Acute Aortic Dissection: Observational Lessons Learned From 11 000 Patients.

BACKGROUND: Over the past 25 years, diagnosis and therapy for acute aortic dissection (AAD) have evolved. We aimed to study the effects of these iterative changes in care. METHODS: Patients with nontraumatic AAD enrolled in the International Registry of Acute Aortic Dissection (61 centers; 15 countries) were divided into time-based tertiles (groups) from 1996 to 2022. The impact of changes in diagnostics, therapeutic care, and in-hospital and 3-year mortality was assessed. Cochran-Armitage trend and Jonckheere-Terpstra tests were conducted to test for any temporal trend. RESULTS: Each group consisted of 3785 patients (mean age, ≈62 years old; ≈65.5% males); nearly two-thirds had type A AAD. Over time, the rates of hypertension increased from 77.8% to 80.4% (P=0.002), while smoking (34.1% to 30.6%, P=0.033) and atherosclerosis decreased (25.6%-16.6%; P<0.001). Across groups, the percentage of surgical repair of type A AAD increased from 89.1% to 92.5% (P<0.001) and was associated with decreased hospital mortality (from 24.1% in group 1 to 16.7% in group 3; P<0.001). There was no difference in 3-year survival (P=0.296). For type B AAD, stent graft therapy (thoracic endovascular aortic repair) was used more frequently (22.3%-35.9%; P<0.001), with a corresponding decrease in open surgery. Endovascular in-hospital mortality decreased from 9.9% to 6.2% (P=0.003). As seen with the type A AAD cohort, overall 3-year mortality for patients with type B AAD was consistent over time (P=0.084). CONCLUSIONS: Over 25 years, substantial improvements in-hospital survival were associated with a more aggressive surgical approach for patients with type A AAD. Open surgery has been partially supplanted by thoracic endovascular aortic repair for complicated type B AAD, and in-hospital mortality has decreased over the time period studied. Postdischarge survival for up to 3 years was similar over time.

Mitral Regurgitation Severity Assessment after Transcutaneous Edge-to-Edge Mitral Valve Repair: Recommended Integration versus Volumetric Assessment Guidelines.

Objectives: This article aims to evaluate the accuracy of the color-Doppler-based technique to evaluate residual mitral regurgitation post TEER. Background: The evaluation of residual mitral regurgitation (MR) post-mitral transcutaneous edge-to-edge repair (mitral TEER) is a critical determinant in patients' outcomes. The common methods used today, based on the integration of color flow Doppler parameters, may be misleading because of the multiple jets and high velocities created by the TEER devices. Methods: Patients undergoing TEER at Hadassah hospital were recruited between 2015 and 2019. Post-procedural MR was evaluated using the integrated qualitative approach as recommended by the guidelines. In addition, the MR volume for each patient was calculated by subtracting the forward stroke volume (calculated by multiplying the LVOT area with the velocity time integral of the LVOT systolic flow) from the total stroke volume (calculated by the biplane Simpson method of discs). We compared the two methods for concordance. Results: Overall, 112 cases were enrolled. In 55.4% of cases, the volumetric residual MR was milder than the MR severity assessed by the guidelines' recommended method. In 25.1%, the MR severity was similar in both methods. In 16.2%, the MR severity was worse when calculated using the volumetric method (pValue < 0.001, Kappameasure of agreement = 0.053). The lower residual MR degree using the volumetric approach was mostly observed in patients classified as "moderate" by the integrated approach. Conclusions: MR severity after TEER is often overestimated by the guideline-recommended integrative method when compared with a volumetric method. Alternative methods should be considered to assess the MR severity after mitral TEER.

Artificial intelligence modelling to assess the risk of cardiovascular disease in oncology patients.

Aims: There are no comprehensive machine learning (ML) tools used by oncologists to assist with risk identification and referrals to cardio-oncology. This study applies ML algorithms to identify oncology patients at risk for cardiovascular disease for referrals to cardio-oncology and to generate risk scores to support quality of care. Methods and results: De-identified patient data were obtained from Vanderbilt University Medical Center. Patients with breast, kidney, and B-cell lymphoma cancers were targeted. Additionally, the study included patients who received immunotherapy drugs for treatment of melanoma, lung cancer, or kidney cancer. Random forest (RF) and artificial neural network (ANN) ML models were applied to analyse each cohort: A total of 20 023 records were analysed (breast cancer, 6299; B-cell lymphoma, 9227; kidney cancer, 2047; and immunotherapy for three covered cancers, 2450). Data were divided randomly into training (80%) and test (20%) data sets. Random forest and ANN performed over 90% for accuracy and area under the curve (AUC). All ANN models performed better than RF models and produced accurate referrals. Conclusion: Predictive models are ready for translation into oncology practice to identify and care for patients who are at risk of cardiovascular disease. The models are being integrated with electronic health record application as a report of patients who should be referred to cardio-oncology for monitoring and/or tailored treatments. Models operationally support cardio-oncology practice. Limited validation identified 86% of the lymphoma and 58% of the kidney cancer patients with major risk for cardiotoxicity who were not referred to cardio-oncology.

