Cardiovascular Outcomes of Uric Acid Lowering Medications: A Meta-Analysis.

BACKGROUND: Although hyperuricemia is a recognized risk factor for cardiovascular diseases, mixed results have been reported regarding the associations between uric acid-lowering medications and cardiovascular events. This meta-analysis compared the cardiovascular outcomes of different uric acid-lowering medications and placebo. METHODS: Following PRISMA guidelines, we searched OVID Medline, Embase, Web of Science, and Cochrane databases to identify potentially relevant articles until December 2023. Studies must be randomized or observational, report cardiovascular and mortality outcomes, and compare uric acid-lowering medications to placebo or each other. Data was analyzed using Revman (version 5.4) software. RESULTS: A total of 3,393 studies were searched, after which 47 studies were included, totaling 3,803,509 patients (28 studies comparing xanthine oxidase inhibitors (XOI) versus placebo, 17 studies comparing allopurinol and febuxostat, and 2 studies comparing XOI and uricosuric agents). Overall mean age was 57.3 years, and females comprised 20.8% of all studies. There were no significant differences between XOI and placebo for cardiovascular outcomes (mortality, myocardial infarction, major adverse cardiovascular events, heart failure, or arrhythmia). There was significant heterogeneity in all these pooled analyses. Comparing Allopurinol to Febuxostat, there was a lower risk of heart failure in febuxostat than allopurinol in 3 RCTs (OR 0.66, 95% CI 0.50-0.89, p = 0.006). Other cardiovascular outcomes were not different. Lastly, when comparing XOI and uricosuric agents, no significant differences in MI rates were evident. CONCLUSION: XOI was not associated with reduced cardiovascular events compared to placebo. When comparing XOI agents, Febuxostat might reduce the risk of HF, but future studies are required to confirm the findings from the current study.

Time shifts: Place, belonging, and future orientation in pandemic everyday life.

The disruptions to everyday life wrought by the COVID-19 pandemic include distortions in the experience of time, as reported widely by ordinary citizens and observed by journalists and social scientists. But how does this temporal disruption play out in different time scales-in the individual day as opposed to the medium- and long-term futures? And how might place influence how individuals experience and understand the pandemic's temporal transformations? This essay examines a range of temporal disruptions reported in day diaries and surveys submitted to the Everyday Life in Middletown project, an online archive that has been documenting ordinary life in Muncie, Indiana, USA since 2016. Viewing these materials as instances of life writing, the essay probes the interactions between temporal disruptions and the local setting as they inflect the autobiographical selves our writers construct in their pandemic writings. It shows how living in Muncie-a postindustrial city with its particular combination of historical, demographic, economic, social, and political dynamics-structures the autobiographical stories available to our writers, and how the disruption of time produces new variations and problems for life writing. In the midst of a global crisis, we glimpse the pandemic's reshaping of a local structure of feeling in which a pervasive, local narrative of civic decline frames individual self-fashioning.

The Association of Cardiac Biomarkers, the Intensity of Tc99 Pyrophosphate Uptake, and Survival in Patients Evaluated for Transthyretin Cardiac Amyloidosis in the Early Therapeutics Era.

