Pre-existing Coronary Heart Disease Research Articles

Routine application of cardiac magnetic resonance imaging in patients with suspected myocarditis from immune checkpoint inhibitor therapy

Abstract Background Cardiovascular adverse events including myocarditis associated with immune checkpoint inhibitor (ICI) therapy remain a challenge in clinical practice. Diagnostic assessment of ICI-related myocarditis (ICI-M) is challenging due to a variable phenotype, confounding effects and limited sensitivity of diagnostic tools. Cardiac magnetic resonance imaging (CMR) is used to diagnose non-ICI myocarditis, but evidence on diagnostic sensitivity is low, particularly in patients with a discrete phenotype. Here, we aim to assess the impact of CMR in patients with suspected ICI-related myocarditis and relate to final diagnosis including endomyocardial biopsy findings. Methods All consecutive patients receiving CMR for suspected ICI-M between September 2019 and January 2024 were included and retrospectively analysed. CMR parameters were correlated with clinical, laboratory and echocardiographic parameters and stratified for presence or absence of myocarditis as per final diagnosis. Results A total of 55 patients who received CMR for suspected ICI-related myocarditis were analysed, including 25 patients with confirmed ICI-M as per final diagnosis and 30 patients with cardiotoxicity other than myocarditis or no cardiotoxicity (ICI-O). The mean age (ICI-M versus ICI-O) was 65.7±13.6 versus (vs.) 67.3±9.9 (p=0.61) years, 32.0% vs. 26.7% (p=0.67) were female, and 40.0% vs. 26.7% (p=0.29) had pre-existing coronary heart disease. Cardiac biomarkers and echocardiographic data did not differ between the groups. In CMR analysis, presence of late gadolinium enhancement (LGE) was associated with ICI-M (56.0% vs. 26.7%, p=0.027). Myocardial oedema was generally rare and not associated with ICI-M. Endomyocardial biopsy (EMB) was used in 6 out of 55 patients (10.9%) with suspected ICI-M. In 4 of these 6 patients (66.7%) EMB confirmed ICI-M diagnosis. Of note, only 2/4 patients with EMB-confirmed myocarditis showed abnormal CMR findings. Conclusion The diagnostic assessment of ICI-M is challenged by low sensitivity of common diagnostic measures, often requiring a multimodal approach. Presence of LGE in CMR was associated with ICI-M, but sensitivity and specificity are low. Our data emphasize the high value of EMB in patients with clinically suspected ICI-M despite inconspicuous CMR. Prospective data to improve diagnostic criteria are needed.

Association between egg consumption and mortality risk in United States adults with established coronary heart disease or stroke: A cohort study using data from NHANES 1999–2018

BackgroundTo investigate the relationship between egg consumption and mortality in individuals with pre-existing coronary heart disease or stroke. MethodsThis study utilized data from the National Health and Nutrition Examination Survey conducted between 1999 and 2018. Egg consumption was evaluated through 24 h dietary recalls at baseline. Mortality status was tracked until December 31, 2019. Survey-weighted Cox proportional hazards models were utilized. ResultsThe study involved 3,975 participants aged 20 years or older with a median follow-up of 89.00 months. A total of 1,675 individuals died during follow-up. Compared to individuals who did not consume eggs, the consumption of 0–50 g/day (hazard ratio [HR] = 1.033, 95% confidence interval [CI] =0.878–1.214) was not found to have a significant association with all-cause mortality. However, consuming 50–100 g/day (HR = 1.281, 95% CI = 1.004–1.635) and >100 g/day (HR = 1.312, 95% CI =1.036–1.661) exhibited a significant association with an increased risk of all-cause mortality. We identified a non-liner relationship between egg consumption and cardiovascular mortality, where the risk was found to be lowest at an intake of about 50 g/day. For individuals consuming more than 50 g/day, each additional 50 g increment in egg consumption was significantly linked to an elevated risk of cardiovascular mortality (HR = 1.276, 95% CI = 1.009–1.614). ConclusionIn U.S. adults with pre-existing cardiovascular disease, a significant positive association was found between consuming over 50 g of eggs per day and the risk of mortality, highlighting the importance of moderate intake.

Methylmalonic acid, vitamin B12, and mortality risk in patients with preexisting coronary heart disease: a prospective cohort study

BackgroundThe inconsistent relationship between Vitamin B12 (B12), methylmalonic acid (MMA, marker of B12 deficiency) and mortality was poorly understood, especially in patients with coronary heart disease (CHD). This study aims to investigate the association of serum MMA, and B12-related biomarkers (serum level, dietary intake, supplement use, and sensibility to B12) with all-cause and cardiovascular mortality in adults with CHD.MethodsThe data of this study were from a subcohort within the US National Health and Nutrition Examination Survey (NHANES). We included adults with preexisting CHD with serum MMA and B12, and dietary B12 intake measurements at recruitment. All participants were followed up until 31 December 2019. Weighted Cox proportional hazard regression was used to estimate hazard ratios (HR) and 95% CI of mortality risk.ResultsOverall, 1755 individuals (weighted mean [SE] age, 65.2 [0.5] years; 1047 men [weighted 58.5%]) with CHD were included, with geometric mean levels of serum MMA 182.4 nmol/L, serum B12 494.5 pg/ml, and dietary B12 intake 4.42 mg/day, and percentage of B12 supplements use 39.1%. During a median follow-up of 7.92 years, 980 patients died. Serum B12 concentration, dietary B12 intake and supplements use were not significantly associated with mortality risk (each p ≥ 0.388). In contrast, individuals in the top tertile of MMA had multivariable-adjusted HRs (95% CIs) of 1.70 (1.31–2.20) for all-cause mortality, and 2.00 (1.39–2.89) for cardiovascular mortality (both p trend < 0.001) compared to those in the bottom tertile of MMA. MMA-related mortality risk was particularly higher among participants with sufficient serum B12 (p < 0.001). CHD patients with increased levels of both MMA and B12 had a doubled mortality risk compared to those with lower MMA and B12 (p < 0.001).ConclusionMMA accumulation but not serum or dietary vitamin B12 was associated with increased cardiovascular mortality risk among patients with CHD. This paradox may be related to decreased response to vitamin B12.