Twenty-five years of observations from the International Registry of Acute Aortic Dissection (IRAD) and its impact on the cardiovascular scientific community.

OBJECTIVE: The International Registry of Acute Aortic Dissection (IRAD) celebrated its 25th anniversary in January 2021. This study evaluated IRAD's role in promoting the understanding and management of acute aortic dissection (AD) over these years. METHODS: IRAD studies were identified, analyzed, and ranked according to their citations per year (c/y) to determine the most-cited IRAD studies and topics. A systematic search of the literature identified cardiovascular guidelines on the diagnosis and management of acute AD. Consequently, IRAD's presence and impact were quantified using these documents. RESULTS: Ninety-seven IRAD studies were identified, of which 82 obtained more than 10 cumulative citations. The median c/y index was 7.33 (25th-75th percentile, 4.01-16.65). Forty-two studies had a greater than median c/y index and were considered most impactful. Of these studies, most investigated both type A and type B AD (n = 17, 40.5%) and short-term outcomes (n = 26, 61.9%). Nineteen guideline documents were identified from 26 cardiovascular societies located in Northern America, Europe, and Japan. Sixty-nine IRAD studies were cited by these guidelines, including 38 of the 42 most-impactful IRAD studies. Among them, partial thrombosis of the false lumen as a predictor of postdischarge mortality and aortic diameters as a predictor of type A occurrence were determined as most-impactful specific IRAD topics by their c/y index. CONCLUSIONS: IRAD has had and continues to have an important role in providing observations, credible knowledge, and research questions to improve the outcomes of patients with acute AD.

Novel Association of the NOTCH Pathway Regulator MIB1 Gene With the Development of Bicuspid Aortic Valve.

Importance: Nonsyndromic bicuspid aortic valve (nsBAV) is the most common congenital heart valve malformation. BAV has a heritable component, yet only a few causative genes have been identified; understanding BAV genetics is a key point in developing personalized medicine. Objective: To identify a new gene for nsBAV. Design, Setting, and Participants: This was a comprehensive, multicenter, genetic association study based on candidate gene prioritization in a familial cohort followed by rare and common association studies in replication cohorts. Further validation was done using in vivo mice models. Study data were analyzed from October 2019 to October 2022. Three cohorts of patients with BAV were included in the study: (1) the discovery cohort was a large cohort of inherited cases from 29 pedigrees of French and Israeli origin; (2) the replication cohort 1 for rare variants included unrelated sporadic cases from various European ancestries; and (3) replication cohort 2 was a second validation cohort for common variants in unrelated sporadic cases from Europe and the US. Main Outcomes and Measures: To identify a candidate gene for nsBAV through analysis of familial cases exome sequencing and gene prioritization tools. Replication cohort 1 was searched for rare and predicted deleterious variants and genetic association. Replication cohort 2 was used to investigate the association of common variants with BAV. Results: A total of 938 patients with BAV were included in this study: 69 (7.4%) in the discovery cohort, 417 (44.5%) in replication cohort 1, and 452 (48.2%) in replication cohort 2. A novel human nsBAV gene, MINDBOMB1 homologue MIB1, was identified. MINDBOMB1 homologue (MIB1) is an E3-ubiquitin ligase essential for NOTCH-signal activation during heart development. In approximately 2% of nsBAV index cases from the discovery and replication 1 cohorts, rare MIB1 variants were detected, predicted to be damaging, and were significantly enriched compared with population-based controls (2% cases vs 0.9% controls; P = .03). In replication cohort 2, MIB1 risk haplotypes significantly associated with nsBAV were identified (permutation test, 1000 repeats; P = .02). Two genetically modified mice models carrying Mib1 variants identified in our cohort showed BAV on a NOTCH1-sensitized genetic background. Conclusions and Relevance: This genetic association study identified the MIB1 gene as associated with nsBAV. This underscores the crucial role of the NOTCH pathway in the pathophysiology of BAV and its potential as a target for future diagnostic and therapeutic intervention.

Myocardial contraction fraction predicts mortality in the oldest old.

