History Of Aortic Stenosis Research Articles

Economic Benefits of Surgical Aortic Valve Replacement on Patients With Symptomatic Aortic Valve Regurgitation.

Aortic regurgitation is distinguished by the backflow of blood from the aorta into the left ventricle. American College of Cardiology/American Heart Association guidelines recommend surgical aortic valve replacement (SAVR) for patients with symptomatic aortic regurgitation (sAR). This study estimates the difference in mortality, health care use, and costs between patients with sAR who receive SAVR within 12 months of diagnosis versus those who do not. We used the Optum United Healthcare database to identify 132 317 patients diagnosed with sAR from 2016 to 2021 who had at least 6 months of enrollment before sAR and 12 months of enrollment after. Criteria were no history of aortic stenosis or transcatheter aortic valve replacement and ≥2 visits for heart failure, angina, dyspnea, or syncope. Outcomes were all-cause mortality, health care use, and annualized cost. Baseline differences in demographics and comorbidities were adjusted with inverse propensity score weighting. We modeled survival and estimated health care use and costs using Cox proportional hazards and general linear models, respectively. Of the 132 317 patients, 400 underwent SAVR within 12 months of diagnosis. They were on average younger, more often men, and with a slightly higher Elixhauser Comorbidity Index score. After inverse propensity score weighting, patients with sAR who had SAVR had lower mortality, fewer inpatient and emergency department visits, fewer hospital days, and lower annualized cost. SAVR performed within 12 months of an sAR diagnosis is associated with improved mortality and lower annualized health care use and costs. These clinical and economic benefits should be considered when managing patients with sAR.

Aortic valve replacement reduces mortality in moderate aortic stenosis: a systematic review and meta-analysis.

With the introduction of transcatheter aortic valve replacement and an evolving understanding of the natural progression and history of aortic stenosis, the potential for earlier intervention in appropriate patients is promising; however, the benefit of aortic valve replacement in moderate aortic stenosis remains unclear. Pubmed, Embase, and the Cochrane Library databases were searched up until 30th of December 2021 using keywords including moderate aortic stenosis and aortic valve replacement. Studies reporting all-cause mortality and outcomes in early aortic valve replacement (AVR) compared to conservative management in patients with moderate aortic stenosis were included. Hazard ratios were generated using random-effects meta-analysis to determine effect estimates. 3470 publications were screened with title and abstract review, which left 169 articles for full-text review. Of these studies, 7 met inclusion criteria and were included, totalling 4,827 patients. All studies treated AVR as a time-dependent co-variable in cox-regression multivariate analysis of all-cause mortality. Intervention with surgical or transcatheter AVR was associated with a 45% decreased risk of all-cause mortality (HR = 0.55 [0.42-0.68], I 2 = 51.5%, P < 0.001). All studies were representative of the overall cohort with appropriate sample sizes, with no evidence of publication, detection, or information biases in any of the studies. In this systematic review and meta-analysis, we report a 45% reduction in all-cause mortality in patients with moderate aortic stenosis who were treated with early aortic valve replacement compared to a strategy of conservative management. Randomised control trials are awaited to determine the utility of AVR in moderate aortic stenosis.