Effects of the pre-existing coronary heart disease on the prognosis of COVID-19 patients: A systematic review and meta-analysis.

Although studies have shown severe Coronavirus disease 2019 (COVID-19) outcomes in patients with pre-existing coronary heart disease (CHD), the prognosis of COVID-19 patients with pre-existing CHD remains uncertain primarily due to the limited number of patients in existing studies. This study aimed to investigate the impacts of pre-existing CHD on the prognosis of COVID-19 patients. Five electronic databases were searched for eligible studies. This article focused on cohort and case-control studies involving the prognosis of COVID-19 patients with pre-existing CHD. The meta-analysis was performed using a random effects model. The odds ratios (ORs) and 95% confidence intervals (CIs) were used as valid indicators. The study was registered in PROSPERO with the identifier: CRD42022352853. A total of 81 studies, involving 157,439 COVID-19 patients, were included. The results showed that COVID-19 patients with pre-existing CHD exhibited an elevated risk of mortality (OR = 2.45; 95%CI: [2.04, 2.94], P < 0.001), severe/critical COVID-19 (OR = 2.57; 95%CI: [1.98, 3.33], P < 0.001), Intensive Care Unit or Coronary Care Unit (ICU/CCU) admission: (OR = 2.75, 95%CI: [1.61, 4.72], P = 0.002), and reduced odds of discharge/recovery (OR = 0.43, 95%CI: [0.28, 0.66], P < 0.001) compared to COVID-19 patients without pre-existing CHD. Subgroup analyses indicated that the prognosis of COVID-19 patients with pre-existing CHD was influenced by publication year, follow-up duration, gender, and hypertension. In conclusion, pre-existing CHD significantly increases the risk of poor prognosis in patients with COVID-19, particularly in those male or hypertensive patients.

Major Cardiovascular Events after Chemoradiotherapy with or without Durvalumab in Patients with Stage III Non-Small Cell Lung Cancer: Supplementary Analysis

RTOG 0617 showed that cardiac events are relatively common after high-dose thoracic radiotherapy. The aim of this study was to investigate the incidence and risk of major cardiovascular events (MACE) after concurrent chemoradiotherapy (CCRT) with or without durvalumab in patients with stage III non-small cell lung cancer (NSCLC) using the data from a multi-institutional study in Japan. Patients who received CCRT for stage III NSCLC between July 2018 and July 2019 were enrolled in a multi-institutional study in Japan. MACE was defined as follows: symptomatic pericardial effusion, acute coronary syndrome, pericarditis, significant arrhythmia, and heart failure. The cumulative incidence of MACE, accounting for death as a competing risk, was calculated. Pre-existing coronary heart disease (CHD) included coronary artery disease, congestive heart failure, peripheral vascular disease, stroke, and extensive coronary artery calcification. The association between patient/treatment-related factors and MACE was assessed by multivariate analysis. Among 178 patients with a median follow-up period of 42.5 months, 13 patients developed MACEs. The 3-year cumulative incidence of MACE was 6.9% (95% confidence interval [CI], 4.0-11.9%). Univariate analysis showed that female sex and mean heart dose (MHD) were marginally associated (3-year cumulative incidence, male 5.6% vs. female 12.1%; P = 0.12; MHD ≥ 6.3 Gy 4.8% vs. < 6.3 Gy 9.1%; P = 0.13), and pre-existing CHD was significantly associated with an increased risk of MACE (no CHD 4.3% vs. CHD 16.8%; P = 0.026). Consolidation durvalumab was not associated with an increased risk of MACE (no durvalumab 5.2% vs. durvalumab 7.4%; P = 0.89). Multivariate analysis showed that pre-existing CHD was significantly associated with MACE (hazard ratio, 4.22; 95% CI, 1.30-13.7; P = 0.016). The incidence of MACE based on the real-world data in Japan was lower than previously reported. Pre-existing CHD was associated with an increased risk of MACE after CCRT in patients with stage III NSCLC, whereas the administration of consolidation durvalumab was not associated with an increased risk of MACE.

Characteristics of Wellens' Syndrome in the Current PCI Era: A Single-Center Retrospective Study.

