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.

Profibrotic VEGFR3-Dependent Lymphatic Vessel Growth in Autoimmune Valvular Carditis.

BACKGROUND: Rheumatic heart disease is the major cause of valvular heart disease in developing nations. Endothelial cells (ECs) are considered crucial contributors to rheumatic heart disease, but greater insight into their roles in disease progression is needed. METHODS: We used a Cdh5-driven EC lineage-tracing approach to identify and track ECs in the K/B.g7 model of autoimmune valvular carditis. Single-cell RNA sequencing was used to characterize the EC populations in control and inflamed mitral valves. Immunostaining and conventional histology were used to evaluate lineage tracing and validate single-cell RNA-sequencing findings. The effects of VEGFR3 (vascular endothelial growth factor receptor 3) and VEGF-C (vascular endothelial growth factor C) inhibitors were tested in vivo. The functional impact of mitral valve disease in the K/B.g7 mouse was evaluated using echocardiography. Finally, to translate our findings, we analyzed valves from human patients with rheumatic heart disease undergoing mitral valve replacements. RESULTS: Lineage tracing in K/B.g7 mice revealed new capillary lymphatic vessels arising from valve surface ECs during the progression of disease in K/B.g7 mice. Unsupervised clustering of mitral valve single-cell RNA-sequencing data revealed novel lymphatic valve ECs that express a transcriptional profile distinct from other valve EC populations including the recently identified PROX1 (Prospero homeobox protein 1)+ lymphatic valve ECs. During disease progression, these newly identified lymphatic valve ECs expand and upregulate a profibrotic transcriptional profile. Inhibiting VEGFR3 through multiple approaches prevented expansion of this mitral valve lymphatic network. Echocardiography demonstrated that K/B.g7 mice have left ventricular dysfunction and mitral valve stenosis. Valve lymphatic density increased with age in K/B.g7 mice and correlated with worsened ventricular dysfunction. Importantly, human rheumatic valves contained similar lymphatics in greater numbers than nonrheumatic controls. CONCLUSIONS: These studies reveal a novel mode of inflammation-associated, VEGFR3-dependent postnatal lymphangiogenesis in murine autoimmune valvular carditis, with similarities to human rheumatic heart disease.

Stages of Valvular Heart Disease Among Older Adults in the Community: The Atherosclerosis Risk in Communities Study.

BACKGROUND: Limited data exist on American College of Cardiology/American Heart Association valvular heart disease (VHD) stage prevalence, progression, and association with incident cardiovascular diseases in late life. METHODS: Participants in the ARIC study (Atherosclerosis Risk in Communities), a prospective community-based cohort study, underwent protocol echocardiography at ARIC visits 5 (2011-2013) and 7 (2018-2019), and their aortic stenosis, aortic regurgitation, mitral stenosis, and mitral regurgitation stage were defined according to American College of Cardiology/American Heart Association guidelines. The overall VHD stage prevalence at visit 5 was measured. The associations between VHD stages and incident adjudicated death, heart failure, coronary heart disease, stroke, and atrial fibrillation were assessed with Cox proportional hazard models adjusted for age, sex, race, hypertension, diabetes, prior myocardial infarction, heart failure, body mass index, study center, systolic blood pressure, estimated glomerular filtration rate, and low-density lipoprotein at visit 5. Longitudinal changes in VHD stage prevalence over ≈6 years were estimated with inverse probability of attrition weights to account for participant attrition. RESULTS: Among 6118 ARIC participants, the mean±SD age was 76±5 years, 42% were male, and 22% reported Black race. Stage A VHD was present in 39%, stage B in 17%, and stage C/D in 1.1%;, 0.7% had previously undergone valve replacement or repair. A graded association was observed between stage A, B, and C/D VHD and risk of all-cause mortality, incident heart failure, incident atrial fibrillation, and incident coronary heart disease, but not incident stroke. Similar findings were observed for stages of each valvular lesion individually. During the 6.6 years (interquartile range, 6.1-7.0 years) between visits 5 and 7 (mean age, 81±4 years), the prevalence of freedom from VHD stage decreased from 43% to 24%, whereas the prevalence of stage C/D VHD increased from 1% to 7%. CONCLUSIONS: Subclinical VHD is common in older adults, with 39% at risk (stage A) and 17% with progressive VHD (stage B), and is independently associated with risk of incident cardiovascular events. VHD stages progress over 6 years in late life, with a several-fold increase in prevalence of severe VHD (stage C/D), highlighting the public health importance of interventions to mitigate VHD progression.