S2315 Epiglottic Calcification, a Rare a Cause of Dysphagia

Introduction: In consideration of dysphagia, most cases predominate in the oropharyngeal region with the remainder caused primarily by esophageal causes. Lesser known and studied is the development of dysphagia and globus sensation from epiglottic pathology, namely epiglottic calcification. With less than a dozen published cases in literature, very little data exists on identification, diagnosis, and treatment of this known cause of morbidity. Here we present a case of oropharyngeal dysphagia arising from a rare cause, epiglottic calcification. Case Description/Methods: An 81-year-old male with history of aortic stenosis and carotid artery stenosis presented with worsening dysphagia over the course of one month. The patient reported significant dysphagia initially to solids and subsequently to liquids causing a weight loss of over 50 pounds. Physical exam of oropharynx and neck was unremarkable. Bedside swallow evaluation suggested mildly decreased hyolaryngeal movement, but no other significant abnormalities were identified. A Barium swallow study revealed incomplete epiglottic excursion during the pharyngeal phase of swallowing. With gastroenterology consultation, patient underwent evaluation with contrast-enhanced esophagogram that showed severe esophageal dysmotility and reflux. CT of neck demonstrated calcification of epiglottis without epiglottal enlargement, which was ultimately found to be the source of his concern. Via ENT, the patient underwent flexible fiberoptic laryngoscopy, and via gastroenterology, patient underwent EGD with biopsy. Yet, no esophageal or gastric pathology other than epiglottic calcification were identified. As no definitive treatment modality was outlined despite evaluation, patient was changed to a modified diet with ongoing speech and swallow therapy with outpatient follow up (Figure). Discussion: Epiglottic calcification is a rare cause of dysphagia that is poorly understood in its etiology, clinical course and outcomes. With our case, we hope to add to literature a unique presentation and imaging. Furthermore, with our case it is demonstrated that despite consultant recommendations, no clear evaluation process or treatment modality currently exists, lending to further study of this pathology. Currently, diagnosis can be accomplished with radiologic evaluation along with exclusion of other causes; however, no definitive treatments are available for this condition. Although the condition itself is rare, it adds to the differential diagnosis as a cause of significant dysphagia.Figure 1.: Calcification of epiglottis (red arrow) visualized on CT scan.

September 2022 Medical Image of the Month: Epiglottic Calcification

No abstract available. Manuscript truncated after 150 words. In consideration of dysphagia, most cases predominate in the oropharyngeal region with the remainder caused primary by esophageal causes. Lesser known and studied is the development of dysphagia and globus sensation from epiglottic pathology, namely epiglottic calcification. With less than a dozen published cases in literature, very little data exists on identification, diagnosis, and treatment of this known cause of morbidity. Here we present a case of oropharyngeal dysphagia arising from a rare cause, epiglottic calcification. An 81-year-old man with a history of aortic stenosis and carotid artery stenosis presented with worsening dysphagia over the course of one month. The patient reported significant dysphagia, initially to solids and subsequently to liquids causing a weight loss of over 50 pounds. Physical exam of the oropharynx and neck were unremarkable. A bedside swallow evaluation suggested mildly decreased hyolaryngeal movement, but no other significant abnormalities. A barium swallow study revealed incomplete epiglottic excursion …

Prognostic Value of Lung Ultrasound in Aortic Stenosis.

Background: Aortic stenosis (AS) is the most common primary valve lesion requiring intervention in Europe and North America. It has a prolonged subclinical period during which, as AS worsens, left ventricular adaptation becomes inadequate and impaired systolic and/or diastolic dysfunction may lead to overt heart failure (HF). The development of HF is an inflexion point in the natural history of AS. Pulmonary congestion is a cardinal feature in HF, and lung ultrasound (LUS) evaluation of B-lines has been proposed as a simple, noninvasive tool to assess pulmonary congestion. Aim: To assess the presence and the prognostic value of sonographic pulmonary congestion in patients with moderate or severe AS. Methods: 75 consecutive patients (39 women, mean age 73.85 ± 7.7 years) with moderate or severe AS were enrolled. All patients underwent comprehensive echocardiography and LUS with the 28 scanning-site assessment. Patients were followed-up for 13.4 ± 6 months to establish the prognostic value of LUS. A composite endpoint of death (of any cause), hospitalization for HF and intensification of loop diuretic therapy was considered. Results: We found a severe degree of B-lines (≥30) in 29.33% of patients. The number of B-lines correlated with the estimated pulmonary artery systolic pressure (p < 0.001, r = 0.574) and increased along with NYHA class (p < 0.05, rho = 0.383). At multivariable analysis, B-lines ≥30, and mean gradient were the independent predictors of events [B-lines: 2.79 (CI 1.03–7.54), p = 0.04; mean gradient: 1.04 (CI 1.01–1.07), p = 0.004]. Conclusion: Evaluation of B-lines is a simple, highly feasible method to detect pulmonary congestion in AS. The number of B-lines correlates with the hemodynamic changes caused by AS and with the functional status of patients. A severe degree of sonographic pulmonary congestion is associated with an increased risk of adverse events.

Aortic Valve Replacement Reduces Mortality in Moderate Aortic Stenosis: A Systematic Review and Meta-Analysis

With the introduction of transcatheter aortic valve replacement and an evolving understanding of the natural progression and history of aortic stenosis, the potential for earlier intervention in appropriate patients is promising; however, the benefit of aortic valve replacement in moderate aortic stenosis remains unclear.