The goal of this retrospective study was to reveal the prevalence, angiographic characteristics, clinical presentation, and long-term outcomes of non-ST-segment elevation myocardial infarction (NSTEMI) patients with Wellens' syndrome. Procedural results for percutaneous coronary intervention (PCI) in acute coronary syndrome (ACS) have improved in recent years. However, there is still a paucity of available clinical trial data for Wellens' syndrome even though it is a well-known high-risk ACS. Among a total of 3528 patients with ACS who underwent angioplasty from 2017 to 2019 at the Cardiovascular Center of Beijing Friendship Hospital, 476 NSTEMI patients with culprit left anterior descending (LAD) vessels were enrolled in this study. According to electrocardiographic criteria of Wellens' syndrome, the patients were divided into a Wellens group (n = 138) and a non-Wellens group (n = 338). The primary endpoint was cardiac death; the secondary endpoints were main adverse cardiovascular and cerebrovascular events (MACCEs), a composite of all-cause death, cardiac death, heart failure, target lesion revascularization, recurrent myocardial infarction, and stroke. All of the medical and follow-up data were obtained from our institutional database. The incidence of Wellens' syndrome in all ACS patients was 5.7% (200 of 3528). Among the 200 patients with Wellens' syndrome, 138 had NSTEMI, for a proportion of 69%. There was a significant decrease in the percentage of preexisting coronary heart disease (CHD), prior myocardial infarction, and previous PCI (P < 0.05) in the Wellens group compared with the non-Wellens group. On coronary angiography, single-vessel lesions were more common in the Wellens group (11.6% vs. 5.3%, P=0.016), and almost all (97.1%) of these patients received drug-eluting stents. Notably, the Wellens group had a higher proportion of early PCI than the non-Wellens group (71% vs. 61.2%, P=0.044). At 24 months, there was no statistically significant difference in cardiac death (P=0.111) between the two groups, but the MACCEs were comparable (Wellens: 5.1% vs. non-Wellens: 13.3%, P=0.009). Age ≥65 years was the largest independent risk factor for adverse prognosis. With early recognition and aggressive intervention, Wellens' syndrome is no longer a risk factor for adverse prognosis in patients with NSTEMI in the current PCI era.

Pre-transplant serum Beta Trace Protein indicates risk for post-transplant major cardiac adverse events.

Beta Trace Protein (BTP) is a biomarker for residual kidney function which has been linked to cardiovascular and all-cause mortality in haemodialysis patients. Following renal transplantation, recipients remain at increased risk for cardiovascular events compared with the general population. We aimed to determine the relationship of pre-transplant BTP to major adverse cardiac events (MACE) in patients following kidney transplantation. We included 384 patients with end-stage renal disease who received a kidney transplant. MACE was defined as myocardial infarction (ST-segment elevation or non-ST-segment elevation, stroke or transient ischemic attack), coronary artery disease requiring intervention or bypass or death for cardiovascular reason. The association between pre-transplant serum BTP concentration and post-transplant MACE was evaluated by Kaplan-Meier and Cox regression analyses. Post-transplant MACE occurred in 70/384 patients. Pre-transplant BTP was significantly higher in patients with post-transplant MACE (14.36 ± 5.73 mg/l vs. 11.26 ± 5.11 mg/l; p < .01). Next to smoking (HR 1.81), age > 56.38 years (HR 1.97) and pre-existing coronary heart disease (HR 8.23), BTP above the cut off value of 12.7 mg/l was confirmed as independent risk factor for MACE (HR 2.02, all p < .05). MACE-free survival inversely correlated with pre-transplant BTP levels. Pre-transplant serum BTP concentration may identify renal transplant recipients with higher risk of post-transplant MACE.

Correlation of Left Anterior Descending Coronary Artery Radiation Dose with Major Adverse Cardiac Events and Feasibility of Coronary Artery Sparing Treatment Planning in Lung Cancer

<h3>Purpose/Objective(s)</h3> Radiation dose to the left anterior descending (LAD) coronary artery is associated with major adverse cardiac events (MACE) in patients with locally advanced non-small cell lung cancer (LA-NSCLC). However, the newly identified LAD metric (percent volume receiving 15 Gy [LAD V15Gy]) has not been independently validated and the extent to which modern radiotherapy (RT) planning techniques can reduce LAD V15Gy without exceeding dose tolerances to other critical organs at risk (OAR) remains uncertain. <h3>Materials/Methods</h3> This is a single institution retrospective study of 98 patients with LA-NSCLC treated with RT between 2005-2020. The LAD was manually delineated for each patient. MACE (unstable angina, myocardial infarction, heart failure, coronary revascularization, and cardiac death) cumulative incidence was estimated and Fine and Gray regressions were performed, adjusting for non-cardiac death as a competing risk. Patients who received LAD V15Gy ≥10% and experienced MACE were re-planned with volumetric-modulated arc therapy (VMAT) to optimize reduction of LAD V15Gy while maintaining target coverage and meeting standard OAR constraints. <h3>Results</h3> The median follow up was 23.2 months. The median age was 69 years, 30.6% of patients had pre-existing coronary heart disease (CHD) or a CHD risk-equivalent. The mean LAD V15Gy was 32% (standard deviation [SD] 27.8%). Ten patients developed at least one MACE, with a 2-year cumulative incidence of 10.2% (95% CI: 3.1-17.0%). Adjusting for pre-existing CHD there was an increased risk of MACE with LAD V15Gy (subdistribution hazard ratio 1.03; 95% CI 1.00-1.06; p=.034), with a significant interaction between LAD V15Gy and CHD (p=.005). Among the 10 patients who developed a MACE, 6 (60%) had an LAD V15Gy ≥ 10% (mean 52%, range 10-100%). The original planning techniques included: 3-dimensional conformal RT (3D-CRT; n=2), static intensity-modulated RT (IMRT; n=2), and VMAT (n=2). In 4 of these plans (n=2 IMRT, n=1 3D-CRT, n=1 VMAT), the re-planned LAD V15Gy was reduced to <10%, however all 6/6 plans achieved some degree of LAD V15Gy reduction (range, 9-100%). Specifically, optimization with LAD-sparing VMAT achieved a mean absolute decrease of 35.1% for LAD V15Gy (SD 32.4%) and 6.2 Gy mean heart dose (SD 10.9 Gy), with a concomitant mean increase of 0.8 Gy mean lung dose (SD 1.8 Gy), and mean lung V20Gy of 0.2% (SD 4.1%). All re-plans achieved similar target coverage and remained within national guideline OAR constraints. <h3>Conclusion</h3> LAD V15Gy is associated with an increased risk of MACE in this independent retrospective cohort. VMAT-based LAD-sparing RT plan optimization is feasible and can achieve meaningful reductions in LAD V15Gy with potentially clinically acceptable tradeoffs in lung dose. Together, these findings underscore the need for more aggressive LAD-sparing RT planning approaches.