Background: People over the age of 85 are the world's most rapidly growing age group. Ejection fraction (EF) may be limited prognostically in this population and myocardial contraction fraction (MCF) may be more accurate. The objective of this longitudinal study was to assess the prognosis of MCF in an age-homogenous, community-dwelling population of subjects. Methods: Subjects were recruited from the Jerusalem Longitudinal Cohort Study. Echocardiography was performed with a portable echocardiograph at the subjects place of residence. Standard echocardiographic assessment of cardiac structure and function including MCF was performed. Values of EF and MCF above and below the median for males and females were defined as normal and abnormal in categorical analysis. 5-year mortality was assessed via a centralized government database. Results: 418 subjects (199 males, 219 females) were enrolled in the study of whom 113 (27 %) died at the time of 5-year follow-up. Subjects who died had significantly lower MCF (32 ± 14 % vs 36 ± 12 %; p < 0.004) and EF (51.6 ± 11.6 % vs 56.3 ± 9.4 %; p < 0.0001) than survivors. The association between MCF and mortality remained significant on clinical multivariate analysis as both a categorical and continuous variable while EF was only significant as a continous variable. When both EF and MCF were added to the model only MCF as a categorical variable remained significant. Conclusions: MCF assessed by home echocardiography provides additional prognostic information to EF and may be a superior predictor of 5-year mortality in a community-dwelling population of the oldest old.

Giant Intracardiac Lipoma: A Case Report and the Role of Multimodality Cardiac Imaging.

Cardiac lipomas, especially ones originating from the left ventricle, are extremely rare. They may be asymptomatic or may present with various non-specific symptoms. Herein, we report a case of a giant lipoma of the left ventricle, with frequent ventricular premature beats on electrocardiogram. An echocardiogram demonstrated a large hyperechoic mass occupying a significant portion of the left ventricle. We further describe the diagnostic workup utilizing multimodality cardiac imaging and treatment options. Cardiac MRI demonstrated fat suppression, and cardiac CT showed a homogenous low-attenuation mass suggesting lipomatous matter. The mass was subsequently surgically removed for pathology examination in order to rule out liposarcoma. Histopathology demonstrated mature adipocytes, entrapped myocytes with hypertrophy, and interstitial fibrosis foci confirming the diagnosis of lipoma.

Mitral valve prolapse: From new mechanisms to diagnostic challenges.

Mitral valve prolapse (MVP) is the most common primary valvular abnormality, associated with various degrees of incompetent function and sequelae, including heart failure and sudden cardiac death. Recent improvements in echocardiographic techniques and new insights into mitral valve anatomy and physiology have rendered the diagnosis of this condition more accurate and reliable. Here we review the genetic etiology, clinical significance, diagnosis, and treatment options for MVP patients.

Percutaneous Mitral Valve Repair in Cancer Patients with Heart Failure and Severe Mitral Regurgitation.

BACKGROUND: Cancer patients with heart failure (HF) and severe mitral regurgitation (MR) are often considered to be at risk for surgical mitral valve repair/replacement. Severe MR inducing symptomatic HF may prevent delivery of potentially cardiotoxic chemotherapy and complicate fluid management with other cancer treatments. OBJECTIVES: To evaluate the outcome of percutaneous mitral valve repair (PMVR) in oncology patients with HF and significant MR. METHODS: Our study comprised 145 patients who underwent PMVR, MitraClip, at Hadassah Medical Center between August 2015 and September 2019, including 28 patients who had active or history of cancer. Data from 28 cancer patients were compared to 117 no-cancer patients from the cohort. RESULTS: There was no significant difference in the mean age of cancer patients and no-cancer patients (76 vs. 80 years, P = 0.16); 67% of the patients had secondary (functional) MR. Among cancer patients, 21 had solid tumor and 7 had hematologic malignancies. Nine patients (32%) had active malignancy at the time of PMVR. The mean short-term risk score of the patients was similar in the two groups, as were both 30-day and 1-year mortality rates (7% vs. 4%, P = 0.52) and (29% vs. 16%, P = 0.13), respectively. CONCLUSIONS: PMVR in cancer patients is associated with similar 30-day and 1-year survival rate compared with patients without cancer. PMVR should be considered for cancer patients presenting with HF and severe MR and despite their malignancy. This approach may allow cancer patients to safely receive planned oncological treatment.

The Diagnosis and Management of Immune Checkpoint Inhibitor Cardiovascular Toxicity: Myocarditis and Beyond.