Sex Differences and Similarities in Valvular Heart Disease.

As populations age worldwide, the burden of valvular heart disease has grown exponentially, and so has the proportion of affected women. Although rheumatic valve disease is declining in high-income countries, degenerative age-related causes are rising. Calcific aortic stenosis and degenerative mitral regurgitation affect a significant proportion of elderly women, particularly those with comorbidities. Women with valvular heart disease have been underrepresented in many of the landmark studies which form the basis for guideline recommendations. As a consequence, surgical referrals in women have often been delayed, with worse postoperative outcomes compared with men. As described in this review, a more recent effort to include women in research studies and clinical trials has increased our knowledge about sex-based differences in epidemiology, pathophysiology, diagnostic criteria, treatment options, outcomes, and prognosis.

[Update on the treatment of aortic valve stenosis in symptomatic and asymptomatic patients]. / Update zur Behandlung der Aortenklappenstenose bei symptomatischen und asymptomatischen Patienten.

Aortic valve stenosis is one of the most frequent valvular heart diseases requiring treatment in industrialized countries. The symptom onset is associated with a significantly increased mortality, so that there is a clear indication for treatment in patients with severe, symptomatic aortic valve stenosis; however, data on the optimal treatment of patients with asymptomatic aortic valve stenosis are scarce. Smaller studies in the field of cardiac surgery suggest that early surgical valve replacement is superior to a conservative approach. For this reason, the results of additional adequately powered randomized trials are awaited with great interest. In this year numerous long-term results from randomized comparisons of the two available treatment options (surgical versus transcatheter aortic valve replacement) were published, which will further guide the heart team to find the best treatment approach for each individual.

Morphology, Clinical Associations, and Pathologic Follow-up of Quadricuspid Aortic Valves in Children.

While quadricuspid morphology is commonly observed in truncal valves, quadricuspid aortic valves (QAV) are rare and their natural history is not well described. This retrospective study of 37 patients describes the diagnostic associations and morphologic variability of QAVs in children (median age at diagnosis 4.3 y IQR 0-12 y). Associated congenital heart diseases were present in 54% (most commonly tetralogy of Fallot (TOF) and valvar pulmonary stenosis). Among patients with isolated QAV, 11 had genetic syndrome and 5 had skeletal anomalies. Valve morphology was most commonly type B (41%) and A (35%; Hurvitz and Roberts). Dilated aortic root (Z ≥ 2) was present in 5 and dilated ascending aorta in 9 patients at diagnosis. All patients with type C (n = 3) and G (n = 1) had aortic dilation. At diagnosis, >mild AR was rare (n = 1), mild regurgitation was common (n = 12, 32%), >mild AS was rare (n = 2), and mild AS was uncommon (n = 4). Over a median follow-up of 3.3y (IQR 0.9-11y), progression of AR was seen in 2 patients and progression of aortic root or ascending aorta dilation (increase in Z score by ≥ 2) was seen in 5 patients. In conclusion, QAV is a rare congenital anomaly and about half of the cases are found in hearts that are otherwise structurally normal. A relatively high prevalence is seen in patients with TOF, pulmonary stenosis, skeletal deformities, and genetic syndromes. Meticulous evaluation of aortic valve morphology should be conducted on echocardiograms performed for these indications.

Prothymosin Alpha: A Novel Contributor to Estradiol Receptor Alpha-Mediated CD8+ T-Cell Pathogenic Responses and Recognition of Type 1 Collagen in Rheumatic Heart Valve Disease.