Deep Learning-Based Automated Cardiac Sub-Structure Contouring with Dosimetric and Clinical Outcomes Validation

<h3>Purpose/Objective(s)</h3> Coronary artery (CA) radiation dose is an independent predictor of major adverse cardiac events (MACE) and all-cause mortality (ACM) following thoracic radiotherapy (RT) for locally-advanced non-small cell lung cancer (LA-NSCLC). However, cardiac sub-structure segmentation is not routinely performed, in part due to technical complexity. Here, we developed a deep learning-based automated cardiac sub-structure contouring tool and compared the overlap with manual contours as well as associations with dosimetric, cardiac, and survival outcomes. <h3>Materials/Methods</h3> A U-Net with ResNet encoders and cross connections was trained to localize the heart and segment its substructures, which included the four chambers and CA (left main, left anterior descending [LAD], left circumflex, right and posterior descending). Our cohort of 700 LA-NCSLC patients treated with RT with non-gated planning CT scans (with and without contrast) and manually segmented cardiac sub-structures was split into training (n=560), validation (n=70), and test (n=70) groups. Validation was performed by comparing the prediction against the manual contours. Geometric analysis evaluated Dice coefficient, overlap measures, and average symmetrical surface distance (ASSD). Dosimetric validation evaluated mean, maximum, and volume (V) receiving 15 Gy (V15Gy). The discrete Fréchet distance evaluated similarity of dose-volume histograms. Cox and Fine and Gray regressions (non-cardiac death as a competing risk) were used for clinical validation. <h3>Results</h3> The average processing and segmentation time was 51.5±9.6 seconds and 2.96±1.51 seconds, respectively. The median dice for the heart was 0.94 [IQR=0.02] and 0.84 [IQR=0.06] for the chambers. The median overlap for the CA was 0.87 [IQR=0.27] with an ASSD of (2.03±1.31) mm. The mean difference between the prediction and ground truth for the mean dose was (0.09±0.64 Gy for the heart, (-0.44±2.16 Gy for the chambers, and -0.35±3.20) Gy for the CA. The maximum dose differed by (-0.9±7.3 Gy. The difference of the V15Gy for the LAD was 0.17+7.34 %. The correlation between manual and prediction based on a linear regression was R²=0.88. The median similarity between DVHs for chambers and CA was 0.99 [IQR=0.31] and 0.80 [IQR=0.46]. In the test group, adjusting for pre-existing coronary heart disease, predicted LAD V15Gy was associated with an increased risk of MACE (HR 1.02 per %, 95% CI 1.00-1.04; p=0.012) and ACM (HR 1.02 per %, 95% CI 1.00-1.03; p=.046). <h3>Conclusion</h3> We developed deep learning automated cardiac sub-structure segmentation algorithms from a large real-world planning CT dataset. The algorithms produced high quality contours with high geometric overlap with manual contours, and were associated with dosimetric, cardiac, and survival outcomes. High segmentation quality and fast processing time will enable clinical translation to improve cardiac toxicity risk prediction.

Cancer history as a predictor in cardiovascular risk scores: a primary care cohort study.

Cardiovascular risks are raised in cancer survivors but cancer history is not included in cardiovascular risk scores that inform preventive decisions. To assess whether cancer diagnosis should be included in cardiovascular risk scores. Cohort study using data from English general practices linked to hospital, cancer registration, and death registration data from 1990 to 2015. Adults alive 1 year after a first cancer diagnosis and age, sex, general practice, and calendar- time matched cancer-free individuals were included. Individuals with <2 years of follow-up before index, recent statin prescriptions, or pre-existing coronary heart or cerebrovascular disease were excluded. Cox proportional hazard models used to develop QRISK3 scores were replicated with added cancer history variables. Whether independent hazard ratios for these variables met thresholds for inclusion in QRISK3 (>10% relative difference with P<0.01) was assessed. In total, 81 420 cancer survivors and 413 547 cancer-free individuals were followed for a median 5.2 years (interquartile range [IQR] 2.8- 9.1) and 6.3 years (IQR 3.5-10.2), respectively. Including a 1-year cancer survivorship variable in a QRISK3-based model met the threshold for inclusion for males (independent hazard ratio [iHR] 1.16, 95% confidence interval [CI] = 1.11 to 1.20, P<0.001) but not females (iHR 1.07, 95% CI = 1.01 to 1.14, P = 0.02). When including cancer type, the threshold was met for both sexes with history of haematological cancer (males: iHR 1.27, 95% CI = 1.16 to 1.40, P <0.001; females: iHR 1.59, 95% CI = 1.32 to 1.91, P<0.001) and for males but not females with history of solid cancers (males: iHR 1.13, 95% CI = 1.08 to 1.18, P <0.001; females: iHR 1.04, 95% CI = 0.98 to 1.10, P = 0.19). Developers should consider including cancer history variables in future cardiovascular risk models.

Triggering of myocardial infarction by heat exposure is modified by medication intake.

