valvulopathy in rats, and thus the development of BMS-986260 was terminated.

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.

Applications of Cardiac Computed Tomography in the Cardio-Oncology Population.

OPINION STATEMENT: The increased risk for cardiovascular events in aging cancer survivors and those undergoing certain chemotherapeutic treatments has raised concern for more rigorous screening and surveillance methods above that of the general population. At this time, there are limited guidelines for how to best manage this vulnerable cohort. Questions regarding timing of screening, choice of imaging modality and risk reduction strategies-especially in those patients with known atherosclerotic disease-remain to be elucidated. Over a decade of case series, retrospective studies and clinical trials have shed light on the evolving role of cardiac computed tomography (CT) in this population, of which there is a relative paucity of data regarding its potential utility in the specific cardio-oncology population. Focusing on ability of cardiac CT to evaluate multiple cardiac and vascular structures, provide diagnostic and prognostic information, as well as assist interventional and surgical colleagues in surgical/percutaneous valve replacement and revascularization strategies is the premise for this review.

Comprehensive MR Analysis of Cardiac Function, Aortic Hemodynamics and Left Ventricular Strain in Pediatric Cohort with Isolated Bicuspid Aortic Valve.

Bicuspid aortic valve (BAV) disease demonstrates a range of clinical presentations and complications. We aim to use cardiac MRI (CMR) to evaluate left ventricular (LV) parameters, myocardial strain and aortic hemodynamics in pediatric BAV patients with and without aortic stenosis (AS) or regurgitation (AR) compared to tricuspid aortic valve (TAV) controls. We identified 58 pediatric BAV patients without additional cardiovascular pathology and 25 healthy TAV controls (15.3 ± 2.2 years) who underwent CMR with 4D flow. BAV cohort included subgroups with no valvulopathy (n = 13, 14.3 ± 4.7 years), isolated AS (n = 19, 14.5 ± 4.0 years), mixed valve disease (AS + AR) (n = 13, 17.1 ± 3.2 years), and prior valvotomy/valvuloplasty (n = 13, 13.9 ± 3.2 years). CMR data included LV volumetric and mass indices, myocardial strain and aortic hemodynamics. BAV patients with no valvulopathy or isolated AS had similar LV parameters to controls excepting cardiac output (p < 0.05). AS + AR and post-surgical patients had abnormal LV volumetric and mass indices (p < 0.01). Post-surgical patients had decreased global longitudinal strain (p = 0.02); other subgroups had comparable strain to controls. Patients with valvulopathy demonstrated elevated velocity and wall shear stress (WSS) in the ascending aorta (AAo) and arch (p < 0.01), while those without valve dysfunction had only elevated AAo velocity (p = 0.03). Across the cohort, elevated AAo velocity and WSS correlated to higher LV mass (p < 0.01), and abnormal hemodynamics correlated to decreased strain rates (p < 0.045). Pediatric BAV patients demonstrate abnormalities in LV parameters as a function of valvular dysfunction, most significantly in children with AS + AR or prior valvotomy/valvuloplasty. Correlations between aortic hemodynamics, LV mass and strain suggest valvular dysfunction could drive LV remodeling. Multiparametric CMR assessment in pediatric BAV may help stratify risk for cardiac remodeling and dysfunction.

Monoclonal antibody targeting of fibroblast growth factor receptor 1c causes cardiac valvulopathy in rats.

Fibroblast Growth Factors (FGFs) and their receptors (FGFRs) have been proposed as potential drug targets for the treatment of obesity. The aim of this study was to assess the potential toxicity in rats of three anti-FGFR1c mAbs with differential binding activity prior to clinical development. Groups of male rats received weekly injections of either one of two FGFR1c-specific mAbs or an FGFR1c/FGFR4-specific mAb at 10 mg/kg for up to 4 weeks. All three mAbs caused significant reductions in food intake and weight loss leading to some animals being euthanized early for welfare reasons. In all three groups given these mAbs, microscopic changes were seen in the bones and heart valves. In the bones of the femoro-tibial joint, thickening of the diaphyseal cortex of long bones, due to deposition of well organized new lamellar bone, indicated that an osteogenic effect was observed. In the heart, valvulopathy described as an endocardial myxomatous change affecting the mitral, pulmonary, tricuspid and aortic valves was observed in all mAb-treated animals. The presence of FGFR1 mRNA expression in the heart valves was confirmed using in situ hybridization. Targeting the FGF-FGFR1c pathway with anti-FGFR1c mAbs leads to drug induced valvulopathy in rats. In effect, this precluded the development of these mAbs as potential anti-obesity drugs. The valvulopathy observed was similar to that described for fenfluramine and dexafenfluramine. The pathogenesis of the drug-induced valvulopathy is considered FGFR1c-mediated, based on the specificity of the mAbs and FGFR1 mRNA expression in the heart valves.