Efficacy and Safety of Acalabrutinib Monotherapy in Patients with Relapsed/Refractory Mantle Cell Lymphoma in the Phase 2 ACE-LY-004 Study

Efficacy and Safety of Acalabrutinib Monotherapy in Patients with Relapsed/Refractory Mantle Cell Lymphoma in the Phase 2 ACE-LY-004 Study

Implications of Coexisting Aortic Regurgitation in Patients With AorticStenosis.

Aortic regurgitation (AR) is a common comorbidity in patients with aortic stenosis (AS), but coexisting AR has often been excluded from major clinical studies on AS. The impact of coexisting AR on the natural history of AS has not been well-described. The authors compared clinical outcomes in medically managed patients with moderate-to-severe AS with or without coexisting AR. Consecutive patients (N=1,188) with index echocardiographic diagnosis of moderate-to-severe AS (aortic valve area<1.5cm2) were studied. All patients were medically managed and were divided into those with coexisting AR (at least moderate severity) and those without. Adverse composite clinical outcomes were defined as mortality or admissions for congestive cardiac failure on subsequent follow-up. The authors compared differences in clinical profile and outcomes between the groups. There were 88 patients (7.4%) with coexisting AR and AS. These patients did not differ significantly in age, but had lower body mass index (22.9 ± 3.8 vs 25.3 ± 5.1kg/m2), lower diastolic blood pressure (68.7 ± 10.7 vs 72.2 ± 12.3mmHg), larger end-diastolic volume index (68.8 ± 18.8 vs 60.4 ± 17.8mL/m2) and larger left ventricular mass index (118.6 ± 36.4 vs 108.9 ± 33.1 g/m2). The prevalence of cardiovascular risk factors did not differ significantly. Coexisting AR was associated with increased incidence of adverse outcomes (log-rank 4.20; P=0.040). On multivariable Cox regression, coexisting AR remained independently associated with adverse outcomes (HR: 1.36; 95%CI: 1.02-1.82) after adjusting for age, AS severity, left ventricular ejection fraction, and year of study. In patients with AS, coexisting AR was associated with changes in echocardiographic profile and adverse outcomes.

Co-existing aortic regurgitation associated with adverse clinical outcomes in patients with moderate to severe aortic stenosis

Abstract Background Aortic regurgitation (AR) is a common comorbidity in patients with aortic stenosis (AS), but co-existing AR has often been an exclusion criterion from major clinical trials. The impact of co-existing AR on the natural history of AS has not been well-described. Purpose We compared clinical outcomes in patients with moderate to severe AS with or without co-existing AR. Methods Consecutive patients (n=1188) with index echocardiographic diagnosis of moderate to severe AS (AVA &amp;lt;1.5cm2) were studied. They were divided into those with co-existing AR (at least moderate severity) and those without. Adverse composite clinical outcomes were defined as either mortality or admissions for congestive cardiac failure on subsequent follow-up for at least five years. Appropriate univariate and multivariable analyses were employed to compare the two groups. Results There were 88 patients (7.4%) with co-existing AR and AS. These patients did not differ significantly in age, but had lower body mass index (22.9±3.8 vs 25.3±5.1 kg/m2). They also had lower diastolic blood pressure (68.7±10.7 vs 72.2±12.3 mmHg), larger end-diastolic volume index (68.8±18.8 vs 60.4±17.8 ml/m2) and left ventricular mass index (118.6±36.4 vs 108.9±33.1 g/m2). The prevalence of cardiovascular risk factors did not differ significantly between the groups. Co-existing AR was associated with adverse outcomes (log-rank 4.20, p=0.040). On multivariable Cox-regression, co-existing AR remained independently associated with adverse outcomes (hazard ratio 1.51, 95% CI 1.13–2.02) after adjusting for age, AS severity and left ventricular ejection fraction. Conclusion In patients with AS, co-existing AR was associated with a distinct echocardiographic profile and adverse outcomes. Funding Acknowledgement Type of funding source: None

Ventricular stroke work and vascular impedance refine the characterization of patients with aortic stenosis.

