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.

Stroke and Noninfective Native Valvular Disease.

PURPOSE OF REVIEW: Embolic stroke of undetermined source is a challenging clinical entity. While less common than atrial fibrillation and endocarditis, many noninfective heart valve lesions have been associated with stroke and may be considered as culprits for cerebral infarcts when other more common causes are excluded. This review discusses the epidemiology, pathophysiology, and management of noninfective valvular diseases that are commonly associated with stroke. RECENT FINDINGS: Calcific debris from degenerating aortic and mitral valves may embolize to the cerebral vasculature causing small- or large-vessel ischemia. Thrombus which may be adherent to calcified valvular structures or left-sided cardiac tumors may also embolize resulting in stroke. Tumors themselves, most commonly myxomas and papillary fibroelastomas, may fragment and travel to the cerebral vasculature. Despite this broad differential, many types of valve diseases are highly comorbid with atrial fibrillation and vascular atheromatous disease. Thus, a high index of suspicion for more common causes of stroke is needed, especially given that treatment for valvular lesions typically involves cardiac surgery whereas secondary prevention of stroke due to occult atrial fibrillation is readily accomplished with anticoagulation.

2020 ACC/AHA Guideline for the Management of Patients With Valvular Heart Disease: Executive Summary: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines.

AIM: This executive summary of the valvular heart disease guideline provides recommendations for clinicians to diagnose and manage valvular heart disease as well as supporting documentation to encourage their use. METHODS: A comprehensive literature search was conducted from January 1, 2010, to March 1, 2020, encompassing studies, reviews, and other evidence conducted on human subjects that were published in English from PubMed, EMBASE, Cochrane, Agency for Healthcare Research and Quality Reports, and other selected database relevant to this guideline. Structure: Many recommendations from the earlier valvular heart disease guidelines have been updated with new evidence and provides newer options for diagnosis and treatment of valvular heart disease. This summary includes only the recommendations from the full guideline which focus on diagnostic work-up, the timing and choice of surgical and catheter interventions, and recommendations for medical therapy. The reader is referred to the full guideline for graphical flow charts, text, and tables with additional details about the rationale for and implementation of each recommendation, and the evidence tables detailing the data considered in developing these guidelines.

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.

Timing of intervention in asymptomatic patients with valvular heart disease.

Current management of valvular heart disease (VHD) seeks to optimize long-term outcome by timely intervention. Recommendations for treatment of patients with symptoms due to severe valvular disease are based on a foundation of solid evidence. However, when to intervene in asymptomatic patients remains controversial and decision requires careful individual weighing of the potential benefits against the risk of intervention and its long-term consequences. The primary rationale for earlier intervention is prevention of irreversible left ventricular (LV) myocardial changes that might result in later clinical symptoms and adverse cardiac events. A number of outcome predictors have been identified that facilitate decision-making. This review summarizes current recommendations and discusses recently published data that challenge them suggesting even earlier intervention. In adults with asymptomatic aortic stenosis (AS), emerging risk markers include very severe valve obstruction, elevated serum natriuretic peptide levels, and imaging evidence of myocardial fibrosis or increased extracellular myocardial volume. Currently, transcatheter aortic valve implantation (TAVI) is not recommended for treatment of asymptomatic severe AS although this may change in the future. In patients with aortic regurgitation (AR), the potential benefit of early intervention in preventing LV dilation and dysfunction must be balanced against the long-term risk of a prosthetic valve, a particular concern because severe AR often occurs in younger patients with a congenital bicuspid valve. In patients with mitral stenosis, the option of transcatheter mitral balloon valvotomy tilts the balance towards earlier intervention to prevent atrial fibrillation, embolic events, and pulmonary hypertension. When chronic severe mitral regurgitation is due to mitral valve prolapse, anatomic features consistent with a high likelihood of a successful and durable valve repair favour early intervention. The optimal timing of intervention in adults with VHD is a constantly changing threshold that depends not only on the severity of valve disease but also on the safety, efficacy, and long-term durability of our treatment options.

Plasma lipids and risk of aortic valve stenosis: a Mendelian randomization study.