Recent years have brought major advancements in the use of immune therapy and specifically immune checkpoint inhibitors (ICIs) in cancer patients, with expanding indications for various malignancies resulting in the treatment of a large and increasing number of patients. While this therapy significantly improves outcomes in a variety of hematologic and solid tumors, the use of ICIs is associated with a substantial risk of immune-related adverse events. Cardiovascular toxicity, while not the most common side effect of ICIs, is associated with significant morbidity and mortality. It is therefore crucial for oncologists and cardiologists, as well as internists and emergency room physicians, to have a good understanding of this increasingly common clinical problem. In the present review, we discuss the cardiac aspects of ICI therapy with special emphasis on the clinical manifestations of their cardiovascular toxicity, diagnostic approaches, treatment and suggested surveillance.

Pleural effusion: a potential surrogate marker for higher-risk patients with acute type B aortic dissections.

OBJECTIVES: Pleural effusions (PEffs) are known to occur in type B acute aortic dissection (TBAAD). We investigated the relationship between pleural effusion and the development of early or late complications following TBAAD. METHODS: The incidence of PEff (defined as at least an obliteration of the costophrenic angle in a frontal projection) diagnosed on their initial chest X-ray in patients with TBAAD enrolled in the International Registry of Acute Aortic Dissection was examined. We analysed in-hospital outcomes and long-term survival separately for patients with and without PEffs (PEff+ versus PEff-, respectively). RESULTS: Included were 1252 patients with TBAAD, of whom 224 (17.9%) had PEff. Compared with patients without PEff in the initial chest X-ray, these were significantly older [mean age 67 (SD: 14.7) vs 63.4 (SD: 14.2) years, P = 0.001] and more often female (42.4% vs 34.2%, P = 0.021) and had more comorbidities (known aortic aneurysm, chronic obstructive pulmonary disease, chronic renal failure, diabetes, congestive heart failure or mitral valve disease). PEff was associated with higher in-hospital mortality (16.1% vs 9.1%, P = 0.002) and increased rates of neurological complications (16.6% vs 11.1%, P = 0.029), acute renal failure (27.2% vs 19.7%, P = 0.017) and hypotension (17.4% vs 9.6%, P = 0.001). In addition, patients with PEff underwent aortic repair more frequently (44.6% vs 32.5%, P < 0.001). In the long-term patients with PEff showed lower 5-year post-discharge survival (67.6% vs 77.6%, P = 0.004). Multivariable analysis with propensity-matched data showed that PEff was not an independent risk factor for in-hospital mortality (odds ratio 1.9, 95% CI 0.8-4.4, P = 0.141). CONCLUSIONS: Patients with TBAAD and evidence of PEff showed a higher in-hospital mortality, are more likely to develop additional in-hospital complications and have a decreased likelihood of survival during follow-up. However, according to propensity-matched analysis, PEff remained not as an independent predictor of worse outcome but might serve as an early surrogate marker to identify higher-risk patients.

Is Bicuspid Aortic Valve Morphology Genetically Determined? A Family-Based Study.

Bicuspid aortic valve (BAV) is a common congenital heart disease, with a 10-fold higher prevalence in first-degree relatives. BAV has different phenotypes based on the morphology of cusp fusion. These phenotypes are associated with different clinical courses and prognoses. Currently, the determinants of the valve phenotype are unknown. In this study we evaluated the role of genetics using familial cohorts. Patients with BAV and their first-degree relatives were evaluated by echocardiography. The concordance in BAV phenotype between pairs of family members was calculated and compared with the concordance expected by chance. We then performed a systematic literature review to identify additional reports and calculated the overall concordance rate. During the study period, 70 cases from 31 families and 327 sporadic cases were identified. BAV was diagnosed in 14% of the screened relatives. The proportions of the morphologies identified was: 12.3% for type 0, 66.2% for type 1-LR, 15.4% for type 1-RN, 4.6% for type 1-NL, and 1.5% for type 2. For the assessment of morphologic concordance, we included 120 pairs of first-degree relatives with BAV from our original cohort and the literature review. Concordance was found only in 62% of the pairs which was not significantly higher than expected by chance. In conclusion, our finding demonstrates intrafamilial variability in BAV morphology, suggesting that morphology is determined by factors other than Mendelian genetics. As prognosis differs by morphology, our findings may suggest that clinical outcomes may vary even between first-degree relatives.

Bicuspid Aortic Valve: Genetic and Clinical Insights.

