Protein-altering and regulatory genetic variants near GATA4 implicated in bicuspid aortic valve.

Bicuspid aortic valve (BAV) is a heritable congenital heart defect and an important risk factor for valvulopathy and aortopathy. Here we report a genome-wide association scan of 466 BAV cases and 4,660 age, sex and ethnicity-matched controls with replication in up to 1,326 cases and 8,103 controls. We identify association with a noncoding variant 151 kb from the gene encoding the cardiac-specific transcription factor, GATA4, and near-significance for p.Ser377Gly in GATA4. GATA4 was interrupted by CRISPR-Cas9 in induced pluripotent stem cells from healthy donors. The disruption of GATA4 significantly impaired the transition from endothelial cells into mesenchymal cells, a critical step in heart valve development.

Proximal thoracic aortic diameters: transesophageal-echocardiography- versus computed-tomography-derived measurements.

PURPOSE: The purpose of the study was to compare proximal aortic measurements from electrocardiogram-gated computed tomography (CT) to transesophageal echocardiography (TEE) and to evaluate differences in cusp-cusp and cusp-commissure CT measurements of sinus of Valsalva (SOV). METHODS: This retrospective study (n=25) compared aortic diameters from CT using manual double-oblique multiplanar reformats (MPRs) and semiautomatic centerline method to TEE. RESULTS: CT MPR and centerline measurements were higher than TEE for sinotubular junction and ascending aorta. At SOV, cusp-cusp diameters (MPR and centerline methods) and cusp-commissure measurement (centerline method) were larger than TEE. CONCLUSIONS: Aortic measurements were larger on CT than TEE. Precise difference depended on location and measurement technique.

The IRAD classification system for characterizing survival after aortic dissection.

BACKGROUND: The classification of aortic dissection into acute (<14 days from symptom onset) versus chronic (≥14 days) is based on survival estimates of patients treated decades before modern diagnostic and treatment modalities were available. A new classification of aortic dissection in the current era may provide clinicians with a more precise method of characterizing the interaction of time, dissection location, and treatment type with survival. METHODS: We developed separate Kaplan-Meier survival curves for Type A and Type B aortic dissection using data from the International Registry of Aortic Dissection (IRAD). Daily survival was stratified based on type of therapy provided: medical therapy alone (medical), nonsurgical intervention plus medical therapy (endovascular), and open surgery plus medical therapy (surgical). The log-rank statistic was used to compare the survival curves of each management type within Type A and Type B aortic dissection. RESULTS: There were 1815 patients included, 67.3% male with mean age 62.0 ± 14.2 years. When survival curves were constructed, 4 distinct time periods were noted: hyperacute (symptom onset to 24 hours), acute (2-7 days), subacute (8-30 days), and chronic (>30 days). Overall survival was progressively lower through the 4 time periods. CONCLUSIONS: This IRAD classification system can provide clinicians with a more robust method of characterizing survival after aortic dissection over time than previous methods. This system will be useful for treating patients, counseling patients and families, and studying new diagnostic and treatment methods.

Prevalence of aortic dilation in hypertrophic cardiomyopathy.

Recent studies have suggested that hypertrophic cardiomyopathy (HCM) is associated with increased stiffness of the aorta. However, a potential relationship between HCM and aortic dilation has not been established. Aorta size was characterized in 223 consecutive patients diagnosed with HCM. Aorta size was measured at the level of the sinuses (n = 223) and ascending aorta (n = 115) using the parasternal long-axis echocardiographic view. Hypertrophy pattern, maximum wall thickness, and left ventricular outflow tract gradient were measured. Aortic dilation was defined using previously published criteria that control for body surface area, age, and gender. Mean aorta size among the HCM cohort was 33.0 ± 5.0 mm at the sinuses and 34.0 ± 5.0 at the tubular aorta. Using the age-based nomogram controlling for body surface area, 10 (4.5%) of the study population had dilated aortas at the sinuses of Valsalva. Only gender (10/10 male in dilated group, 127/213 in non-dilated group, p = 0.008) was associated with dilation, while characteristics of HCM (LVOT obstruction, maximum wall thickness, hypertrophy pattern) were not. Use of other criteria for dilation did not result in an association with HCM characteristics. Aortic dilation in HCM does not seem to occur more frequently than in the general population and is not related to the extent of hypertrophy or LVOT obstruction.