BACKGROUND: Rheumatic heart valve disease (RHVD) is a leading cause of cardiovascular death in low- and middle-income countries and affects predominantly women. The underlying mechanisms of chronic valvular damage remain unexplored and regulators of sex predisposition are unknown. METHODS: Proteomics analysis of human heart valves (nondiseased aortic valves, nondiseased mitral valves [NDMVs], valves from patients with rheumatic aortic valve disease, and valves from patients with rheumatic mitral valve disease; n=30) followed by system biology analysis identified ProTα (prothymosin alpha) as a protein associated with RHVD. Histology, multiparameter flow cytometry, and enzyme-linked immunosorbent assay confirmed the expression of ProTα. In vitro experiments using peripheral mononuclear cells and valvular interstitial cells were performed using multiparameter flow cytometry and quantitative polymerase chain reaction. In silico analysis of the RHVD and Streptococcuspyogenes proteomes were used to identify mimic epitopes. RESULTS: A comparison of NDMV and nondiseased aortic valve proteomes established the baseline differences between nondiseased aortic and mitral valves. Thirteen unique proteins were enriched in NDMVs. Comparison of NDMVs versus valves from patients with rheumatic mitral valve disease and nondiseased aortic valves versus valves from patients with rheumatic aortic valve disease identified 213 proteins enriched in rheumatic valves. The expression of the 13 NDMV-enriched proteins was evaluated across the 213 proteins enriched in diseased valves, resulting in the discovery of ProTα common to valves from patients with rheumatic mitral valve disease and valves from patients with rheumatic aortic valve disease. ProTα plasma levels were significantly higher in patients with RHVD than in healthy individuals. Immunoreactive ProTα colocalized with CD8+ T cells in RHVD. Expression of ProTα and estrogen receptor alpha correlated strongly in circulating CD8+ T cells from patients with RHVD. Recombinant ProTα induced expression of the lytic proteins perforin and granzyme B by CD8+ T cells as well as higher estrogen receptor alpha expression. In addition, recombinant ProTα increased human leukocyte antigen class I levels in valvular interstitial cells. Treatment of CD8+ T cells with specific estrogen receptor alpha antagonist reduced the cytotoxic potential promoted by ProTα. In silico analysis of RHVD and Spyogenes proteomes revealed molecular mimicry between human type 1 collagen epitope and bacterial collagen-like protein, which induced CD8+ T-cell activation in vitro. CONCLUSIONS: ProTα-dependent CD8+ T-cell cytotoxicity was associated with estrogen receptor alpha activity, implicating ProTα as a potential regulator of sex predisposition in RHVD. ProTα facilitated recognition of type 1 collagen mimic epitopes by CD8+ T cells, suggesting mechanisms provoking autoimmunity.

rECHOmmend: An ECG-Based Machine Learning Approach for Identifying Patients at Increased Risk of Undiagnosed Structural Heart Disease Detectable by Echocardiography.

BACKGROUND: Timely diagnosis of structural heart disease improves patient outcomes, yet many remain underdiagnosed. While population screening with echocardiography is impractical, ECG-based prediction models can help target high-risk patients. We developed a novel ECG-based machine learning approach to predict multiple structural heart conditions, hypothesizing that a composite model would yield higher prevalence and positive predictive values to facilitate meaningful recommendations for echocardiography. METHODS: Using 2 232 130 ECGs linked to electronic health records and echocardiography reports from 484 765 adults between 1984 to 2021, we trained machine learning models to predict the presence or absence of any of 7 echocardiography-confirmed diseases within 1 year. This composite label included the following: moderate or severe valvular disease (aortic/mitral stenosis or regurgitation, tricuspid regurgitation), reduced ejection fraction <50%, or interventricular septal thickness >15 mm. We tested various combinations of input features (demographics, laboratory values, structured ECG data, ECG traces) and evaluated model performance using 5-fold cross-validation, multisite validation trained on 1 site and tested on 10 independent sites, and simulated retrospective deployment trained on pre-2010 data and deployed in 2010. RESULTS: Our composite rECHOmmend model used age, sex, and ECG traces and had a 0.91 area under the receiver operating characteristic curve and a 42% positive predictive value at 90% sensitivity, with a composite label prevalence of 17.9%. Individual disease models had area under the receiver operating characteristic curves from 0.86 to 0.93 and lower positive predictive values from 1% to 31%. Area under the receiver operating characteristic curves for models using different input features ranged from 0.80 to 0.93, increasing with additional features. Multisite validation showed similar results to cross-validation, with an aggregate area under the receiver operating characteristic curve of 0.91 across our independent test set of 10 clinical sites after training on a separate site. Our simulated retrospective deployment showed that for ECGs acquired in patients without preexisting structural heart disease in the year 2010, 11% were classified as high risk and 41% (4.5% of total patients) developed true echocardiography-confirmed disease within 1 year. CONCLUSIONS: An ECG-based machine learning model using a composite end point can identify a high-risk population for having undiagnosed, clinically significant structural heart disease while outperforming single-disease models and improving practical utility with higher positive predictive values. This approach can facilitate targeted screening with echocardiography to improve underdiagnosis of structural heart disease.

The role of echocardiographic screening in reducing the burden of rheumatic heart disease in Latin America.