BACKGROUND: Transthyretin amyloid cardiomyopathy (ATTR-CM) is an increasingly recognized cause of heart failure. Given the expansion of noninvasive diagnosis with 99mTc-pyrophosphate (99mTc-PYP) scanning, and clinical use of the transthyretin stabilizer, tafamidis, we sought to examine the interplay of planar imaging heart-to-contralateral lung (H/CL) ratio, cardiac biomarkers, and survival probability in a contemporary cohort of patients referred for noninvasive evaluation of ATTR-CM. METHODS: This single-center retrospective cohort study included 351 consecutive patients who underwent a standardized imaging protocol with 99mTc-PYP scanning for the evaluation of ATTR-CM from January 1, 2018, to January 1, 2020. After the exclusion of light chain amyloidosis, patients were characterized as scan consistent with ATTR (+ATTR-CM) or scan not consistent with ATTR (-ATTR-CM) using current guidelines. Linear regression was used to examine the relationship between biomarkers and H/CL and univariate Cox proportional hazards models were used to assess the probability of transplant-free survival. RESULTS: We included 318 patients in the analysis (n = 86 patients +ATTR-CM; n = 232 patients -ATTR-CM). The median follow-up time was 20.1 months. During the study period, 67% of +ATTR-CM patients received tafamidis (median treatment duration, 17 months). The median H/CL ratio was 1.58 (interquartile range, 1.40-1.75). An H/CL ratio of more than 1.6 or less than 1.6 did not seem to have an impact on survival probability in +ATTR-CM patients (P = .30; hazard ratio, 0.65; 95% confidence interval, 0.31-1.41). Cardiac biomarkers were poorly correlated with H/CL (troponin T, R2 = 0.024; N-terminal pro-B-type natriuretic peptide, R2 =0.023). The Gillmore staging system predicted survival probability in +ATTR-CM as well as in the entire cohort referred for scanning. There was a trend toward longer survival among those who were -ATTR-CM compared with +ATTR-CM (P = .051; hazard ratio, 0.64; 95% confidence interval, 0.40-1.00). CONCLUSIONS: At a large referral center, the intensity of 99mTc-PYP uptake (H/CL ratio) has neither correlation with cardiac biomarker concentrations nor prognostic usefulness in an analysis of intermediate term outcomes in the early therapeutics era. The H/CL ratio has diagnostic value, but offers little prognostic value in patients with ATTR-CM. Established staging schema were predictive of survival in this contemporary cohort, re-emphasizing the importance of cardiac biomarkers and renal function in assessing disease severity and prognosis.

Cardiac risk stratification in cancer patients: A longitudinal patient-patient network analysis.

BACKGROUND: Cardiovascular disease is a leading cause of death in general population and the second leading cause of mortality and morbidity in cancer survivors after recurrent malignancy in the United States. The growing awareness of cancer therapy-related cardiac dysfunction (CTRCD) has led to an emerging field of cardio-oncology; yet, there is limited knowledge on how to predict which patients will experience adverse cardiac outcomes. We aimed to perform unbiased cardiac risk stratification for cancer patients using our large-scale, institutional electronic medical records. METHODS AND FINDINGS: We built a large longitudinal (up to 22 years' follow-up from March 1997 to January 2019) cardio-oncology cohort having 4,632 cancer patients in Cleveland Clinic with 5 diagnosed cardiac outcomes: atrial fibrillation, coronary artery disease, heart failure, myocardial infarction, and stroke. The entire population includes 84% white Americans and 11% black Americans, and 59% females versus 41% males, with median age of 63 (interquartile range [IQR]: 54 to 71) years old. We utilized a topology-based K-means clustering approach for unbiased patient-patient network analyses of data from general demographics, echocardiogram (over 25,000), lab testing, and cardiac factors (cardiac). We performed hazard ratio (HR) and Kaplan-Meier analyses to identify clinically actionable variables. All confounding factors were adjusted by Cox regression models. We performed random-split and time-split training-test validation for our model. We identified 4 clinically relevant subgroups that are significantly correlated with incidence of cardiac outcomes and mortality. Among the 4 subgroups, subgroup I (n = 625) has the highest risk of de novo CTRCD (28%) with an HR of 3.05 (95% confidence interval (CI) 2.51 to 3.72). Patients in subgroup IV (n = 1,250) had the worst survival probability (HR 4.32, 95% CI 3.82 to 4.88). From longitudinal patient-patient network analyses, the patients in subgroup I had a higher percentage of de novo CTRCD and a worse mortality within 5 years after the initiation of cancer therapies compared to long-time exposure (6 to 20 years). Using clinical variable network analyses, we identified that serum levels of NT-proB-type Natriuretic Peptide (NT-proBNP) and Troponin T are significantly correlated with patient's mortality (NT-proBNP > 900 pg/mL versus NT-proBNP = 0 to 125 pg/mL, HR = 2.95, 95% CI 2.28 to 3.82, p < 0.001; Troponin T > 0.05 µg/L versus Troponin T ≤ 0.01 µg/L, HR = 2.08, 95% CI 1.83 to 2.34, p < 0.001). Study limitations include lack of independent cardio-oncology cohorts from different healthcare systems to evaluate the generalizability of the models. Meanwhile, the confounding factors, such as multiple medication usages, may influence the findings. CONCLUSIONS: In this study, we demonstrated that the patient-patient network clustering methodology is clinically intuitive, and it allows more rapid identification of cancer survivors that are at greater risk of cardiac dysfunction. We believed that this study holds great promise for identifying novel cardiac risk subgroups and clinically actionable variables for the development of precision cardio-oncology.