Proximal thoracic aortic diameter measurements at CT: repeatability and reproducibility according to measurement method.

AIM: To determine the variability in CT measurements of proximal thoracic aortic diameters obtained using double-oblique short axis and semiautomatic centerline analysis techniques. Institutional review board approval, with waiver of informed consent, was obtained for this HIPAA-compliant, retrospective study. Cardiac gated thoracic aortic CT scans were evaluated in 25 patients. Maximum aortic diameter measurements at the annulus, sinuses, sinotubular junction and ascending aorta were generated using double-oblique short axis and semiautomatic centerline analysis techniques. Intraobserver and interobserver variability and variability between techniques were assessed using the Wilcoxon signed rank test, Spearman's correlation coefficients and Bland-Altman plots. Mean intraobserver diameter differences using double oblique views ranged from -0.3 to 0.6 mm. The 95 % confidence interval for difference in diameters was ±2.4 to ±5.1 mm for radiologist #1 and ±2.6 to ±5.2 mm for radiologist #2, depending on location. Mean intraobserver diameter differences using centerline analysis ranged from 0.2 to 2.3 mm, and the 95 % confidence interval for difference in diameters was ±2.0 to ±4.6 mm, depending on location. Significant interobserver differences were seen for both double oblique views and centerline analysis. Measurements obtained using the two methods were strongly correlated (r = 0.81-0.99), although they were consistently larger using centerline analysis (95 % confidence interval, ±1.8 to ±3.2 mm). Although measurement variability of the proximal thoracic aorta was generally low using double oblique and centerline analysis techniques, differences of up to approximately 5 mm in diameter occurred within the 95 % confidence interval. Neither technique was clearly more reliable than the other.

The impact of percutaneous coronary intervention on ischemic mitral regurgitation.

BACKGROUND AND AIM OF THE STUDY: The study aim was to determine if significant ischemic mitral regurgitation (IMR) is adequately addressed in patients undergoing multi-vessel percutaneous coronary intervention (PCI). METHODS: The cardiac catheterization laboratory database at the authors' institution was accessed over a five-year interval to identify those patients who had undergone multi-vessel PCI. Both, pre- and post-revascularization echocardiographic data were retrieved, and clinical data, MR presence and severity, and outcomes were each assessed. RESULTS: In total, 150 patients (100 males, 50 females; mean age 63 +/- 12 years) underwent PCI. Of these 150 patients, pre-procedural echocardiograms were not performed in 54 cases (35%); hence, the study group comprised 96 patients with both pre- and postprocedural echocardiograms. Of these patients, 21 (22%) had moderate or greater (2+) IMR. The severity of the IMR did not change significantly after multivessel PCI (2 +/- 0.8+ preoperatively versus 1.9 +/- 1.0+ postoperatively). CONCLUSION: Clinically significant IMR occurred not infrequently among patients treated with multivessel PCI, but the severity did not change with percutaneous revascularization, despite this being predominantly complete. In more than one-third of the patients, adequate pre-PCI echocardiography was unavailable, which suggested the possibility that not all IMR had been identified.

Cause and circumstance of in-hospital mortality among patients undergoing contemporary percutaneous coronary intervention: a root-cause analysis.