Hemodynamics driven cardiac valve morphogenesis.

Mechanical forces are instrumental to cardiovascular development and physiology. The heart beats approximately 2.6 billion times in a human lifetime and heart valves ensure that these contractions result in an efficient, unidirectional flow of the blood. Composed of endocardial cells (EdCs) and extracellular matrix (ECM), cardiac valves are among the most mechanically challenged structures of the body both during and after their development. Understanding how hemodynamic forces modulate cardiovascular function and morphogenesis is key to unraveling the relationship between normal and pathological cardiovascular development and physiology. Most valve diseases have their origins in embryogenesis, either as signs of abnormal developmental processes or the aberrant re-expression of fetal gene programs normally quiescent in adulthood. Here we review recent discoveries in the mechanobiology of cardiac valve development and introduce the latest technologies being developed in the zebrafish, including live cell imaging and optical technologies, as well as modeling approaches that are currently transforming this field. This article is part of a Special Issue entitled: Cardiomyocyte Biology: Integration of Developmental and Environmental Cues in the Heart edited by Marcus Schaub and Hughes Abriel.

Surveillance for Q Fever Endocarditis in the United States, 1999-2015.

BACKGROUND: Q fever is a worldwide zoonosis caused by Coxiella burnetii. In some persons, particularly those with cardiac valve disease, infection with C. burnetii can cause a life-threatening infective endocarditis. There are few descriptive analyses of Q fever endocarditis in the United States. METHODS: Q fever case report forms submitted during 1999-2015 were reviewed to identify reports describing endocarditis. Cases were categorized as confirmed or probable using criteria defined by the Council for State and Territorial Epidemiologists (CSTE). Demographic, laboratory, and clinical data were analyzed. RESULTS: Of 140 case report forms reporting endocarditis, 49 met the confirmed definition and 36 met the probable definition. Eighty-two percent were male and the median age was 57 years (range, 16-87 years). Sixty-seven patients (78.8%) were hospitalized, and 5 deaths (5.9%) were reported. Forty-five patients (52.9%) had a preexisting valvulopathy. Eight patients with endocarditis had phase I immunoglobulin G antibody titers >800 but did not meet the CSTE case definition for Q fever endocarditis. CONCLUSIONS: These data summarize a limited set of clinical and epidemiological features of Q fever endocarditis collected through passive surveillance in the United States. Some cases of apparent Q fever endocarditis could not be classified by CSTE laboratory criteria, suggesting that comparison of phase I and phase II titers could be reexamined as a surveillance criterion. Prospective analyses of culture-negative endocarditis are needed to better assess the clinical spectrum and magnitude of Q fever endocarditis in the United States.

No Such Thing as Chronic Q Fever.

Modern diagnostic methods enable clinicians to look beyond a diagnosis of chronic Q fever and discern whether patients instead have persistent focalized Coxiella burnetii infection(s). Use of these methods and development of criteria to define and treat such infections, especially cardiovascular infections, will improve the prognosis for patients previously thought to have chronic Q fever.

Risk of cardiac valvulopathy with use of bisphosphonates: a population-based, multi-country case-control study.

UNLABELLED: Analyses of healthcare data from 30 million individuals in three countries showed that current use of bisphosphonates may be associated with a small increased risk of cardiac valvulopathy (vs. those not exposed within the previous year), although confounding cannot be entirely ruled out. The observed tendency for decreased valvulopathy risk with cumulative duration of bisphosphonate use >6 months may even indicate a protective effect with prolonged use. Further studies are still needed to evaluate whether bisphosphonates increase or decrease the risk of valvulopathy. INTRODUCTION: A signal of cardiac valve disorders with use of bisphosphonates was identified in the literature and EudraVigilance database, which contains reports of suspected adverse drug reactions from worldwide sources. The aim of this study was to evaluate the association using population-based healthcare data. METHODS: This was a case-control study among users of bisphosphonates and other drugs for osteoporosis in six healthcare databases covering over 30 million individuals in Italy, Netherlands and the UK from 1996 to 2012. Prescriptions/dispensations were used to assess drug exposure. Newly diagnosed cases of cardiac valvulopathy were identified via disease codes/free-text search. Controls were matched to each case by age, sex, database and index date. Adjusted odds ratios (ORs) were estimated using conditional logistic regression for the pooled data and meta-analysis of individual database risk estimates. RESULTS: A small but statistically significant association was found between exposure to bisphosphonates as a class and risk of valvulopathy. Overall risk was 18 % higher (95 % CI 12-23 %) in those currently exposed to any bisphosphonate (mainly alendronate and risedronate) vs. those not exposed within the previous year. Risk of valve regurgitation was 14 % higher (95 % CI 7-22 %). Decreased valvulopathy risk was observed with longer cumulative duration of bisphosphonate use, compared to use of less than 6 months. Meta-analyses of database-specific estimates confirmed results from pooled analyses. CONCLUSIONS: The observed increased risks of cardiac valvulopathy with bisphosphonate use, although statistically significant, were quite small and unlikely to be clinically significant. Further studies are still needed to evaluate whether bisphosphonates increase or decrease the risk of valvulopathy and to investigate possible mechanisms for the association.