Bicuspid aortic valve (BAV) is the most common valvular congenital heart disease, with a prevalence of 0.5 to 2% in the general population. Patients with BAV are at risk for developing cardiovascular complications, some of which are life-threatening. BAV has a wide spectrum of clinical presentations, ranging from silent malformation to severe and even fatal cardiac events. Despite the significant burden on both the patients and the health systems, data are limited regarding pathophysiology, risk factors, and genetics. Family studies indicate that BAV is highly heritable, with autosomal dominant inheritance, incomplete penetrance, variable expressivity, and male predominance. Owing to its complex genetic model, including high genetic heterogenicity, only a few genes were identified in association with BAV, while the majority of BAV genetics remains obscure. Here, we review the different forms of BAV and the current data regarding its genetics. Given the clear heritably of BAV with the potential high impact on clinical outcome, the clinical value and cost effectiveness of cascade screening are discussed.

The Role Played by Transcription Factor E3 in Modulating Cardiac Hypertrophy.

Transcription factor E3 (TFE3), which is a key regulator of cellular adaptation, is expressed in most tissues, including the heart, and is reportedly overexpressed during cardiac hypertrophy. In this study, TFE3's role in cardiac hypertrophy was investigated. To understand TFE3's physiological importance in cardiac hypertrophy, pressure-overload cardiac hypertrophy was induced through transverse aortic constriction (TAC) in both wild-type (WT) and TFE3 knockout mice (TFE3-/-). Eleven weeks after TAC induction, cardiac hypertrophy was observed in both WT and TFE3-/- mice. However, significant reductions in ejection fraction and fractional shortening were observed in WT mice compared to TFE3-/- mice. To understand the mechanism, we found that myosin heavy chain (Myh7), which increases during hemodynamic overload, was lower in TFE3-/- TAC mice than in WT TAC mice, whereas extracellular signal-regulated protein kinases (ERK) phosphorylation, which confers cardioprotection, was lower in the left ventricles of WT mice than in TFE3-/- mice. We also found high expressions of TFE3, histone, and MYH7 and low expression of pERK in the normal human heart compared to the hypertensive heart. In the H9c2 cell line, we found that ERK inhibition caused TFE3 nuclear localization. In addition, we found that MYH7 was associated with TFE3, and during TFE3 knockdown, MYH7 and histone were downregulated. Therefore, we showed that TFE3 expression was increased in the mouse model of cardiac hypertrophy and tissues from human hypertensive hearts, whereas pERK was decreased reversibly, which suggested that TFE3 is involved in cardiac hypertrophy through TFE3-histone-MYH7-pERK signaling.

Cost-effectiveness analysis of screening for first-degree relatives of patients with bicuspid aortic valve.

AIMS: Bicuspid aortic valve (BAV) is the commonest congenital heart valve malformation, and is associated with life-threatening complications. Given the high heritability index of BAV, many experts recommend echocardiography screening for first-degree relatives (FDRs) of an index case. Here, we aim to evaluate the cost-effectiveness of such cascade screening for BAV. METHODS AND RESULTS: Using a decision-analytic model, we performed a cost-effectiveness analysis of echocardiographic screening for FDRs of a BAV index case. Data on BAV probabilities and complications among FDRs were derived from our institution's BAV familial cohort and from the literature on population-based BAV cohorts with long-term follow-up. Health gain was measured as quality-adjusted life years (QALYs). Cost inputs were based on list prices and literature data. One-way and probabilistic sensitivity analyses were performed to account for uncertainty in the model's variables. Screening of FDRs was found to be the dominant strategy, being more effective and less costly than no screening, with savings of €644 and gains of 0.3 QALY. Results were sensitive throughout the range of the main model's variables, including the full range of reported BAV rates among FDRs across the literature. A gradual decrease of the incremental effect was found with the increase in screening age. CONCLUSION: This economic evaluation model found that echocardiographic screening of FDRs of a BAV index case is not only clinically important but also cost-effective and cost-saving. Sensitivity analysis supported the model's robustness, suggesting its generalization.

Update in carcinoid heart disease - the heart of the matter.

Carcinoid heart disease (CHD) is a paraneoplastic cardiac manifestation occurring in patients with carcinoid syndrome (CS) and advanced neuroendocrine malignancy. In about 20-40% of patients with CS, chronic exposure to tumor-released circulating vasoactive peptides typically results in right-sided valvular fibrosis leading to valve dysfunction and right heart failure. CHD remains a significant cause of morbidity and mortality. The management of patients with CHD is complex, as both the systemic malignant disease and the heart involvement have to be addressed. Early diagnosis and timely surgical intervention in selected patients are of utmost importance and offer a survival benefit. In patients with advanced carcinoid heart disease, valve replacement surgery is the most effective option to alleviate cardiac symptoms and contribute to survival outcomes. A collaboration of a multidisciplinary team in centers with experience is required to provide optimal patient management. Here, we review the current literature regarding CHD presentation, pathophysiology, diagnostic tools, and available treatment strategies.