BACKGROUND: Prior studies suggest that most deaths in patients undergoing percutaneous coronary intervention (PCI) are related to procedural complications. Mortality associated with PCI has steadily declined during the past decade, and the cause and circumstance of death among patients undergoing PCI in the contemporary era remain unknown. METHODS AND RESULTS: We evaluated all patients undergoing PCI at the University of Michigan from 2001 to 2009. There were 85 deaths among a total of 5520 patients undergoing PCI during this time period. By using a standardized data collection form, 3 cardiologists (2 interventional, H.S.G. and D.S.M.; 1 noninvasive, A.M.B.) determined the cause and circumstance of death, in addition to grading the preventability of death. Left ventricular failure was the most common cause of death (35.3%, n=30), followed by neurological compromise (16.5%, n=14) and arrhythmia (12.1%, n=12). The circumstance of death was mostly acute cardiac (52.9%, n=45), with a procedural complication composing a small fraction (7.1%, n=6). Reviewers determined 93% of deaths to be mostly or entirely unpreventable. CONCLUSIONS: Procedural complications are responsible for a small fraction of deaths among patients undergoing contemporary PCI. Measures to further enhance procedural safety are unlikely to translate into meaningful reductions in PCI mortality.

Type-selective benefits of medications in treatment of acute aortic dissection (from the International Registry of Acute Aortic Dissection [IRAD]).

The effects of medications on the outcome of aortic dissection remain poorly understood. We sought to address this by analyzing the International Registry of Acute Aortic Dissection (IRAD) global registry database. A total of 1,301 patients with acute aortic dissection (722 with type A and 579 with type B) with information on their medications at discharge and followed for ≤5 years were analyzed for the effects of the medications on mortality. The initial univariate analysis showed that use of ß blockers was associated with improved survival in all patients (p = 0.03), in patients with type A overall (p = 0.02), and in patients with type A who received surgery (p = 0.006). The analysis also showed that use of calcium channel blockers was associated with improved survival in patients with type B overall (p = 0.02) and in patients with type B receiving medical management (p = 0.03). Multivariate models also showed that the use of ß blockers was associated with improved survival in those with type A undergoing surgery (odds ratio 0.47, 95% confidence interval 0.25 to 0.90, p = 0.02) and the use of calcium channel blockers was associated with improved survival in patients with type B medically treated patients (odds ratio 0.55, 95% confidence interval 0.35 to 0.88, p = 0.01). In conclusion, the present study showed that use of ß blockers was associated with improved outcome in all patients and in type A patients (overall as well as in those managed surgically). In contrast, use of calcium channel blockers was associated with improved survival selectively in those with type B (overall and in those treated medically). The use of angiotensin-converting enzyme inhibitors did not show association with mortality.

Diagnosis and management issues in thoracic aortic aneurysm.

Thoracic aortic enlargement is an increasingly recognized condition that is often diagnosed on imaging studies performed for unrelated indications. The risk of unrecognized and untreated aortic enlargement and aneurysm includes aortic rupture and dissection which carry a high burden of morbidity and mortality. The etiologies underlying thoracic aortic enlargement are diverse and can range from degenerative or hypertension associated aortic enlargement to more rare genetic disorders. Therefore, the evaluation and management of these patients can be complex and requires knowledge of the pathophysiology associated with thoracic aortic dilation and aneurysm. Additionally, there have been important advances in the treatment available to patients with thoracic aortic disease, including an increased role of endovascular therapy. Given the risk of mortality, increased clinical recognition and advances in therapeutics, the American College of Cardiology, American Heart Association and related professional societies have recently published guidelines on the management of thoracic aortic disease. This review focuses on the pathophysiology and various etiologies that lead to thoracic aortic aneurysm along with the diagnostic modalities and management of asymptomatic patients with thoracic aortic disease.

Sensitivity of the aortic dissection detection risk score, a novel guideline-based tool for identification of acute aortic dissection at initial presentation: results from the international registry of acute aortic dissection.