Novel X-linked syndrome of cardiac valvulopathy, keloid scarring, and reduced joint mobility due to filamin A substitution G1576R.

Filamin A (FLNA) is known to be involved in intracellular actin binding, cell migration, scaffolding, and signaling. We report a novel X-linked syndrome characterized by cardiac valvular disease, keloid scarring and reduced joint mobility in male second cousins due to a previously unreported mutation in FLNA. Whole exome sequencing was performed using standard methods and segregation analysis was performed in affected and non-affected family members. A novel hemizygous c.4726G>A (p.G1576R) mutation in FLNA was detected. Segregation analysis performed on multiple maternal family members showed c.4726G>A (p.G1576R) segregated with disease in an X-linked inheritance pattern. The findings in these cases are distinct from previously described FLNA related disorders by virtue of decreased joint mobility and spontaneous keloid scarring. They occur in association with a novel mutation and represent a novel genetic syndrome.

Association of Mitral Valve Prolapse With Infective Endocarditis Due to Viridans Group Streptococci.

Although patients with certain cardiac valve abnormalities have increased risk of infective endocarditis (IE), it is unknown whether these abnormalities are associated with specific pathogens in IE cases. We report a strong association between mitral valve prolapse and viridans group streptococcal IE in a population-based cohort from Olmsted County, Minnesota.

Cardiovascular manifestations in Marfan syndrome and related diseases; multiple genes causing similar phenotypes.

Cardiovascular abnormalities are the major cause of morbidity and mortality in Marfan syndrome (MFS) and a few clinically related diseases that share, with MFS, the pathogenic contribution of dysregulated transforming growth factor ß (TGFß) signaling. They include Loeys-Dietz syndrome, Shprintzen-Goldberg syndrome, aneurysm-osteoarthritis syndrome and syndromic thoracic aortic aneurysms. Unlike the causal association of MFS with mutations in an extracellular matrix protein (ECM), the aforementioned conditions are due to defects in components of the TGFß pathway. While TGFß antagonism is being considered as a potential new therapy for these heritable syndromes, several points still need to be clarified in relevant animal models before this strategy could be safely applied to patients. Among others, unresolved issues include whether elevated TGFß signaling is responsible for all MFS manifestations and is the common trigger of disease in MFS and related conditions. The scope of our review is to highlight the clinical and experimental findings that have forged our understanding of the natural history and molecular pathogenesis of cardiovascular manifestations in this group of syndromic conditions.

High hematocrit resulting from administration of erythropoiesis-stimulating agents is not fully predictive of mortality or toxicities in preclinical species.

We conducted a retrospective analysis of publicly available preclinical toxicology studies with erythropoiesis-stimulating agents (ESAs) to examine common adverse events in rats, Beagle dogs, and cynomolgus monkeys. Mortality and/or thrombotic events were reported sporadically in a subset of studies and attributed to the high hematocrit (HCT) achieved in the animals. However, similarly high HCT was achieved in both high-dose and low-dose groups, but there were no reported adverse events in the low-dose group suggesting HCT was not the sole contributing factor leading to toxicity. Our analysis indicated that increased dose, dose frequency, and dosing duration in addition to high HCT contributed to mortality and thrombosis. To further evaluate this relationship, the incidence of toxicities was compared in rats administered an experimental hyperglycosylated analog of recombinant human erythropoietin (AMG 114) at varying dosing schedules in 1-month toxicity studies. The incidence of mortality and thrombotic events increased in higher dose groups and when dosed more frequently, despite a similarly high HCT in all animals. The results from the investigative study and retrospective analysis demonstrate that ESA-related toxicities in preclinical species are associated with dose level, dose frequency, and dosing duration, and not solely dependent upon a high HCT.