The impact of right ventricular injury on the mortality in patients with acute respiratory distress syndrome: a systematic review and meta-analysis.

BACKGROUND: Previous studies have found various incidences of right ventricular (RV) injury and its association with clinical outcome in patients with acute respiratory distress syndrome (ARDS). In this systematic review and meta-analysis, we aimed to investigate the impact of the presence of RV injury on mortality in patients with ARDS. METHOD: We searched Medline, Embase, and the Cochrane Central Register of Controlled Trials for studies investigating the association between RV injury and mortality. Two authors independently evaluated whether studies meet eligibility criteria and extracted the selected patients' and studies' characteristics and outcomes. RV injury was diagnosed by trans-thoracic echocardiogram (TTE), trans-esophageal echocardiogram (TEE) and PAC (pulmonary artery catheter) in the included studies. The primary outcome was the association between mortality and the presence of RV injury in patients with ARDS. The overall reported mortality was defined as either the intensive care unit (ICU) mortality, in-hospital mortality, or mortality within 90 days, and short-term mortality was defined as ICU-mortality, in-hospital mortality, or mortality within 30 days. RESULTS: We included 9 studies (N = 1861 patients) in this meta-analysis. RV injury that included RV dysfunction, RV dysfunction with hemodynamic compromise, RV failure, or acute cor-pulmonale was present in 21.0% (391/1,861). In the pooled meta-analysis, the presence of RV injury in patients with ARDS was associated with significantly higher overall mortality (OR 1.45, 95% CI 1.13-1.86, p-value = 0.003, I2 = 0%), as well as short-term mortality (OR 1.48, 95% CI 1.14-1.93, p-value = 0.003, I2 = 0%). CONCLUSION: In this systematic review and meta-analysis including 1861 patients with ARDS, the presence of RV injury was significantly associated with increased overall and short-term mortality. TRIAL REGISTRATION: The protocol was registered at PROSPERO (CRD42020206521).

Global longitudinal strain is a better metric than left ventricular ejection fraction: lessons learned from cancer therapeutic-related cardiac dysfunction.

PURPOSE OF THE REVIEW: This review aims to highlight the utility of global longitudinal strain (GLS) in cancer therapeutic-related cardiac dysfunction (CTRCD), with an attempt to stipulate that GLS might be a better measure than left ventricular ejection fraction (LVEF). RECENT FINDINGS: Increasingly, GLS quantification has been employed in various cardiovascular diseases especially with its ability to detect left ventricular dysfunction subclinically, even before a change in LVEF is visualized. In fact, several studies reveal that GLS may be a superior predictor of mortality and morbidity than LVEF in this context. A recent metaanalysis supported the prognosticating value of GLS in CTRCD, however, endorsed the need for larger multicenter studies to establish the value of this metric. Studies in other cardiovascular disease processes showed GLS as a better metric than LVEF. SUMMARY: GLS has been heralded as a new echocardiographic measure that can detect subclinical cardiac disease. At a minimum, GLS can provide incremental value in prognosticating, diagnosing, and predicting LVEF recovery and at best, a better measure of left ventricular dysfunction.

Teamwork using strain imaging in the echocardiographic assessment of right ventricular systolic function: A cardiac magnetic resonance imaging correlation study.

AIM: The aim of this study was to investigate whether conventional echocardiographic assessment of right ventricular (RV) systolic function can be improved by the addition of RV strain imaging. Additionally, we also aimed to investigate whether dedicated reading sessions and education can improve echocardiographic interpretation of RV systolic function. METHODS: Readers of varying expertise (staff echocardiologists, advanced cardiovascular imaging fellows, sonographers) assessed RV systolic function. In session 1, 20 readers graded RV function of 19 cases, using conventional measures. After dedicated education, in session 2, the same cases were reassessed, with the addition of RV strains. In session 3, 18 readers graded RV function of 20 additional cases, incorporating RV strains. Computer simulations were performed to obtain 230 random teams. RV ejection fraction (RVEF) by cardiac magnetic resonance (CMR) was the reference standard. RESULTS: Correlation between RV GLS and CMR-derived RVEF was moderate: Spearman's rho: 0.70, n = 19, P < 0.001 (first two sessions); 0.55, n = 20, P < 0.05 (third session). Individual readers' assessment moderately correlated with RVEF (Spearman's rho first session: 0.67 ± 0.2; second session: 0.61 ± 0.2; and third session: 0.68 ± 0.09). Team estimates of RV systolic function showed consistently better correlation with RVEF, which were improved further by averaging across all readers. RV strain parameters influenced echocardiographic interpretation, with a net reclassification index of 8.0 ± 3.6% (P = 0.014). CONCLUSIONS: The RV strain parameters showed moderate correlations with CMR-derived RVEF and appropriately influenced echocardiographic interpretation of RV systolic function. "Wisdom of the crowd" applied by averaging echocardiographic assessments of RV systolic function across teams of echocardiography readers, further improved echocardiographic assessment of RV systolic function.