BACKGROUND: In 2010, the American Heart Association and American College of Cardiology released guidelines for the diagnosis and management of patients with thoracic aortic disease, which identified high-risk clinical features to assist in the early detection of acute aortic dissection. The sensitivity of these risk markers has not been validated. METHODS AND RESULTS: We examined patients enrolled in the International Registry of Acute Aortic Dissection from 1996 to 2009. The number of patients with confirmed acute aortic dissection who presented with 1 or more of 12 proposed clinical risk markers was determined. An aortic dissection detection (ADD) risk score of 0 to 3 was calculated on the basis of the number of risk categories (high-risk predisposing conditions, high-risk pain features, high-risk examination features) in which patients met criteria. The ADD risk score was tested for sensitivity. Of 2538 patients with acute aortic dissection, 2430 (95.7%) were identified by 1 or more of 12 proposed clinical risk markers. With the use of the ADD risk score, 108 patients (4.3%) were identified as low risk (ADD score 0), 927 patients (36.5%) were intermediate risk (ADD score 1), and 1503 patients (59.2%) were high risk (ADD score 2 or 3). Among 108 patients with no clinical risk markers present (ADD score 0), 72 had chest x-rays recorded, of which 35 (48.6%) demonstrated a widened mediastinum. CONCLUSIONS: The clinical risk markers proposed in the 2010 thoracic aortic disease guidelines and their application as part of the ADD risk score comprise a highly sensitive clinical tool for the detection of acute aortic dissection.

Exercise hemodynamics in valvular heart disease.

Exercise hemodynamics play an important role in the evaluation and management of patients with both severe stenotic or regurgitant valve lesions. Exercise testing in patients with valvular heart disease can help to unmask latent symptoms and define the timing of surgical intervention. Additionally, exercise-induced hemodynamics are an important tool to assess prosthetic valve function. This review summarizes both background literature and recent publications that assess the use of exercise hemodynamics in the evaluation and management of valvular heart disease.

Ascending thoracic aorta dimension and outcomes in acute type B dissection (from the International Registry of Acute Aortic Dissection [IRAD]).

It is not well known if the size of the ascending thoracic aorta at presentation predicts features of presentation, management, and outcomes in patients with acute type B aortic dissection. The International Registry of Acute Aortic Dissection (IRAD) database was queried for all patients with acute type B dissection who had documentation of ascending thoracic aortic size at time of presentation. Patients were categorized according to ascending thoracic aortic diameters ≤4.0, 4.1 to 4.5, and ≥4.6 cm. Four hundred eighteen patients met inclusion criteria; 291 patients (69.6%) were men with a mean age of 63.2 ± 13.5 years. Ascending thoracic aortic diameter ≤4.0 cm was noted in 250 patients (59.8%), 4.1 to 4.5 cm in 105 patients (25.1%), and ≥4.6 cm in 63 patients (15.1%). Patients with an ascending thoracic aortic diameter ≥4.6 cm were more likely to be men (p = 0.01) and have Marfan syndrome (p <0.001) and known bicuspid aortic valve disease (p = 0.003). In patients with an ascending thoracic aorta ≥4.1 cm, there was an increased incidence of surgical intervention (p = 0.013). In those with an ascending thoracic aorta ≥4.6 cm, the root, ascending aorta, arch, and aortic valve were more often involved in surgical repair. Patients with an ascending thoracic aorta ≤4.0 were more likely to have endovascular therapy than those with larger ascending thoracic aortas (p = 0.009). There was no difference in overall mortality or cause of death. In conclusion, ascending thoracic aortic enlargement in patients with acute type B aortic dissection is common. Although its presence does not appear to predict an increased risk of mortality, it is associated with more frequent open surgical intervention that often involves replacement of the proximal aorta. Those with smaller proximal aortas are more likely to receive endovascular therapy.

Case report: the effect of proton pump inhibitor administration on hemodynamics in a cardiac intensive care unit.

Ex vivo studies have suggested that high dose proton pump inhibitors (PPI) may have negative inotropic effects in myocardial tissue. We sought to investigate this concept in a real-world clinical setting. In this case series, we enrolled critically ill patients in the coronary and cardiothoracic intensive care units who had a preexisting pulmonary artery (PA) catheter in place for hemodynamic monitoring and were on a PPI for prespecified clinical indications. Hemodynamic measurements were made at baseline and then at 15 minute intervals for 1 hour after PPI administration. A total of 18 patients were evaluated; 72% were male with a mean age of 59.9 years. A total of 9 patients were evaluated on 2 consecutive days, yielding 26 patient-exposures to the medication. The majority of patients (72%) were receiving 1 or more inotropic agents (n = 6), a vasopressor (n = 4), or both (n = 4). When compared to baseline values, there was no significant change in mean arterial pressure (baseline 80 +/- 11 mm Hg), heart rate (87 +/- 11 bpm), or Fick cardiac index (2.7 +/- 1.8 L/min/m(2)). Mean PA pressure did decrease transiently at 45 minutes following PPI administration (28.5 +/- 7.7 mm Hg at baseline vs 26.5 +/- 7.5 mm Hg, P = 0.017), but is unlikely to be of clinical significance. In conclusion, these data suggest that IV PPIs do not immediately impact important hemodynamic parameters and are likely safe in a high-risk intensive care setting.