Acute myocardial infarction (MI) can be triggered by heat exposure, but it remains unknown whether patients taking certain cardiovascular medications have elevated vulnerability. Based on a validated and complete registration of all 2,494 MI cases in Augsburg, Germany, during warm seasons (May to September) from 2001 to 2014, here we show that heat-related non-fatal MI risk was elevated among users of anti-platelet medication and beta-receptor blockers, respectively, but not among non-users, with significant differences between users and non-users. We also found that these effect modifications were stronger among younger patients (25-59 years), who had a lower prevalence of pre-existing coronary heart disease (CHD, a potential confounder by indication), than among older patients (60-74 years), who had a higher prevalence of pre-existing CHD. Users of these medications may be more vulnerable than non-users to non-fatal MI risk due to heat exposure. Further research is needed to disentangle effect modification by medication use from effect modification by pre-existing CHD.

Cardiovascular Risk Factors and Clinical Outcomes among Patients Hospitalized with COVID-19: Findings from the World Heart Federation COVID-19 Study.

Background and aims:Limited data exist on the cardiovascular manifestations and risk factors in people hospitalized with COVID-19 from low- and middle-income countries. This study aims to describe cardiovascular risk factors, clinical manifestations, and outcomes among patients hospitalized with COVID-19 in low, lower-middle, upper-middle- and high-income countries (LIC, LMIC, UMIC, HIC).Methods:Through a prospective cohort study, data on demographics and pre-existing conditions at hospital admission, clinical outcomes at hospital discharge (death, major adverse cardiovascular events (MACE), renal failure, neurological events, and pulmonary outcomes), 30-day vital status, and re-hospitalization were collected. Descriptive analyses and multivariable log-binomial regression models, adjusted for age, sex, ethnicity/income groups, and clinical characteristics, were performed.Results:Forty hospitals from 23 countries recruited 5,313 patients with COVID-19 (LIC = 7.1%, LMIC = 47.5%, UMIC = 19.6%, HIC = 25.7%). Mean age was 57.0 (±16.1) years, male 59.4%, pre-existing conditions included: hypertension 47.3%, diabetes 32.0%, coronary heart disease 10.9%, and heart failure 5.5%. The most frequently reported cardiovascular discharge diagnoses were cardiac arrest (5.5%), acute heart failure (3.8%), and myocardial infarction (1.6%). The rate of in-hospital deaths was 12.9% (N = 683), and post-discharge 30 days deaths was 2.6% (N = 118) (overall death rate 15.1%). The most common causes of death were respiratory failure (39.3%) and sudden cardiac death (20.0%). The predictors of overall mortality included older age (≥60 years), male sex, pre-existing coronary heart disease, renal disease, diabetes, ICU admission, oxygen therapy, and higher respiratory rates (p < 0.001 for each). Compared to Caucasians, Asians, Blacks, and Hispanics had almost 2–4 times higher risk of death. Further, patients from LIC, LMIC, UMIC versus. HIC had 2–3 times increased risk of death.Conclusions:The LIC, LMIC, and UMIC’s have sparse data on COVID-19. We provide robust evidence on COVID-19 outcomes in these countries. This study can help guide future health care planning for the pandemic globally.

Long-term low-dose acetylsalicylic use shows protective potential for the development of both vascular dementia and Alzheimer’s disease in patients with coronary heart disease but not in other individuals from the general population: results from two large cohort studies

BackgroundNo population-based cohort study investigated a potential inverse association between long-term low-dose acetylsalicylic acid (ASA) use and all-cause dementia and its two most common sub-types Alzheimer’s disease (AD) and vascular dementia (VD) so far.MethodsCox regression models with inverse probability of treatment weighting to model the underlying cardiovascular risk were used to assess the associations of low-dose ASA use with all-cause dementia, AD, and VD incidence in community-dwelling older adults from the German ESTHER study (N = 5258) and the UK Biobank (N = 305,394). Inclusion criteria were age of 55 years or older and completed drug assessment. Meta-analyses of the individual participant data from the two prospective cohort studies were performed.ResultsFour hundred seventy-six cases of all-cause dementia, 157 cases of AD, and 183 cases of VD were diagnosed over a median of 14.3 years of follow-up in ESTHER. In the UK Biobank, 5584 participants were diagnosed with all-cause dementia, 2029 with AD, and 1437 with VD over a median of 11.6 years. The meta-analysis of both cohorts revealed a weak reduction in hazards for all-cause dementia (hazard ratio (HR) [95% confidence interval (CI)]: 0.96 [0.93 to 0.99]). The strongest protective effect of low-dose ASA was observed in participants with coronary heart disease (CHD) in both cohorts, and a significant interaction was detected. In particular, in meta-analysis, a 31% reduction in hazard for AD, 69% for VD and 34% for all-cause dementia were observed (HR [95% CI]: 0.69 [0.59 to 0.80], 0.31 [0.27 to 0.35], 0.46 [0.42 to 0.50], respectively). Furthermore, compared to non-users, users of low-dose ASA for 10 years or longer (who likely use it because they have CHD or a related diagnosis putting them at an increased risk for cardiovascular events) demonstrated a strong protective effect on all dementia outcomes, especially for VD (HR [95% CI]: 0.48 [0.42 to 0.56]) whereas no protective associations were observed with shorter low-dose ASA use.ConclusionsThe protective potential of low-dose ASA for all-cause dementia, AD, and VD seems to strongly depend on pre-existing CHD and the willingness of patients to take it for a minimum of ten years.

The Relationship Between Pre-existing Coronary Heart Disease and Cognitive Impairment Is Partly Explained by Reduced Left Ventricular Ejection Fraction in the Subjects Without Clinical Heart Failure: A Cross-Sectional Study.