Aortic stenosis (AS) management is classically guided by symptoms and valvular metrics. However, the natural history of AS is dictated by coupling of the left ventricle, aortic valve, and vascular system. We investigated whether metrics of ventricular and vascular state add to the appreciation of AS state above valve gradient alone. Seventy patients with severe symptomatic AS were prospectively followed from baseline to 30 days after transcatheter aortic valve replacement (TAVR). Quality of life (QOL) was assessed using the Kansas City Cardiomyopathy Questionnaire. Left ventricular stroke work (SWLV) and vascular impedance spectrums were calculated noninvasively using in-house models based on central blood pressure waveforms, along with hemodynamic parameters from echocardiograms. Patients with higher preprocedural SWLV and lower vascular impedance were more likely to experience improved QOL after TAVR. Patients fell into two categories: those who did and those who did not exhibit increase in blood pressure after TAVR. In patients who developed hypertension (19%), vascular impedance increased and SWLV remained unchanged (impedance at zeroth harmonic: Z 0, from 3964.4 to 4851.8 dyne·s/cm3, P = 0.039; characteristic impedance: Z c, from 376.2 to 603.2 dyne·s/cm3, P = 0.033). SWLV dropped only in patients who did not develop new hypertension after TAVR (from 1.58 to 1.26 J; P < 0.001). Reduction in valvular pressure gradient after TAVR did not predict change in SWLV (r = 0.213; P = 0.129). Reduction of SWLV after TAVR may be an important metric in management of AS, rather than relying solely on the elimination of transvalvular pressure gradients.

Post-Cholecystectomy Clip Migration-Induced Acute Pancreatitis: A New Case and Review of the Literature

Acute pancreatitis (AP) after laparoscopic cholecystectomy (LC) prompts a search for an inciting cause including stone/sludge, hypertriglyceridemia, drugs and genetic abnormalities. Our aim is to report a case and review the literature on post-cholecystectomy biliary clip migration as a cause of “unrecognized” AP. A 61 y/o man with a history of aortic stenosis, diabetes mellitus, & hyperlipidemia underwent uncomplicated LC for cholelithiasis with cholecystitis. He had 2 episodes of AP 15 & 19 months post-LC. He denied alcohol, smoking & family history of AP. His labs values at the time of diagnosis of AP are unknown. CT from first AP episode showed endoclips at the cystic duct stump and 1 endoclip within the distal end of the bile duct. After the first episode, he underwent ERCP without significant findings. At the time of his second episode of AP, an endoclip was noted in the duodenum. (Figure 1). Subsequent EUS revealed normal bile ducts & pancreatic parenchymal lobularity & honeycombing. He has been managed conservatively with no further AP episodes.1326_A.tif Figure 1: AP Secondary to Biliary Clip Migration1326_B.tif Figure 2: Image on left shows clip in bile duct (arrow) at first episode of AP. Image on right shows clip in duodenum (arrow) at second episode of AP.Proposed mechanisms for biliary clip migration induced AP include dehiscence at the cystic duct & clip slippage & migration or inadvertent clip placement into the bile duct with passage through the Ampulla of Vater. Clips within the biliary tree may also become a nidus for stone formation. This clip/stone combination can pass through the ampulla without incident or cause obstructive pathology such as recurrent AP or cholangitis. Review of the literature revealed 4 cases associating clip migration with AP (Table 1). Clip migration should be considered as a cause of AP in patients post-LC presenting with AP or recurrent AP with or without elevated liver enzymes. Diagnosis can be suggested by comparison of abdominal X-Rays to prior images to assess for changes in the number or location of clips. ERCP is a successful therapeutic option.

Clinical Context and Detection of the Murmur of Advanced Aortic Stenosis.

Auscultation is an important clue to the presence of aortic stenosis (AS). We sought to assess the effect of symptom status, prior knowledge of diagnosis, and other patient factors on murmur detection. Patients with moderate-to-severe AS by echocardiography at a single center between June 2015 and June 2016 were included. Five consecutive patient encounters (inpatient and outpatient) within 12 months before the echocardiogram were analyzed. Ninety-five patients (418 different clinician encounters) were studied. The murmur of AS was identified by only 39% of clinicians. In multivariate analysis, significant determinants of murmur detection were examination in outpatient setting (odds ratio [OR] 3.40, 95% confidence interval [CI] 1.75-6.61), known history of AS (OR 2.77, 95% CI 1.53-5.01), female sex (OR 1.97, 95% CI 1.07-3.60), and presence of symptoms (OR 1.91 95% CI 1.12-3.26). Compared with the murmur detection findings by clinicians in medicine, the findings of surgical specialty clinicians were significantly lower (OR 0.12, 95% CI 0.06-0.26, P < 0.001). In this real-world assessment, clinical context played an important role in the auscultation of AS murmur. The findings have important implications for the clinical diagnosis of asymptomatic advanced AS.