Prevention of Cardiotoxicities With Traditional and Novel Chemotherapeutic Agents.

PURPOSE OF REVIEW: This review will discuss strategies to prevent cardiotoxicity associated with chemotherapeutics. Forty years ago, investigators identified dose-dependent cardiotoxicity related to anthracycline-based regimens. Over recent decades, the development of more selective, mechanism-based chemotherapeutics has been associated with both on-target and off-target adverse cardiovascular sequelae. RECENT FINDINGS: Strategies to prevent or attenuate cardiotoxicities include limitation of anthracycline dose, appropriate patient selection, referral/access to cardio-oncology programs, early recognition of cardiac side effects, active cardio-surveillance, cardio-protective medical therapy, treatment-specific concerns, and follow-up. The importance of accurate diagnosis of cardiotoxicity is important as false-positive testing may result in inappropriate holding or stopping potentially life-saving chemotherapy. Data to support use of cardio-protective medical therapy to prevent chemotherapy-related cardiotoxicity is modest at best, limited by marginal effect size, small patient numbers, and short follow-up. The rapid growth in cardio-oncology clinics may facilitate larger multi-center randomized controlled trials in this area.

Reliability of updated left ventricular diastolic function recommendations in predicting elevated left ventricular filling pressure and prognosis.

An updated 2016 echocardiographic algorithm for diagnosing left ventricular (LV) diastolic dysfunction (DD) was recently proposed. We aimed to assess the reliability of the 2016 echocardiographic LVDD grading algorithm in predicting elevated LV filling pressure and clinical outcomes compared to the 2009 version. METHODS: We retrospectively identified 460 consecutive patients without atrial fibrillation or significant mitral valve disease who underwent transthoracic echocardiography within 24 hours of elective heart catheterization. LV end-diastolic pressure (LVEDP) and the time constant of isovolumic pressure decay (Tau) were determined. The association between DD grading by 2009 LVDD Recommendations and 2016 Recommendations with hemodynamic parameters and all-cause mortality were compared. RESULTS: The 2009 LVDD Recommendations classified 55 patients (12%) as having normal, 132 (29%) as grade 1, 156 (34%) as grade 2, and 117 (25%) as grade 3 DD. Based on 2016 Recommendations, 177 patients (38%) were normal, 50 (11%) were indeterminate, 124 (27%) patients were grade 1, 75 (16%) were grade 2, 26 (6%) were grade 3 DD, and 8 (2%) were cannot determine. The 2016 Recommendations had superior discriminatory accuracy in predicting LVEDP (P<.001) but were not superior in predicting Tau. During median follow-up of 416 days (interquartile range: 5 to 2004 days), 54 patients (12%) died. Significant DD by 2016 Recommendations was associated with higher risk of mortality (P=.039, subdistribution HR1.85 [95% CI, 1.03-3.33]) in multivariable competing risk regression. CONCLUSIONS: The grading algorithm proposed by the 2016 LV diastolic dysfunction Recommendations detects elevated LVEDP and poor prognosis better than the 2009 Recommendations.

Hypoxia-induced epigenetic modifications are associated with cardiac tissue fibrosis and the development of a myofibroblast-like phenotype.