The objectives of this article are to reflect on the rationale behind the use of echocardiographic screening for rheumatic heart disease and to provide key recommendations about steps needed to implement and improve echocardiographic screening programs in Latin America. Rheumatic heart disease remains a public health problem affecting mainly low-income and lower-middle-income countries and populations. Latin America is an area with economic inequalities, and the epidemiology of rheumatic heart disease remains largely unknown. Echocardiographic screening is useful for updating the epidemiology and providing early diagnosis of the disease. We discuss different approaches used in successful echocardiographic screening programs worldwide and in Latin America. We then identify the key elements needed to establish successful echocardiographic screening programs in Latin America, including increased awareness and involvement from multiple sectors (e.g. the community, health care professionals, scientific organizations and public health entities), identification of areas in need, development of a plan and structure that include different screening approaches, and how to ensure appropriate follow up for those who screen positive.

Los objetivos de este artículo son reflexionar sobre los fundamentos que justifican el uso del tamizaje ecocardiográfico para detectar la cardiopatía reumática y ofrecer algunas recomendaciones importantes sobre los pasos que habría que dar para poner en marcha programas de tamizaje ecocardiográfico y mejorar los existentes en América Latina. La cardiopatía reumática sigue siendo un problema de salud pública que afecta principalmente a países y grupos poblacionales de ingresos bajos y medianos bajos. América Latina es una región de grandes desigualdades económicas y las características epidemiológicas de la cardiopatía reumática siguen siendo desconocidas en gran medida. El tamizaje ecocardiográfico resulta útil para actualizar los datos epidemiológicos y posibilitar un diagnóstico temprano de la enfermedad. En este artículo se analizan los diferentes enfoques empleados en algunos programas de tamizaje ecocardiográfico eficaces de distintas partes del mundo, incluida América Latina. A continuación se determinan los elementos clave necesarios para establecer programas eficaces de tamizaje ecocardiográfico en América Latina, incluida una mayor concientización y participación de diversos sectores (p. ej., la comunidad, los profesionales de salud, las organizaciones científicas y las entidades de salud pública), la identificación de las zonas más necesitadas, la elaboración de un plan y una estructura que incluyan diferentes abordajes del tamizaje, y el modo de garantizar un seguimiento adecuado de aquellas personas con un resultado positivo en el tamizaje.

Os objetivos deste artigo são oferecer observações sobre a fundamentação do uso da triagem ecocardiográfica para doença cardíaca reumática e fornecer recomendações importantes sobre as etapas necessárias para implementar e melhorar os programas de triagem ecocardiográfica na América Latina. A doença cardíaca reumática continua sendo um problema de saúde pública que afeta principalmente países e populações de renda baixa e média-baixa. A América Latina é uma área com desigualdades econômicas, e a epidemiologia da doença cardíaca reumática continua amplamente desconhecida. A triagem ecocardiográfica serve para atualizar a epidemiologia e proporcionar o diagnóstico precoce da doença. Examinamos as diferentes abordagens usadas em programas de triagem ecocardiográfica bem-sucedidos em todo o mundo e na América Latina. Em seguida, identificamos os principais elementos necessários para estabelecer programas de triagem ecocardiográfica com sucesso na América Latina. Tais programas incluiriam maior conscientização e envolvimento de vários setores (por exemplo, a comunidade, profissionais de saúde, organizações científicas e entidades de saúde pública), identificação de áreas carentes, desenvolvimento de um plano e estrutura abrangendo diferentes abordagens de triagem e formas de garantir o seguimento adequado de pessoas com resultado positivo na triagem.

CARDIOKIN1: Computational Assessment of Myocardial Metabolic Capability in Healthy Controls and Patients With Valve Diseases.

BACKGROUND: Many heart diseases can result in reduced pumping capacity of the heart muscle. A mismatch between ATP demand and ATP production of cardiomyocytes is one of the possible causes. Assessment of the relation between myocardial ATP production (MVATP) and cardiac workload is important for better understanding disease development and choice of nutritional or pharmacologic treatment strategies. Because there is no method for measuring MVATP in vivo, the use of physiology-based metabolic models in conjunction with protein abundance data is an attractive approach. METHOD: We developed a comprehensive kinetic model of cardiac energy metabolism (CARDIOKIN1) that recapitulates numerous experimental findings on cardiac metabolism obtained with isolated cardiomyocytes, perfused animal hearts, and in vivo studies with humans. We used the model to assess the energy status of the left ventricle of healthy participants and patients with aortic stenosis and mitral valve insufficiency. Maximal enzyme activities were individually scaled by means of protein abundances in left ventricle tissue samples. The energy status of the left ventricle was quantified by the ATP consumption at rest (MVATP[rest]), at maximal workload (MVATP[max]), and by the myocardial ATP production reserve, representing the span between MVATP(rest) and MVATP(max). RESULTS: Compared with controls, in both groups of patients, MVATP(rest) was increased and MVATP(max) was decreased, resulting in a decreased myocardial ATP production reserve, although all patients had preserved ejection fraction. The variance of the energetic status was high, ranging from decreased to normal values. In both patient groups, the energetic status was tightly associated with mechanic energy demand. A decrease of MVATP(max) was associated with a decrease of the cardiac output, indicating that cardiac functionality and energetic performance of the ventricle are closely coupled. CONCLUSIONS: Our analysis suggests that the ATP-producing capacity of the left ventricle of patients with valvular dysfunction is generally diminished and correlates positively with mechanical energy demand and cardiac output. However, large differences exist in the energetic state of the myocardium even in patients with similar clinical or image-based markers of hypertrophy and pump function. Registration: URL: https://www.clinicaltrials.gov; Unique identifiers: NCT03172338 and NCT04068740.