THE ROLE OF VENTRICULAR STROKE WORK AND VASCULAR IMPEDANCE IN DEFINING AORTIC STENOSIS

Aortic stenosis (AS) management remains guided by symptoms and valvular metrics. Yet the natural history of AS is dictated by the coupling of the left ventricle (LV) proximally, the valve itself, and vascular system distally. our objectives were to investigate the role of LV stroke work (SWLV) and

Small Intestinal Angioectasia: Characterization, Risk Factors, and Rebleeding.

Gastrointestinal angioectasias (AEs) represent the most common vascular malformation within the gastrointestinal tract. This study sought to characterize epidemiologic/comorbid risk factors for AEs, rebleeding, and patterns of anatomic distribution within the small intestine. This retrospective observational cohort study included 158 patients with AEs on capsule endoscopy (CE) from 2007 to 2015. Epidemiologic/comorbid data were collected and incorporated into final analysis. Each AE was categorized by location using a small bowel transit time-based quartile system. Rebleeding was evaluated following CE. Multivariate logistic regression was applied to statistically significant factors on univariate analysis to determine independent risk factors for rebleeding. Most lesions were found in the first quartile (67.1%). Rebleeding occurred in 46 (29.7%) of the 156 patients for whom data were available. Rates of rebleeding were significantly higher among older patients (74.4 vs. 67.7 y, P=0.001), those with active bleeding on CE (41.3% vs. 16.5%, P=0.001), those with a history of aortic stenosis (21.7% vs. 9.2%, P=0.033), and those with AEs presents in quartile 3 (26.1% vs. 8.3%, P=0.003). Age, active bleeding on CE, and AE presence in quartile 3 were independently associated with rebleeding in multivariate analysis (P=0.009, 0.023, and 0.008, respectively). These data help improve our knowledge of AEs regarding risk factors for rebleeding, and utilizes a novel small bowel transit time-based quartile localization method that may simplify future research and comparisons of anatomic distribution and behavior of small bowel AEs.

Blood Pressure and Arterial Load After Transcatheter Aortic Valve Replacement for Aortic Stenosis

After aortic valve replacement, left ventricular afterload is often characterized by the residual valve obstruction. Our objective was to determine whether higher systemic arterial afterload-as reflected in blood pressure, pulsatile and resistive load-is associated with adverse clinical outcomes after transcatheter aortic valve replacement (TAVR). Total, pulsatile, and resistive arterial load were measured in 2141 patients with severe aortic stenosis treated with TAVR in the PARTNER I trial (Placement of Aortic Transcatheter Valve) who had systolic blood pressure (SBP) and an echocardiogram obtained 30 days after TAVR. The primary end point was 30-day to 1-year all-cause mortality. Lower SBP at 30 days after TAVR was associated with higher mortality (20.0% for SBP 100-129 mm Hg versus 12.0% for SBP 130-170 mm Hg; P<0.001). This association remained significant after adjustment, was consistent across subgroups, and confirmed in sensitivity analyses. In adjusted models that included SBP, higher total and pulsatile arterial load were associated with increased mortality (P<0.001 for all), but resistive load was not. Patients with low 30-day SBP and high pulsatile load had a 3-fold higher mortality than those with high 30-day SBP and low pulsatile load (26.1% versus 8.1%; hazard ratio, 3.62; 95% confidence interval, 2.36-5.55). Even after relief of valve obstruction in patients with aortic stenosis, there is an independent association between post-TAVR blood pressure, systemic arterial load, and mortality. Blood pressure goals in patients with a history of aortic stenosis may need to be redefined. Increased pulsatile arterial load, rather than blood pressure, may be a target for adjunctive medical therapy to improve outcomes after TAVR. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00530894.