BackgroundCoronary heart disease (CHD) is closely associated with cognitive impairment, especially in severe cases of heart failure. However, it is unclear whether cardiac systolic function plays a role in the relationship between pre-existing CHD and cognitive impairment in subjects without clinical heart failure.MethodsIn total, 208 subjects from the First Affiliated Hospital of Xi’an Jiaotong University were recruited from June 2014 to January 2015, and were divided into CHD (n = 118) and non-CHD (n = 90) groups according to the inclusion and exclusion criteria. The global cognitive function of all subjects was assessed by the Mini-Mental State Examination (MMSE) and cognitive impairment was defined as the score lower than the cutoff value. Left ventricular ejection fraction (LVEF) was measured using transthoracic echocardiograms. The relationship among pre-existing CHD, LVEF, and cognitive impairment was analyzed by multivariate logistic regression.ResultsIn total, 34 subjects met the criteria of cognitive impairment. Univariate analysis showed that the cognitive impairment prevalence in the CHD group was significantly higher than that in the non-CHD group (22.0 vs. 8.9%, p = 0.011). Multivariate logistic analysis revealed that CHD was significantly associated with a higher risk of cognitive impairment (odds ratio [OR] = 3.284 [95% CI, 1.032–10.450], p = 0.044) after adjusting for confounds except for LVEF. However, the OR of CHD decreased (OR = 2.127 [95% CI, 0.624–7.254], p = 0.228) when LVEF was further corrected as a continuous variable, and LVEF was negatively associated with the risk of cognitive impairment (OR = 0.928 [95% CI, 0.882–0.976], p = 0.004).ConclusionPre-existing CHD is associated with a higher risk of cognitive impairment, and such an association can be considerably explained by reduced LVEF. An impaired cardiac systolic function may play a key role in the relationship between CHD and cognitive impairment among patients with pre-heart failure conditions.

Wellens\u2019 syndrome: incidence, characteristics, and long-term clinical outcomes

BackgroundFew studies with large sample sizes are available regarding patients with Wellens’ syndrome. Therefore, we sought to assess the current incidence, risk factors, clinical presentation and long-term outcomes of this population.MethodsAmong a total of 3528 patients with ACS who underwent angioplasty from 2017 to 2019 in our centre, 2127 NSTE-ACS patients with culprit LAD vessels were enrolled in this study. According to electrocardiographic criteria, the patients were divided into a Wellens’ group (n = 200) and non-Wellens’ group (n = 1927). The primary endpoint was cardiac death; the secondary endpoint was MACCE, a composite of all-cause death, cardiac death, recurrent myocardial infarction, target lesion revascularization, heart failure and stroke.ResultsThe incidence of Wellens’ syndrome was 5.7% (200 of 3528) of all ACS patients. Wellens’ syndrome more often manifested as NSTEMI (69% vs. 17.5%, P < 0.001). The percentages of preexisting coronary heart disease (39.6% vs. 23%) and previous PCI (19.5% vs. 9%) were significantly higher in the non-Wellens’ group than in the Wellens’ group (all P < 0.001). More importantly, the proportion of early PCI was higher in the Wellens’ group (68% vs. 59.3%, P = 0.017). At a median follow-up of 24 months, Wellens’ syndrome was not associated with an increased risk of MACCE (P = 0.05) or cardiac death (P = 0.188).ConclusionsThe presence of Wellens’ syndrome is not definitively associated with adverse prognosis in patients with NSTE-ACS. Age ≥ 65 years, diabetes, NSTEMI, eGFR < 60 ml/min and left main disease are associated with the incidence of cardiac death. Early recognition and aggressive intervention are critical, as they may help to attenuate adverse outcomes.

Associations of pre-existing cardiovascular morbidity with severity and the fatality rate in COVID-19 patients: a systematic review and meta-analysis.

ObjectivesThe aim of this study was to evaluate the association of pre-existing cardiovascular comorbidities, including hypertension and coronary heart disease, with coronavirus disease 2019 (COVID-19) severity and mortality.MethodsPubMed, ScienceDirect, and Scopus were searched between January 1, 2020, and July 18, 2020, to identify eligible studies. Random-effect models were used to estimate the pooled event rates of pre-existing cardiovascular disease comorbidities and odds ratio (OR) with 95% confidence intervals (95% CIs) of disease severity and mortality associated with the exposures of interest.ResultsA total of 34 studies involving 19,156 patients with COVID-19 infection met the inclusion criteria. The prevalence of pre-existing cardiovascular disease in the included studies was 14.0%. Pre-existing cardiovascular disease in COVID-19 patients was associated with severe outcomes (OR, 4.1; 95% CI, 2.9 to 5.7) and mortality (OR, 6.1; 95% CI, 2.9 to 12.7). Hypertension and coronary heart disease increased the risk of severe outcomes by 3 times (OR, 3.2; 95% CI, 2.0 to 3.6) and 2.5 times (OR, 2.5; 95% CI, 1.7 to 3.8), respectively. No significant publication bias was indicated.ConclusionCOVID-19 patients with pre-existing cardiovascular comorbidities have a higher risk of severe outcomes and mortality. Awareness of pre-existing cardiovascular comorbidity is important for the early management of COVID-19.

Using a Systems Approach to Explore the Mechanisms of Interaction Between Severe Covid-19 and Its Coronary Heart Disease Complications.