A deep learning-based automatic analysis of cardiovascular borders on chest radiographs of valvular heart disease: development/external validation.

OBJECTIVES: Cardiovascular border (CB) analysis is the primary method for detecting and quantifying the severity of cardiovascular disease using posterior-anterior chest radiographs (CXRs). This study aimed to develop and validate a deep learning-based automatic CXR CB analysis algorithm (CB_auto) for diagnosing and quantitatively evaluating valvular heart disease (VHD). METHODS: We developed CB_auto using 816 normal and 798 VHD CXRs. For validation, 640 normal and 542 VHD CXRs from three different hospitals and 132 CXRs from a public dataset were assigned. The reliability of the CB parameters determined by CB_auto was evaluated. To evaluate the differences between parameters determined by CB_auto and manual CB drawing (CB_hand), the absolute percentage measurement error (APE) was calculated. Pearson correlation coefficients were calculated between CB_hand and echocardiographic measurements. RESULTS: CB parameters determined by CB_auto yielded excellent reliability (intraclass correlation coefficient > 0.98). The 95% limits of agreement for the cardiothoracic ratio were 0.00 ± 0.04% without systemic bias. The differences between parameters determined by CB_auto and CB_hand as defined by the APE were < 10% for all parameters except for carinal angle and left atrial appendage. In the public dataset, all CB parameters were successfully drawn in 124 of 132 CXRs (93.9%). All CB parameters were significantly greater in VHD than in normal controls (all p < 0.05). All CB parameters showed significant correlations (p < 0.05) with echocardiographic measurements. CONCLUSIONS: The CB_auto system empowered by deep learning algorithm provided highly reliable CB measurements that could be useful not only in daily clinical practice but also for research purposes. KEY POINTS: • A deep learning-based automatic CB analysis algorithm for diagnosing and quantitatively evaluating VHD using posterior-anterior chest radiographs was developed and validated. • Our algorithm (CB_auto) yielded comparable reliability to manual CB drawing (CB_hand) in terms of various CB measurement variables, as confirmed by external validation with datasets from three different hospitals and a public dataset. • All CB parameters were significantly different between VHD and normal control measurements, and echocardiographic measurements were significantly correlated with CB parameters measured from normal control and VHD CXRs.

Non-vitamin K antagonist oral anticoagulants in patients with valvular heart disease.

The non-vitamin K antagonist oral anticoagulants (NOACs) dabigatran, rivaroxaban, apixaban, and edoxaban have transformed the management of atrial fibrillation (AF), but are only approved by regulatory authorities for stroke prophylaxis in patients with so-called "non-valvular AF." This terminology has spawned confusion about which patients with valvular heart disease benefit from NOACs and which should be treated with vitamin K antagonists (VKAs) instead. Patients with valvular heart disease other than mechanical prosthetic valves or severe mitral stenosis (including those with bioprosthetic valves) were included in pivotal trials demonstrating the benefit of NOACs over VKAs, and consensus guidelines recommend NOACs over VKAs in these patients. Subsequent devoted randomized controlled trials in patients with AF and bioprosthetic valves, including transcatheter valves, have confirmed the safety of NOACs in this population. In patients with rheumatic mitral stenosis, observational studies indicate that NOACs may be safe and effective, but randomized controlled trials are ongoing. By contrast, a randomized controlled trial showed that dabigatran is harmful in patients with mechanical prosthetic mitral valves; however, these data may not extrapolate to patients with mechanical valve prostheses in other locations or to other NOACs, and randomized controlled trials are ongoing. In this review, we discuss these data in greater depth, and make recommendations for the use of NOACs in patients with valvular heart disease.