Left Ventricular Hypertrophy in Asymptomatic Nonsevere Aortic Stenosis

Increased biomechanical stress on cardiomyocytes because of outflow obstruction secondary to aortic stenosis (AS) is thought to induce reexpression of the fetal gene program, which modifies myocyte efficiency, sarcomere composition, and regulation of extracellular matrix, as well as various nuclear signal transduction pathways resulting in autocrine production and secretion of cytokines, neurohormones and growth factors that ultimately promote ventricular hypertrophy.1,2 See Article by Gerdts et al The traditional view of adaptative concentric left ventricular hypertrophy (LVH) because of parallel replication of new sarcomeres is that wall thickness increases to normalize LV systolic wall stress and preserve systolic performance. This view, accepted for the past 40 years3 and perhaps counterintuitively expected to mitigate the effects of LV pressure overload on cardiovascular morbidity and mortality, has begun to be challenged by new clinical data, suggesting that moderate or severe LVH may be associated with adverse outcomes in AS4,5 and that inappropriately increased LV mass, found in 17% of patients with mild to moderate AS6 and in 67% of patients with asymptomatic severe AS, was associated with a 4.5-fold increased risk of cardiovascular events.7 Conversely, the absence of hypertrophy in one third of the patients with severe AS seems to have no adverse effects on systolic function or survival.8,9 Experimental studies in genetically modified animal models are consistent with clinical observations.10 In addition, no association was found between AS severity and the magnitude or pattern of LVH using cardiac magnetic resonance.11 Thus, it seems that the presence, severity, and the geometric pattern of LVH in AS vary widely, are …

Abstract 17297: 9p21 CAD Risk Allele is Protective Against Calcific Aortic Stenosis

The 9p21 locus has emerged as one of the strongest risk variants associated with coronary artery disease (CAD). The risk allele for CAD is also associated with other vascular pathologies, including abdominal aortic aneurysms and intracranial aneurysms. Calcific aortic stenosis (AS) and CAD share some risk factors and histopathologic features. However, a considerable proportion of severe AS patients have no significant CAD, indicating the presence of unique mechanisms underlying each condition. To date only one common genetic variant, rs10455872 in the LPA gene, has been robustly associated with risk of AS. Here we investigated the association of the lead CAD-associated variant (rs1333049) at the 9p21 locus with the risk of AS in 1044 cases and 4527 controls. We also typed the LPA SNP (rs10455872) as a validated variant. All cases had either echo confirmed AS of abnormal valve morphology and peak velocity across the aortic valve of more than 2.5 meters/second, or they had previously undergone surgery for severe AS. We used logistic regression analysis to investigate the additive effect of both variants on risk of AS, adjusting for CAD status. For the LPA locus, we observed the previously reported association of the G allele at rs10455872 with risk of AS (OR 1.23; 95% CI, 1.06 to 1.44, P= 0.008). Interestingly for the 9p21 locus, the CAD associated allele (C) for rs1333049 was associated with a lower risk of AS (OR 0.88; 95% CI, 0.80 to 0.98, P= 0.014). In an additional analysis, we examined the association of rs1333049 with AS in our 1044 cases against an independent set of 828 controls with no history of AS, and the results were consistent with the initial findings (OR 0.76; 95% CI, 0.66 to 0.87, P= 0.0001). This unexpected finding requires further validation, but suggests that the 9p21 locus CAD-associated variant is not uniformly deleterious for other vascular pathologies - and for AS may be protective. If the 9p21 finding is confirmed, then understanding the differential effect of this locus on AS and CAD may help to better understand the specific pathogenesis of each condition.

Accurate Assessment of Aortic Stenosis

Aortic valve (AV) stenosis is one of the most common valvular diseases and is the third most common cardiovascular disease in developed countries. It occurs in ≈2.8% of patients ≥75 years of age and can occur because of degenerative calcification and congenital valvular defects such as bicuspid AVs or rheumatic disease.1–3 Calcific aortic stenosis (AS) is associated with increased leaflet stiffness and a narrowed AV orifice, resulting in increased pressure gradients across the valve. The presence of a bicuspid AV significantly increases the risk of AS.4 The natural history of AS is a prolonged asymptomatic period, with progressive reduction of the AV orifice area due to sclerosis initially, culminating in calcific AS. This is accompanied by a corresponding increase in the transaortic pressure gradient (Δ P ) and myocardial pressure overload. Through the preload reserve, the left ventricle (LV) compensates for the increased workload until the sarcomeres stretch to their maximum diastolic length. Once the preload reserve is exhausted, increases in afterload are accompanied by a reduction in stroke volume (SV), resulting in afterload mismatch. Ultimately, this causes LV hypertrophy, associated with an enlargement of cardiac myocytes and increased LV wall thickness.5 Initial diagnosis of AS typically occurs during routine physical examination with the presence of a heart murmur, click, or other abnormal sounds, but undiagnosed patients may experience the onset of severe symptoms such as angina, syncope, and heart failure. Without intervention, patient mortality typically occurs within 5 years of the onset of symptoms.6–11 Multiple studies and reviews have focused on the clinical aspects of this disease, including disease progression, markers of disease severity, treatment guidelines, and outcomes.1–3,6,12–16 Very few reviews have focused on the hemodynamic principles underlying AS and on comparing data obtained across different …