Acquired pulmonary vein stenosis: one problem, two mechanisms.

Until the last decade, acquired pulmonary vein (PV) stenosis in the adult population was a rare finding, caused by neoplasm or inflammatory conditions such as sarcoidosis or fibrosing mediastinitis. With the increased use of catheter-based ablation for the treatment of atrial fibrillation, PV stenosis is increasingly recognized as a complication of this procedure. Additionally, PV stenosis has been described as a rare complication of cardiac surgery. This report describes two cases of PV stenosis, one acquired as a result of multiple left atrial ablation procedures and the other after surgical cannulation of the right upper PV.

Geographic differences in clinical presentation, treatment, and outcomes in type A acute aortic dissection (from the International Registry of Acute Aortic Dissection).

Although several studies have provided robust evidence about global differences for several cardiovascular emergencies, such as myocardial infarction and stroke, data were limited for aortic disease. The aim was to explore geographic variation in type A acute aortic dissection (TA-AAD) in a large group of consecutive patients. Patients (n = 615) from the IRAD with TA-AAD were studied with respect to presenting symptoms and signs, diagnosis, management, and outcomes in Europe versus North America. Compared with Europeans, North Americans were more likely to be older and present with atypical features and without many of the classic chest X-ray findings of AAD. In the North American cohort, electrocardiographic findings showed higher rates of nonspecific ST changes and a trend toward ST-elevation or new myocardial infarction (North Americans vs Europeans 7.9% vs 4.4%; p = 0.09). Use of imaging studies to confirm the diagnosis of AAD varied between North American and European centers. North American centers performed an average of 1.6 imaging studies compared with 1.8 in the European group (p = 0.002). Furthermore, they were significantly less likely to use computed tomography and significantly more likely to use transesophageal examination as part of the overall diagnostic algorithm. Compared with Europeans, TA-AAD occurred at smaller aortic diameters and there was a substantial delay to presentation and diagnosis in North Americans. No significant differences for early mortality rates were observed between the 2 groups. In conclusion, geographic differences in presentation and initial management were highlighted, but this did not translate into a difference in early mortality.

Primary-care physicians' perceptions and practices on the management of GERD: results of a national survey.

BACKGROUND: Gastroesophageal reflux disease (GERD) is frequently managed by primary-care physicians (PCPs) although little is known about their current practices and management patterns. METHODS: We administered a questionnaire-based survey to PCPs attending sponsored educational conferences on GERD. Questionnaires were completed anonymously before the conferences and asked about prescribing patterns, indications for surgical referral, and issues concerning Barrett's esophagus and H. pylori infection. RESULTS: A total of 1046 completed questionnaires (97% acceptance rate) were received. Most PCPs prescribed a proton pump inhibitor (PPI) for GERD without prior authorization and without first using an H2-receptor antagonist (H2RA). Many gave an H2RA with once-daily PPI treatment for patients with nocturnal heartburn. Most referrals for anti-reflux surgery were for inadequate response to medical treatment, although PCPs usually first sought gastroenterological consultation. There was a widespread acceptance of screening GERD patients for Barrett's esophagus. There was general confusion about any relationship between H. pylori infection and GERD; 80% of PCPs tested for the infection in at least some patients who only had symptoms of GERD. CONCLUSIONS: Our survey has identified a number of areas of controversy and confusion related to the management of GERD. We hope that our findings can assist in the development of educational materials on GERD for PCPs.