AIMS: Aortic valve stenosis is commonly considered a degenerative disorder with no recommended preventive intervention, with only valve replacement surgery or catheter intervention as treatment options. We sought to assess the causal association between exposure to lipid levels and risk of aortic stenosis. METHODS AND RESULTS: Causality of association was assessed using two-sample Mendelian randomization framework through different statistical methods. We retrieved summary estimations of 157 genetic variants that have been shown to be associated with plasma lipid levels in the Global Lipids Genetics Consortium that included 188 577 participants, mostly European ancestry, and genetic association with aortic stenosis as the main outcome from a total of 432 173 participants in the UK Biobank. Secondary negative control outcomes included aortic regurgitation and mitral regurgitation. The odds ratio for developing aortic stenosis per unit increase in lipid parameter was 1.52 [95% confidence interval (CI) 1.22-1.90; per 0.98 mmol/L] for low density lipoprotein (LDL)-cholesterol, 1.03 (95% CI 0.80-1.31; per 0.41 mmol/L) for high density lipoprotein (HDL)-cholesterol, and 1.38 (95% CI 0.92-2.07; per 1 mmol/L) for triglycerides. There was no evidence of a causal association between any of the lipid parameters and aortic or mitral regurgitation. CONCLUSION: Lifelong exposure to high LDL-cholesterol increases the risk of symptomatic aortic stenosis, suggesting that LDL-lowering treatment may be effective in its prevention.

Standardized Definition of Structural Valve Degeneration for Surgical and Transcatheter Bioprosthetic Aortic Valves.

Bioprostheses are prone to structural valve degeneration, resulting in limited long-term durability. A significant challenge when comparing the durability of different types of bioprostheses is the lack of a standardized terminology for the definition of a degenerated valve. This issue becomes especially important when we try to compare the degeneration rate of surgically inserted and transcatheter bioprosthetic valves. This document, by the VIVID (Valve-in-Valve International Data), proposes practical and standardized definitions of valve degeneration and provides recommendations for the timing of clinical and imaging follow-up assessments accordingly. Its goal is to improve the quality of research and clinical care for patients with deteriorated bioprostheses by providing objective and strict criteria that can be utilized in future clinical trials. We hope that the adoption of these criteria by both the cardiological and surgical communities will lead to improved comparability and interpretation of durability analyses.

Elevated blood pressure and risk of aortic valve disease: a cohort analysis of 5.4 million UK adults.

Aims: To test two related hypotheses that elevated blood pressure (BP) is a risk factor for aortic valve stenosis (AS) or regurgitation (AR). Methods and results: In this cohort study of 5.4 million UK patients with no known cardiovascular disease or aortic valve disease at baseline, we investigated the relationship between BP and risk of incident AS and AR using multivariable-adjusted Cox regression models. Over a median follow-up of 9.2 years, 20 680 patients (0.38%) were diagnosed with AS and 6440 (0.12%) patients with AR. Systolic BP (SBP) was continuously related to the risk of AS and AR with no evidence of a nadir down to 115 mmHg. Each 20 mmHg increment in SBP was associated with a 41% higher risk of AS (hazard ratio 1.41, 95% confidence interval 1.38-1.45) and a 38% higher risk of AR (1.38, 1.31-1.45). Associations were stronger in younger patients but with no strong evidence for interaction by gender or body mass index. Each 10 mmHg increment in diastolic BP was associated with a 24% higher risk of AS (1.24, 1.19-1.29) but not AR (1.04, 0.97-1.11). Each 15 mmHg increment in pulse pressure was associated with a 46% greater risk of AS (1.46, 1.42-1.50) and a 53% higher risk of AR (1.53, 1.45-1.62). Conclusion: Long-term exposure to elevated BP across its whole spectrum was associated with increased risk of AS and AR. The possible causal nature of the observed associations warrants further investigation.

Infective Endocarditis: Update on Epidemiology, Outcomes, and Management.

PURPOSE OF REVIEW: Infective endocarditis remains a highly mortal disease, yet the diagnosis often is missed or made only late in the disease course. The spectrum of patients presenting with endocarditis is shifting with different risk factors, predisposing patient characteristics, and treatment recommendations than in the past. This review addresses changes in the epidemiology of infective endocarditis, along with current diagnostic imaging modalities, treatment recommendations, and mortality trends. RECENT FINDINGS: Risk factors for endocarditis now include the growing population of adults with congenital heart disease and patients with frequent healthcare contact for other comorbidities, as well as patients who are hemodialysed and immunocompromised or use intravenous drugs. Although transthoracic and transesophageal echocardiography are essential for diagnosis, additional testing (nuclear, computed tomographic, and magnetic resonance imaging) is helpful in selected patients. Early surgical management, even in high-risk patients, has a mortality benefit because eradication of infection with antibiotics alone is difficult and because valve destruction often results in hemodynamic compromise. As part of a broad differential diagnosis, clinicians should consider the diagnosis of endocarditis in patients with risk factors, even when the clinical presentation is nonspecific. Blood cultures and echocardiography are the first steps for diagnosis. Other imaging modalities can enhance diagnosis, particularly in patients with intracardiac devices or prosthetic material. Evidence from observational studies support early surgical intervention to reduce morbidity and mortality from this lethal condition.