Ischemia caused by coronary artery disease and myocardial infarction leads to aberrant ventricular remodeling and cardiac fibrosis. This occurs partly through accumulation of gene expression changes in resident fibroblasts, resulting in an overactive fibrotic phenotype. Long-term adaptation to a hypoxic insult is likely to require significant modification of chromatin structure in order to maintain the fibrotic phenotype. Epigenetic changes may play an important role in modulating hypoxia-induced fibrosis within the heart. Therefore, the aim of the study was to investigate the potential pro-fibrotic impact of hypoxia on cardiac fibroblasts and determine whether alterations in DNA methylation could play a role in this process. This study found that within human cardiac tissue, the degree of hypoxia was associated with increased expression of collagen 1 and alpha-smooth muscle actin (ASMA). In addition, human cardiac fibroblast cells exposed to prolonged 1% hypoxia resulted in a pro-fibrotic state. These hypoxia-induced pro-fibrotic changes were associated with global DNA hypermethylation and increased expression of the DNA methyltransferase (DNMT) enzymes DNMT1 and DNMT3B. Expression of these methylating enzymes was shown to be regulated by hypoxia-inducible factor (HIF)-1α. Using siRNA to block DNMT3B expression significantly reduced collagen 1 and ASMA expression. In addition, application of the DNMT inhibitor 5-aza-2'-deoxycytidine suppressed the pro-fibrotic effects of TGFß. Epigenetic modifications and changes in the epigenetic machinery identified in cardiac fibroblasts during prolonged hypoxia may contribute to the pro-fibrotic nature of the ischemic milieu. Targeting up-regulated expression of DNMTs in ischemic heart disease may prove to be a valuable therapeutic approach.

Grading diastolic function by echocardiography: hemodynamic validation of existing guidelines.

BACKGROUND: While echocardiographic grading of left ventricular (LV) diastolic dysfunction (DD) is used every day, the relationship between echocardiographic DD grade and hemodynamic abnormalities is uncertain. METHODS: We identified 460 consecutive patients who underwent transthoracic echocardiography within 24 h of elective left heart catheterization and had: normal sinus rhythm, no confounding structural heart disease, no change in medications between catheterization and echo, and complete echocardiographic data. Patients were grouped based on echocardiographic DD grade. Hemodynamic tracings were used to determine time constant of isovolumic pressure decay (Tau), LV end-diastolic pressure (LVEDP) and end-diastolic volume index at a pressure of 20 mmHg (EDVi20). RESULTS: Normal diastolic function was found in 55 (12.0%) patients, while 132 (28.7%) patients had grade 1, 156 (33.9%) grade 2 and 117 (25.4%) grade 3 DD. The median value for Tau was 46.9 ms for the overall population (interquartile range 38.6-58.1 ms), with a prevalence of a prolonged Tau (>48 ms) of 47.5%. While there was an association between DD grade and Tau (p = 0.003), LV dysfunction (ejection fraction <50%) was more strongly associated with increased Tau (p < 0.001) than was DD grade (p = 0.19). There was also an association between DD grade and LVEDP (p < 0.001), with both LV dysfunction (p = 0.029) and DD grade (p < 0.001) independently associated with LVEDP. Calculated EDVi20 was related to DD grade, but this relationship was driven by findings of paradoxically increased compliance in patients with severe DD. CONCLUSIONS: Although echocardiographic grading of DD was related to invasive hemodynamics in this population, the relationship was modest.

Extracellular matrix sub-types and mechanical stretch impact human cardiac fibroblast responses to transforming growth factor beta.

Understanding the impact of extracellular matrix sub-types and mechanical stretch on cardiac fibroblast activity is required to help unravel the pathophysiology of myocardial fibrotic diseases. Therefore, the purpose of this study was to investigate pro-fibrotic responses of primary human cardiac fibroblast cells exposed to different extracellular matrix components, including collagen sub-types I, III, IV, VI and laminin. The impact of mechanical cyclical stretch and treatment with transforming growth factor beta 1 (TGFß1) on collagen 1, collagen 3 and alpha smooth muscle actin mRNA expression on different matrices was assessed using quantitative real-time PCR. Our results revealed that all of the matrices studied not only affected the expression of pro-fibrotic genes in primary human cardiac fibroblast cells at rest but also affected their response to TGFß1. In addition, differential cellular responses to mechanical cyclical stretch were observed depending on the type of matrix the cells were adhered to. These findings may give insight into the impact of selective pathological deposition of extracellular matrix proteins within different disease states and how these could impact the fibrotic environment.

Unmasking Severe Systolic Anterior Motion With Left Ventricular Outflow Tract Obstruction Following Mitral Valve Repair.