Natural history of bicuspid aortic valves and ascending aortic aneurysms: Aortic center experience.

BACKGROUND AND AIM: The American Association of Thoracic Surgery published guidelines in 2018 encouraging regular surveillance rather than surgical intervention for ascending aortic aneurysms under 5.5 cm in both bicuspid aortic valve (BAV) and tricuspid aortic valve (TAV) patients. Since then, there have been limited studies reporting outcomes, especially by valve type. We aimed to analyze clinical outcomes including survival and aortic events in a cohort of BAV and TAV patients with ascending aortic aneurisms followed conservatively with routine computerized tomography  (CT) surveillance per current guidelines. METHODS: We followed 188 patients in our clinic between 2016 and 2019; 147 had two or more CT scans which allowed measurement of aortic growth. Echocardiogram data was evaluated for each patient. We identified similar cohorts of BAV (n = 32) and TAV (n = 64) patients matched by age, sex, hypertension, smoking history, family history of aortic disease, coronary artery disease, and hyperlipidemia. Univariate and multivariate analyses of the unmatched cohorts were performed. RESULTS: The mean aneurysm size was 4.3 ± 0.58 cm with 95% confidence interval (3.14, 5.46). This did not differ between BAV and TAV patients, nor did aneurysm growth rates. Overall adverse event rate (dissection, rupture, and death) was low for the entire cohort (BAV group, 3% and TAV group, 3.5%). Survival at 10 years for the entire cohort was 90 ± 32%. CONCLUSIONS: Regardless of aortic valve type, there was a similar natural history and low adverse event rate. In the absence of risk factors, conservative management can be accomplished with minimal risk to the patient.

Complete transcatheter versus complete surgical treatment in patients with aortic valve stenosis and concomitant coronary artery disease: Study-level meta-analysis with reconstructed time-to-event data.

OBJECTIVES: To compare outcomes of complete transcatheter (TAVI plus PCI) versus complete surgical (SAVR plus CABG) approach to treat patients with aortic stenosis (AS) and concomitant coronary artery disease (CAD). METHODS: Study-level meta-analysis with reconstructed time-to-event data including studies published by November 2021. The primary endpoints were 30-day mortality, overall survival, and major adverse cardiovascular and cerebrovascular events (MACCE). The secondary endpoints were 30-day stroke, myocardial infarction, and permanent pacemaker implantation (PPI); in-hospital major vascular events and acute kidney injury (AKI). RESULTS: Eight studies met our eligibility criteria, including a total of 33,286 patients (3448 for TAVI plus PCI and 29,838 for SAVR plus CABG). The pooled risk of 30-day mortality was lower for TAVI plus PCI (OR 0.63; 95% CI 0.51-0.80; p < .001). Patients undergoing TAVI plus PCI had lower risk of in-hospital AKI (OR 0.49; 95% CI 0.28-0.85; p = .01), however, higher risk of major vascular events (OR 7.33; 95% CI 1.80-29.85; p = .005) and higher risk of PPI (OR 2.96; 95% CI 1.80-4.85; p < .001). No statistically significant difference was observed for myocardial infarction and stroke between the groups. In the follow-up analyses, we observed a higher risk of mortality (HR 1.64, 95% CI 1.36-1.96, p < .001) and MACCE with TAVI plus PCI (HR 1.35 (95% CI 1.08-1.69, p = .009). CONCLUSION: Patients who undergo TAVI plus PCI (in comparison with SAVR plus CABG) initially experience lower rates of in-hospital death and AKI; however, they experience significantly lower survival rates and more MACCE at 5-year follow up. Structural heart surgeons and interventional cardiologists should consider these aspects when referring patients for one approach or the other.

Impact of left ventricle outflow tract calcification on the outcomes of transcatheter aortic valve implantation: A study-level meta-analysis.