Familial aggregation of aortic stenosis

Purpose: Aortic stenosis is the most common valve disease in the elderly and is considered to be multifactorial and genetic components have been suggested. However, knowledge on familial occurrence on a population based level is missing. We aimed to describe the familial aggregation of aortic stenosis in the adult population. Methods: From nationwide Danish registers we included a cohort of persons born in or after 1910, with identifiable relatives. From 1977 to 2012 we identified all cases diagnosed with aortic stenosis in the cohort and relatives aged 35 years or more, who did not have a registered diagnose of cardiovascular disease before age 35 years. We also assessed for familial occurrence of aortic stenosis presenting with frequently seen cardiac co-morbidities such as ischemic heart disease and endocarditis in cohort members. We estimated incidence rate ratios (IRR) adjusted for sex, age and calendar period for aortic stenosis by family history of aortic stenosis in first degree relatives; this was done by log-linear Poisson regression analysis. Results: We followed a cohort of 4,764,969 persons free of CVD before age 35 years, for 95,871,697 persons-years and identified 59,362 persons with aortic stenosis. The median age at diagnosis of aortic stenosis in persons (n=258) with a family history of aortic stenosis in a first degree relative was 58 years, and in those (n=59,104) without such a family history the median age was 74 years (p<0.01). Given a first degree relative with aortic stenosis the IRR and 95% confidence interval (CI) for aortic stenosis was 1.61 (95% CI 1.42-1.82). In persons aged 35-55 years the IRR was 1.36 (95% CI 1.12-1.65 for aortic stenosis and in those aged 56 to 75 years the IRR was 2.13 (95% CI 1.75-2.59), and in those aged 76 years or older the IRR was 1.89 (95% CI 1.43-2.50). The risk by family history in those with certain cardiac co-morbidities was stronger. Conclusion: To our knowledge this is the first nationwide study to report and quantify the risk of aortic stenosis by family history of aortic stenosis. The risk was increased up to two-fold given a first degree relative with aortic stenosis, and the disease occurred 15-20 years earlier in life in those with a family history.

Cardiac Defects Are Infrequent Findings in Individuals With 8p23.1 Genomic Duplications Containing GATA4

The GATA4 gene is critical to regulating myocardial differentiation and function. Haploinsufficiency of GATA4 is strongly associated with congenital heart defects (CHD). However, it is inconclusive whether duplicated GATA4 causes CHD. We evaluated 1645 consecutive pediatric patients with various developmental disorders by high-resolution microarray-based comparative genomic hybridization and found 8 probands and 2 relatives with pathogenic genomic imbalances containing GATA4. Four probands contain an ≈4.0-Mb interstitial duplication of 8p23.1 flanked by the 2 olfactory receptor gene clusters REPD and REPP, representing 0.24% (4/1645) of the patients analyzed. None of the 4 patients has CHD or any other heart diseases and 1 mother who transmitted the duplication to her child has a history of aortic stenosis. Two patients who carry multiple genomic abnormalities, including a duplication containing GATA4, have complex CHD. Only 1 of the 3 individuals carrying genomic deletion containing GATA4 has atrial septal and ventricular septal defects. Cardiac defects are infrequent findings in individuals with 8p23.1 genomic duplications containing GATA4. A 0.24% detection rate of this duplication in this study is significantly higher than previously estimated. Observation in 2 patients with multiple genomic abnormalities and complex CHD is consistent with a 2-hit model that emphasizes accumulative effects of >1 insult to the genome, leading to a visible or more severe clinical manifestation. Haploinsufficient GATA4 may show variable expressivity with a wide spectrum of clinical findings, including CHD.