A 38-year-old male with a history of myxomatous mitral valve disease post-repair presented with recurrent dyspnea during exertion. Initial evaluation showed mild systolic anterior motion and mitral regurgitation, but medical management was unsuccessful. The patient underwent reoperation; intraoperative transesophageal echocardiogram with provocation unmasked severe systolic anterior motion and torrential mitral regurgitation.

Proteomic Characterisation of Heart Failure Reveals a Unique Molecular Phenotype for Hypertrophic Cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is a disease, which is difficult to diagnose at an early stage and for which there is a pressing need for more effective treatment options. The purpose of this study was to compare the molecular profile of HCM to that of ischaemic cardiomyopathy (ISCM) and dilated cardiomyopathy (DCM) for identification of protein and pathway targets that could support the development of better diagnostic and treatment options for HCM. A high-throughput mass spectrometry workflow was applied to achieve deep quantitative coverage of left ventricular tissue from HCM, DCM, ISCM and non-heart-failure control patients. HCM had a diverse proteomic profile compared to that of DCM and ISCM. Differentially expressed proteins unique to HCM were identified based on an observed fold change of ≥1.5 or ≤0.67 and q-value ≤ 0.05. Candidate proteins of interest were found to be significantly associated with clinical features of HCM. The significant association between these proteins and HCM was validated in an independent dataset. This represents one of the largest and deepest proteomic datasets for myocardial tissue reported to date. The dataset highlights the diverse proteomic profile of HCM, relative to other cardiomyopathies, and reveals disease-relevant pathways and promising biomarker candidates that are uniquely associated with HCM.

Single-Cell RNA Sequencing Reveals Cardiac Fibroblast-Specific Transcriptomic Changes in Dilated Cardiomyopathy.

Dilated cardiomyopathy (DCM) is the most common cause of heart failure, with a complex aetiology involving multiple cell types. We aimed to detect cell-specific transcriptomic alterations in DCM through analysis that leveraged recent advancements in single-cell analytical tools. Single-cell RNA sequencing (scRNA-seq) data from human DCM cardiac tissue were subjected to an updated bioinformatic workflow in which unsupervised clustering was paired with reference label transfer to more comprehensively annotate the dataset. Differential gene expression was detected primarily in the cardiac fibroblast population. Bulk RNA sequencing was performed on an independent cohort of human cardiac tissue and compared with scRNA-seq gene alterations to generate a stratified list of higher-confidence, fibroblast-specific expression candidates for further validation. Concordant gene dysregulation was confirmed in TGFß-induced fibroblasts. Functional assessment of gene candidates showed that AEBP1 may play a significant role in fibroblast activation. This unbiased approach enabled improved resolution of cardiac cell-type-specific transcriptomic alterations in DCM.

Hemodynamic profile of cirrhotic patients with sepsis and septic shock: A propensity score matched case-control study.

PURPOSE: Our understanding of hemodynamics in cirrhotic patients with sepsis remains limited. Our study aims to investigate differences in hemodynamic profiles using echocardiography between septic patients with and without cirrhosis. MATERIALS AND METHODS: This is a single-center, retrospective study of septic patients with echocardiogram within 3 days of ICU admission. We compared baseline characteristics, echocardiographic markers of LV systolic function arterial load between patients with and without cirrhosis. A propensity score-matched case-control model was developed to describe the differences in those echocardiography derived parameters between the groups. RESULTS: 3151 patients with sepsis were included of which 422 (13%) had cirrhosis. In the propensity score matched group with 828 patients, cirrhotic patients had significantly higher left ventricular ejection fraction (64 vs.56%, p < 0.001) and stroke volume (72 vs.48 ml, p < 0.001) along with lower arterial elastance (Ea) (1.35 1vs.20.3, p < 0.001) and systemic vascular resistance (SVR) (851 vs.1209 dynes/s/m-5, p = 0.001). The left ventricular elastance (Ees) (2.83 vs 2.45, p = 0.002) was higher and ventricular-arterial coupling (Ea/Ees) (0.48 vs. 0.86, p < 0.001) lower in cirrhotic compared to non-cirrhotic. CONCLUSIONS: Septic patients with cirrhosis had higher LVEF with lower Ea and SVR with higher Ees and significantly lower Ea/Ees suggesting vasodilation as the principal driver of the hyperdynamic profile in cirrhosis.

Use of computed tomography coronary calcium score for prediction of cardiovascular events in cancer patients: a retrospective cohort analysis.