Elevated blood pressure and risk of mitral regurgitation: A longitudinal cohort study of 5.5 million United Kingdom adults.

BACKGROUND: Mitral regurgitation in people without prior cardiac disease is considered a degenerative disease with no established risk factors for its prevention. We aimed to test the hypothesis that elevated systolic blood pressure (SBP) across its usual spectrum is associated with higher risk of mitral regurgitation. METHODS AND FINDINGS: We used linked electronic health records from the United Kingdom Clinical Practice Research Datalink (CPRD) from 1 January 1990 to 31 December 2015. CPRD covers approximately 7% of the current UK population and is broadly representative of the population by age, sex, and ethnicity. About 5.5 million UK patients with no known cardiovascular or valve disease at baseline were included in this cohort study. We investigated the relationship between blood pressure (BP) and risk of mitral regurgitation using Cox regression models. Our primary exposure variable was SBP and our primary outcome was incident reports of mitral regurgitation, which were identified from hospital discharge reports or primary care records. Of the 5,553,984 patients in the CPRD that met our inclusion criteria, during the 10-year follow-up period, 28,655 (0.52%) were diagnosed with mitral regurgitation and a further 1,262 (0.02%) were diagnosed with mitral stenosis. SBP was continuously related to the risk of mitral regurgitation with no evidence of a nadir down to 115 mmHg (p < 0.001). Each 20 mmHg increment in SBP was associated with a 26% higher risk of mitral regurgitation (hazard ratio [HR] 1.26; CI 1.23, 1.29). The observed association was partially mediated by diseases affecting the left ventricle during follow-up (myocardial infarction [MI], ischaemic heart disease [IHD], cardiomyopathy, and heart failure). However, the percentage of excess risk mediated (PERM) by these proximate causes of secondary mitral regurgitation was only 13% (CI 6.1%, 20%), and accounting for them had little effect on the long-term association between SBP and mitral regurgitation (mediator-adjusted HR 1.22; CI 1.20, 1.25; p < 0.001). Associations were similar for each 10 mmHg increment in diastolic blood pressure (DBP) (p < 0.001) or each 15 mmHg increment in pulse pressure (PP) (p < 0.001). By contrast, there was no association between SBP and risk of mitral stenosis (HR per 20 mmHg higher SBP 1.03; CI 0.93, 1.14; p = 0.58). These analyses are based on routinely collected data from health records which may be sensitive to measurement errors, and the observed associations may not be generalizable to less severe and subclinical cases of mitral regurgitation. CONCLUSIONS: Long-term exposure to elevated BP across its whole spectrum is associated with an increased risk of primary and secondary mitral regurgitation. These findings suggest that BP control may be of importance in the prevention of mitral regurgitation.

Quantitating aortic regurgitation by cardiovascular magnetic resonance: significant variations due to slice location and breath holding.

OBJECTIVES: Compare variability in flow measurements by phase contrast MRI, performed at different locations in the aorta and pulmonary artery (PA) using breath-held (BH) and free-breathing (FB) sequences. METHODS: Fifty-seven patients with valvular heart disease, confirmed by echocardiography, were scanned using BH technique at 3 locations in the ascending aorta (SOV = sinus of Valsalva, STJ = sinotubular junction, ASC = ascending aorta at level of right pulmonary artery) and 2 locations in PA. Single FB measurement was obtained at STJ for aorta. Obtained metrics (SV = stroke volume, FV = forward volume, BV = backward volume, RF = regurgitant fraction) were evaluated separately for patients with aortic regurgitation (AR, n = 31) and mitral regurgitation (n = 26). RESULTS: No difference was noted between the two measurements in the PA. Significant differences were noted in measured SV at different aortic locations. SV measurements obtained at ASC correlated best with the measurements obtained in the PA. Strongest correlation of AR was measured at the STJ. CONCLUSION: Measurements of flow volumes by phase contrast MRI differ depending on slice location. When using stroke volumes to calculate pulmonary to systemic blood flow ratio (Qp/Qs), ASC should be used. For quantifying aortic regurgitation, measurement should be obtained at STJ. KEY POINTS: • Aortic regurgitation can be accurately measured by MRI. • Aortic regurgitation measurement by MRI varies according to the location where measured. • Aortic regurgitation can also be measured by MRI without breath hold.