OBJECTIVES: To assess the impact of left ventricle outflow tract calcification (LVOT) on the outcomes of transcatheter aortic valve implantation (TAVI). METHODS: Meta-analysis including studies published by October 2021. Primary endpoints were operative and 1-year mortality. The secondary endpoints were stroke, myocardial infarction, paravalvular leakage (PVL), new permanent pacemaker implantation (PPI), aortic annulus/root rupture. RESULTS: Nine studies met our eligibility criteria, including a total of 4459 patients (1330 patients with significant LVOT calcification and 3129 patients without significant LVOT calcification). Pooled risk of operative death was higher in the group with significant LVOT calcification (odds ratio [OR]: 2.28; 95% confidence interval [CI]: 1.33-3.91; p < .001). Worse 1-year survival was observed in the group with LVOT calcification (hazard ratio 1.53, 95% CI: 1.26-1.87, p < .001). Patients with significant LVOT calcification had higher risk of stroke (OR: 1.83; 95% CI: 1.08-3.09; p = .032), myocardial infarction (OR: 1.74; 95% CI: 1.08-2.80; p = .034), PVL (OR: 1.88; 95% CI: 1.09-3.22; p = .028) and aortic annulus/root rupture (OR: 7.48; 95% CI: 3.58-15.65; p = .002). We did not observe a statistically significant difference in the pooled results for new PPI between the groups (OR: 1.19; 95% CI: 0.79-1.80; p = .337). CONCLUSION: The presence of significant LVOT calcification increases the risk of periprocedural and 1-year mortality, stroke, myocardial infarction, PVL and aortic annulus/root rupture after TAVI. Self-expandable valves may be a preferrable option in this scenario. Structural heart surgeons and interventional cardiologists should consider this factor when referring patients for TAVI and technical aspects (such as the type of transcatheter heart valve to be deployed or the use of pre-/post-dilatation) should be factored in.

[Intraoperative transesophageal echocardiography for emergency diagnostics in noncardiac surgery patients]. / Intraoperative transösophageale Echokardiographie als Notfalldiagnostik bei nichtkardiochirurgischen Patienten.

Due to the development of compact and mobile devices, transesophageal echocardiography (TEE) is now being used as one important point-of-care diagnostic method in emergency rooms, intensive care units and operating rooms. In the first part of this advanced training series, general aspects of the examination method and the procedure as well as indications and contraindications were outlined. In addition, an overview of application areas beyond cardiac surgery in which TEE can be used to monitor the patient or to assist with the operative procedure was provided. In the second part, the main findings during intraoperative TEE in the event of hemodynamic instability or unexplained hypoxemia are presented. A shortened emergency examination as proposed by Reeves et al. is outlined. The article concludes with an outlook on semiautomatic interpretation software and computer-aided image acquisition.

Global, Regional, and National Burden of Calcific Aortic Valve and Degenerative Mitral Valve Diseases, 1990-2017.

BACKGROUND: Nonrheumatic valvular diseases are common; however, no studies have estimated their global or national burden. As part of the Global Burden of Disease Study 2017, mortality, prevalence, and disability-adjusted life-years (DALYs) for calcific aortic valve disease (CAVD), degenerative mitral valve disease, and other nonrheumatic valvular diseases were estimated for 195 countries and territories from 1990 to 2017. METHODS: Vital registration data, epidemiologic survey data, and administrative hospital data were used to estimate disease burden using the Global Burden of Disease Study modeling framework, which ensures comparability across locations. Geospatial statistical methods were used to estimate disease for all countries, because data on nonrheumatic valvular diseases are extremely limited for some regions of the world, such as Sub-Saharan Africa and South Asia. Results accounted for estimated level of disease severity as well as the estimated availability of valve repair or replacement procedures. DALYs and other measures of health-related burden were generated for both sexes and each 5-year age group, location, and year from 1990 to 2017. RESULTS: Globally, CAVD and degenerative mitral valve disease caused 102 700 (95% uncertainty interval [UI], 82 700-107 900) and 35 700 (95% UI, 30 500-42 500) deaths, and 12.6 million (95% UI, 11.4 million-13.8 million) and 18.1 million (95% UI, 17.6 million-18.6 million) prevalent cases existed in 2017, respectively. A total of 2.5 million (95% UI, 2.3 million-2.8 million) DALYs were estimated as caused by nonrheumatic valvular diseases globally, representing 0.10% (95% UI, 0.09%-0.11%) of total lost health from all diseases in 2017. The number of DALYs increased for CAVD and degenerative mitral valve disease between 1990 and 2017 by 101% (95% UI, 79%-117%) and 35% (95% UI, 23%-47%), respectively. There is significant geographic variation in the prevalence, mortality rate, and overall burden of these diseases, with highest age-standardized DALY rates of CAVD estimated for high-income countries. CONCLUSIONS: These global and national estimates demonstrate that CAVD and degenerative mitral valve disease are important causes of disease burden among older adults. Efforts to clarify modifiable risk factors and improve access to valve interventions are necessary if progress is to be made toward reducing, and eventually eliminating, the burden of these highly treatable diseases.