BACKGROUND: CT- coronary calcium score, is one of the most studied and widely available modalities in cardiovascular medicine. Coronary artery calcium score (CACS) is an established predictor of coronary artery disease. The 'standard of care' diagnostic modality to measure CACS is ECG-gated Cardiac Multi-Detector Computed Tomography. There is convincing evidence of a strong association between CACS and major cardiovascular (CV) events in asymptomatic individuals. Cancer patients (C) may have a higher risk for CV disease than non-cancer patients (NC) related not only to cancer treatments but also to shared biological factors and pathways. Thus, identifying tools for early detection of CV disease in this population is of utmost importance. METHODS: A retrospective cohort analysis was performed with patients from Cleveland Clinic Florida and Ohio who had CACS from 2017 to 2021. Patients who had cancer diagnosis prior to CACS were matched to NC for age and sex. CV events after their index CACS events were compared between C and NC, and matched control and propensity analysis were conducted. RESULTS: Ten thousand seven hundred forty-two patients had CACS; 703 cancer patients had CACS and were eligible. Extensive CACS (> 400) were significantly higher in cancer, 94 (13.37%) vs non-cancer patients, 76 (10.83%), P = 0.011. Furthermore, after propensity matched analysis, CACS > 400 was 14.8% in C vs 9.6% in NC, P = < 0.05. CV events were similar in both cohorts (p = NS), despite less CV risk factors in cancer patients (P = < 0.05). For the combined moderate (101-400) & extensive (> 400) CACS, the prevalence of stroke and peripheral arterial disease, a marker of systemic atherosclerosis, was significantly higher in patients with cancer (P < 0.01). CONCLUSIONS: Despite having fewer CV risk factors in our study, similar CACS in cancer patients are suggestive of a higher prevalence of CV disease independent of traditional risk factors. High CACS and the overall prevalence of vascular events were more frequent in patients with cancer. Higher prevalence of peripheral arterial disease and cerebrovascular accident further suggests the increased atherosclerotic burden in C.

Integrin beta-like 1 is regulated by DNA methylation and increased in heart failure patients.

AIMS: Dynamic alterations in cardiac DNA methylation have been implicated in the development of heart failure (HF) with evidence of ischaemic heart disease (IHD); however, there is limited research into cell specific, DNA methylation sensitive genes that are affected by dysregulated DNA methylation patterns. In this study, we aimed to identify DNA methylation sensitive genes in the ischaemic heart and elucidate their role in cardiac fibrosis. METHODS: A multi-omics integrative analysis was carried out on RNA sequencing and methylation sequencing on HF with IHD (n = 9) versus non-failing (n = 9) left ventricular tissue, which identified Integrin beta-like 1 (ITGBL1) as a gene of interest. Expression of Itgbl1 was assessed in three animal models of HF; an ischaemia-reperfusion pig model, a myocardial infarction mouse model and an angiotensin-II infused mouse model. Single nuclei RNA sequencing was carried out on heart tissue from angiotensin-II infused mice to establish the expression profile of Itgbl1 across cardiac cell populations. Subsequent in vitro analyses were conducted to elucidate a role for ITGBL1 in human cardiac fibroblasts. DNA pyrosequencing was applied to assess ITGBL1 CpG methylation status in genomic DNA from human cardiac tissue and stimulated cardiac fibroblasts. RESULTS: ITGBL1 was >2-fold up-regulated (FDR adj P = 0.03) and >10-fold hypomethylated (FDR adj P = 0.01) in human HF with IHD left ventricular tissue compared with non-failing controls. Expression of Itgbl1 was up-regulated in three isolated animal models of HF and showed conserved correlation between increased Itgbl1 and diastolic dysfunction. Single nuclei RNA sequencing highlighted that Itgbl1 is primarily expressed in cardiac fibroblasts, while functional studies elucidated a role for ITGBL1 in cardiac fibroblast migration, evident in 50% reduced 24 h fibroblast wound closure occurring subsequent to siRNA-targeted ITGBL1 knockdown. Lastly, evidence provided from DNA pyrosequencing supports the theory that differential expression of ITGBL1 is caused by DNA hypomethylation. CONCLUSIONS: ITGBL1 is a gene that is mainly expressed in fibroblasts, plays an important role in cardiac fibroblast migration, and whose expression is significantly increased in the failing heart. The mechanism by which increased ITGBL1 occurs is through DNA hypomethylation.