Frontiers requested research on how a systems approach can explore the mechanisms of cardiovascular complications in Covid-19. The focus of this paper will thus be on these detailed mechanisms. It will elucidate the integrated pathogenic pathways based on an extensive review of literature. Many severe Covid-19 cases and deaths occur in patients with chronic cardiovascular comorbidities. To help understand all the mechanisms of this interaction, Covid-19 complications were integrated into a pre-existing systems-based coronary heart disease (CHD) model. Such a complete model could not be found in literature. A fully integrative view could be valuable in identifying new pharmaceutical interventions, help understand how health factors influence Covid-19 severity and give a fully integrated explanation for the Covid-19 death spiral phenomenon seen in some patients. Covid-19 data showed that CHD hallmarks namely, Hypercoagulability, Hypercholesterolemia, Hyperglycemia/Hyperinsulinemia, Inflammation and Hypertension have an important effect on disease severity. The pathogenic pathways that Covid-19 activate in CHD were integrated into the CHD model. This fully integrated model presents a visual explanation of the mechanism of interaction between CHD and Covid-19 complications. This includes a detailed integrated explanation of the death spiral as a result of interactions between Inflammation, endothelial cell injury, Hypercoagulability and hypoxia. Additionally, the model presents the aggravation of this death spiral through the other CHD hallmarks namely, Hyperglycemia/Hyperinsulinemia, Hypercholesterolemia, and/or Hypertension. The resulting model further suggests systematically how the pathogenesis of nine health factors (stress, exercise, smoking, etc.) and seven pharmaceutical interventions (statins, salicylates, thrombin inhibitors, etc.) may either aggravate or suppress Covid-19 severity. A strong association between CHD and Covid-19 for all the investigated health factors and pharmaceutical interventions, except for β-blockers, was found. It is further discussed how the proposed model can be extended in future to do computational analysis to help assess the risk of Covid-19 in cardiovascular disease. With insight gained from this study, recommendations are made for future research in potential new pharmacotherapeutics. These recommendations could also be beneficial for cardiovascular disease, which killed five times more people in the past year than Covid-19.

Optimal Management of Glucose in Patients with Diabetes and Heart Failure

Type 2 diabetes confers a two-fold excess risk of heart failure. Established risk factors for developing heart failure in people with type 2 diabetes include old age, obesity, poor glycemic control, impaired kidney function and pre-existing coronary heart disease. Prognosis of people with comorbid type 2 diabetes and heart failure is poor with up to one quarter of them dying at 1 year and half not surviving at 5 years. Glucose-lowering drugs have divergent effects on the progression of heart failure. Thiazolidinediones and dipeptidyl-peptidase 4 inhibitors may induce or worsen symptoms of heart failure, although these risks do not appear to extend to other incretin-based therapy, namely glucagon-like peptide-1 receptor agonists, whereas metformin has been shown to improve prognosis in people with comorbid type 2 diabetes and heart failure in observational studies. Recent cardiovascular outcome trials provided robust evidence for sodium-glucose co-transporter-2 (SGLT-2) inhibitors in preventing death and/or hospitalization for heart failure. Current guideline recommends initiation of SGLT-2 inhibitors in people with type 2 diabetes and heart failure, independent of the need of additional glucose lowering. However, consideration must be given to risks of hypoglycemia, dehydration and euglycemic ketoacidosis upon initiation of SGLT-2 inhibitors, as the majority of people in the treatment group are old, have kidney dysfunction, on diuretics, or have long diabetes duration with high likelihood of insulin deficiency. Type 2 diabetes confers a two-fold excess risk of heart failure. Established risk factors for developing heart failure in people with type 2 diabetes include old age, obesity, poor glycemic control, impaired kidney function and pre-existing coronary heart disease. Prognosis of people with comorbid type 2 diabetes and heart failure is poor with up to one quarter of them dying at 1 year and half not surviving at 5 years. Glucose-lowering drugs have divergent effects on the progression of heart failure. Thiazolidinediones and dipeptidyl-peptidase 4 inhibitors may induce or worsen symptoms of heart failure, although these risks do not appear to extend to other incretin-based therapy, namely glucagon-like peptide-1 receptor agonists, whereas metformin has been shown to improve prognosis in people with comorbid type 2 diabetes and heart failure in observational studies. Recent cardiovascular outcome trials provided robust evidence for sodium-glucose co-transporter-2 (SGLT-2) inhibitors in preventing death and/or hospitalization for heart failure. Current guideline recommends initiation of SGLT-2 inhibitors in people with type 2 diabetes and heart failure, independent of the need of additional glucose lowering. However, consideration must be given to risks of hypoglycemia, dehydration and euglycemic ketoacidosis upon initiation of SGLT-2 inhibitors, as the majority of people in the treatment group are old, have kidney dysfunction, on diuretics, or have long diabetes duration with high likelihood of insulin deficiency.

Cardiac Radiation Dose and Patient Risk Factors for Predicting Major Adverse Cardiac Events in Lung Cancer Patients