Omega-3 Polyunsaturated Fatty Acids Decrease Aortic Valve Disease Through the Resolvin E1 and ChemR23 Axis.

BACKGROUND: Aortic valve stenosis (AVS), which is the most common valvular heart disease, causes a progressive narrowing of the aortic valve as a consequence of thickening and calcification of the aortic valve leaflets. The beneficial effects of omega-3 polyunsaturated fatty acids (n-3 PUFAs) in cardiovascular prevention have recently been demonstrated in a large randomized, controlled trial. In addition, n-3 PUFAs serve as the substrate for the synthesis of specialized proresolving mediators, which are known by their potent beneficial anti-inflammatory, proresolving, and tissue-modifying properties in cardiovascular disease. However, the effects of n-3 PUFA and specialized proresolving mediators on AVS have not yet been determined. The aim of this study was to identify the role of n-3 PUFA-derived specialized proresolving mediators in relation to the development of AVS. METHODS: Lipidomic and transcriptomic analyses were performed in human tricuspid aortic valves. Apoe-/- mice and wire injury in C57BL/6J mice were used as models for mechanistic studies. RESULTS: We found that n-3 PUFA incorporation into human stenotic aortic valves was higher in noncalcified regions compared with calcified regions. Liquid chromatography tandem mass spectrometry-based lipid mediator lipidomics identified that the n-3 PUFA-derived specialized proresolving mediator resolvin E1 was dysregulated in calcified regions and acted as a calcification inhibitor. Apoe-/- mice expressing the Caenorhabditis elegans Fat-1 transgene (Fat-1tg×Apoe-/-), which enables the endogenous synthesis of n-3 PUFA and increased valvular n-3 PUFA content, exhibited reduced valve calcification, lower aortic valve leaflet area, increased M2 macrophage polarization, and improved echocardiographic parameters. Finally, abrogation of the resolvin E1 receptor ChemR23 enhanced disease progression, and the beneficial effects of Fat-1tg were abolished in the absence of ChemR23. CONCLUSIONS: n-3 PUFA-derived resolvin E1 and its receptor ChemR23 emerge as a key axis in the inhibition of AVS progression and may represent a novel potential therapeutic opportunity to be evaluated in patients with AVS.

Differentiation of left atrial appendage thrombus from circulatory stasis using cardiac CT radiomics in patients with valvular heart disease.

OBJECTIVES: To determine whether quantitative radiomic features from cardiac CT could differentiate the left atrial appendage (LAA) thrombus from circulatory stasis in patients with valvular heart disease. METHODS: Ninety-five consecutive patients with valvular heart disease and filling defects in LAA on two-phase cardiac CT from March 2016 to August 2018 were retrospectively enrolled and classified as having thrombus or stasis by transesophageal echocardiography or cardiac surgery. The ratio of Hounsfield units in the filling defects to those in the ascending aorta (AA) was calculated on early- and late-phase CT (LAA/AAE and LAA/AAL, respectively). Radiomic features were extracted from semi-automated three-dimensional segmentation of the filling defect on early-phase CT. The diagnostic ability of radiomic features for differentiating thrombus from stasis was assessed and compared to LAA/AAE and LAA/AAL by comparing the AUC of ROC curves. Diagnostic performances of CT attenuation ratios and radiomic features were validated with an independent validation set. RESULTS: Thrombus was diagnosed in 25 cases and stasis in 70. Sixty-eight radiomic features were extracted. Values of 8 wavelet-transformed features were lower in thrombus than in stasis (p < 0.001). The AUC value of a radiomic feature, wavelet_LHL, for diagnosing thrombus was 0.78, which was higher than that of LAA/AAE (AUC = 0.54, p = 0.025) and similar to that of LAA/AAL (AUC = 0.76, p = 0.773). In the validation set, the AUC of wavelet_LHL was 0.71, which was higher than that of LAA/AAE (AUC = 0.57, p = 0.391) and similar to that of LAA/AAL (AUC = 0.75, p = 0.707). CONCLUSIONS: Quantitative radiomic features from the early phase of cardiac CT may help diagnose LAA thrombus in patients with valvular heart disease. KEY POINTS: • Wavelet-transformed grey-level non-uniformity values from radiomic analysis are significantly lower for LAA thrombus than for circulatory stasis. • Radiomic features may have an additional value for differentiating LAA thrombus from circulatory stasis when interpreting single-phase cardiac CT. • Radiomic features extracted from single-phase images may show similar diagnostic ability as conventional quantitative analysis from two-phase images.

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.