<h3>Purpose/Objective(s)</h3> Thoracic radiotherapy (TRT) is a mainstay treatment for locally advanced non-small cell lung cancer (LA-NSCLC). Mean heart dose (MHD) and left anterior descending (LAD) receiving ≥15 Gy (LADV15) was shown to predict major adverse cardiac events (MACE) in LA-NSCLC patients receiving TRT. We aim to develop a clinically applicable MACE risk prediction score model, including both cardiac dosimetric and baseline risk factors. <h3>Materials/Methods</h3> Retrospective data from 748 consecutive patients with LA-NSCLC treated with curative intent between November 1998 to December 2013 were included. The data was split based on diagnosis dates to allow external validation. Model development was performed on 500 consecutive patients diagnosed before December 2010 using multivariable Cox-proportional hazard model; backward elimination scheme (α = 0.05) was used to select the predictors for the final model. Potential predictors were selected <b>a priori</b> based on prior literature: age, pre-existing coronary heart disease (CHD), Framingham Risk, hypertension (HTN), MHD, LADV15, intensity modulated RT (IMRT) use, and interaction between CHD and LADV15 (CHD:LADV15). Model performance was assessed by the Harrell's c-index and internally validated using leave-one out cross validation (LOOCV). The model was applied to the remaining 248 consecutive patients from the initial cohort as the external validation "test" dataset. <h3>Results</h3> The development and test cohorts had median age 64 vs 66 years (<i>P</i> = 0.02), 51.0 vs. 50.4% females (<i>P</i> = 0.88), and 89.4 vs 89.1% stage III cancer (<i>P</i> = 0.91). The final model incorporated CHD, HTN, LADV15, and CHD:LADV15 (β coefficients: 2.703, 1.129, 0.043, -0.047; all <i>P</i> < 0.001; c-index 0.773). LOOCV Pseudo R² = 0.0195. The c-index on the external test dataset was 0.727. Actuarial 3-year MACE rates were 10.7% for development cohort and 15.4% for test cohort. Stratifying development cohort patients into terciles based on MACE risk prediction scores yielded 3-year MACE rates of 0%, 5.7%, and 25.6% for lowest to highest risk-terciles, respectively; among test cohort, the 3-year MACE rates were 4.9%, 10.5%, and 31.9%. Respectively, the 3-year overall survival rates for lowest to highest MACE risk-terciles were 47.3%, 35.2%, and 32.8% among development cohort, and 52.3%, 43.9% and 30.6% within test cohort (both Log-rank <i>P</i> < 0.05). <h3>Conclusion</h3> The 3-year MACE rates spans 5% to 32% from lowest to highest risk groups. Both LADV15 and pre-existing cardiac risk factors are important in predicting MACE risk post-TRT. MACE risk score was associated with survival. This tool has the potential to estimate personalized LADV15 constraints based on patient risk factors and acceptable MACE risk thresholds (e.g., 5-10%), thus may help identify patients who may benefit most from the application of advanced RT techniques to further reduce LAD dose as a modifiable risk factor during RT planning.

Critical Volumetric Threshold of 15 Gy Exposure to Left Coronary Arteries Predicts Major Adverse Cardiac Events and Mortality in Lung Cancer Radiotherapy

<h3>Purpose/Objective(s)</h3> Left anterior descending (LAD) coronary artery volume receiving 15 Gy (V15 Gy) ≥10% and left circumflex (LCX) V15 Gy ≥14% are associated with an increased risk of major adverse cardiac events (MACE), while LAD V15 Gy ≥10% can significantly increase the risk of mortality in patients with non-small cell lung cancer (NSCLC). Given that reduction of coronary dose is a modifiable risk factor during RT planning, we identified absolute critical volume (vol) thresholds of left coronary artery (LCA) exposure to 15 Gy that predict for MACE and all-cause mortality (ACM). <h3>Materials/Methods</h3> Retrospective analysis of 701 patients with locally advanced NSCLC treated with RT between 2003 and 2014. Coronary arteries were manually segmented with an 8-mm brush size. The absolute vol (cc) of LAD, LCX, or LCA (combined LAD+LCX) structures receiving ≥15 Gy were calculated. Area under the receiver operating curve (AUC) and cut-point analyses estimating MACE (unstable angina, heart failure, myocardial infarction, coronary revascularization, and cardiac death) were performed. Fine and Gray and Cox regressions were performed, adjusting for pre-existing coronary heart disease (CHD) and other cardiovascular and cancer prognostics factors. <h3>Results</h3> The median age was 65 years (interquartile range, 57-73 years) and 50.8% (n = 356) were men. The optimal cut-point (C-index) for the absolute vol. receiving ≥15 Gy for the LAD, LCX, and LCA was ≥1.1 cc (0.63), ≥1.3 cc (0.65), and ≥2.6 cc (0.64), respectively. Adjusting for baseline CHD and other factors, there was an increased risk of MACE with an LAD V15 Gy vol. ≥1.1 cc (adjusted hazard ratio [AHR], 7.59; 95% confidence interval [CI], 2.24-25.69; P = 0.001), an LCX V15 Gy vol. ≥1.3 cc (AHR, 8.24; 95% CI, 2.84-23.90; P < 0.001), and an LCA V15 Gy vol. ≥2.6 cc (AHR, 9.01; 95% CI, 2.66-30.56; P < 0.001), while only LAD-containing variables (not LCX alone) were associated with an increased risk of ACM as follows; LAD V15 Gy vol. ≥1.1 cc (AHR, 1.44; 95% CI, 1.14-1.81; P = 0.002) and LCA V15 Gy vol. ≥2.6 cc (AHR, 1.31; 95% CI, 1.04-1.64; P = 0.023). There was a significantly increased risk of all-cause mortality in CHD-negative patients with an LAD V15 Gy vol. ≥1.1 (HR, 1.39; 95% CI, 1.10-1.74; P = 0.005) and LCA V15 Gy vol. ≥2.6 (HR, 1.32; 95% CI, 1.05-1.65; P = 0.019); but not among CHD-positive patients, (P > 0.05). Specifically, the 2-year ACM estimates in CHD-negative patients for LAD V15 Gy vol. (≥1.1 vs. < 1.1 cc) was 50.9% vs. 42.3%, and for LCA V15 Gy vol. (≥2.6 vs. < 2.6 cc) was 51.1% vs. 43.0%, respectively (P for interaction ≤.01). <h3>Conclusion</h3> Critical volume thresholds of 15 Gy for the LAD and LCA were independent predictors of MACE and ACM, particularly in patients without CHD. These constraints may help inform RT planning by guiding LCA dose reduction and identify patients who may benefit most from advanced RT techniques to mitigate excess cardiac risk.