Relationship Between Preexisting Cardiovascular Disease and Death and Cardiovascular Outcomes in Critically Ill Patients With COVID-19

BACKGROUND: Preexisting cardiovascular disease (CVD) is perceived as a risk factor for poor outcomes in patients with COVID-19. We sought to determine whether CVD is associated with in-hospital death and cardiovascular events in critically ill patients with COVID-19. METHODS: This study used data from a multicenter cohort of adults with laboratory-confirmed COVID-19 admitted to intensive care units at 68 centers across the United States from March 1 to July 1, 2020. The primary exposure was CVD, defined as preexisting coronary artery disease, congestive heart failure, or atrial fibrillation/flutter. Myocardial injury on intensive care unit admission defined as a troponin I or T level above the 99th percentile upper reference limit of normal was a secondary exposure. The primary outcome was 28-day in-hospital mortality. Secondary outcomes included cardiovascular events (cardiac arrest, new-onset arrhythmias, new-onset heart failure, myocarditis, pericarditis, or stroke) within 14 days. RESULTS: Among 5133 patients (3231 male [62.9%]; mean age 61 years [SD, 15]), 1174 (22.9%) had preexisting CVD. A total of 1178 (34.6%) died, and 920 (17.9%) had a cardiovascular event. After adjusting for age, sex, race, body mass index, history of smoking, and comorbidities, preexisting CVD was associated with a 1.15 (95% CI, 0.98-1.34) higher odds of death. No independent association was observed between preexisting CVD and cardiovascular events. Myocardial injury on intensive care unit admission was associated with higher odds of death (adjusted odds ratio, 1.93 [95% CI, 1.61-2.31]) and cardiovascular events (adjusted odds ratio, 1.82 [95% CI, 1.47-2.24]), regardless of the presence of CVD. CONCLUSIONS: CVD risk factors, rather than CVD itself, were the major contributors to outcomes in critically ill patients with COVID-19. The occurrence of myocardial injury, regardless of CVD, and its association with outcomes suggests it is likely due to multiorgan injury related to acute inflammation rather than exacerbation of preexisting CVD. REGISTRATION: NCT04343898; https://clinicaltrials.gov/ct2/show/NCT04343898

A review of research on the intersection between breast cancer and cardiovascular research in the Women’s Health Initiative (WHI)

Both obesity and metabolic syndrome are linked to increased incidence of type 2 diabetes, cardiovascular disease (CVD), and cancers of the breast (post-menopausal), and other obesity-related cancers. Over the past 50 years, the worldwide prevalence of obesity and metabolic syndrome has increased, with a concomitant higher incidence of associated co-morbidities and mortality. The precise mechanism linking metabolic syndrome to increased cancer incidence is incompletely understood, however, individual components of metabolic syndrome have been linked to increased breast cancer incidence and worse survival. There is a bidirectional relationship between the risk of CVD and cancer due to a high burden of shared risk factors and higher rates of CVD among cancer survivors, which may be impacted by the pro-inflammatory microenvironment associated with metabolic syndrome and cancer-directed therapies. The Women’s Health Initiative (WHI) is an excellent resource to study a dual relationship between cancer and CVD (cardio-oncology) with extensive information on risk factors and long-term outcomes. The purpose of this review is to provide an overview of research on cardio-oncology conducted utilizing WHI data with focus on studies evaluating both breast cancer and CVD including shared risk factors and outcomes after cancer. The review also includes results on other obesity related cancers which were included in the analyses of breast cancer, articles looking at cancer after heart disease (reverse cardio-oncology) and the role of Clonal Hematopoiesis of Indeterminate Potential (CHIP) as a shared risk factor between CVD and cancer. A summary of pertinent WHI literature helps to delineate the direction of future research evaluating the relationship between CVD and other cancer sites, and provides information on the opportunity for other novel analyses within the WHI

Radiation-Induced Cardiovascular Disease and Fatigue in Breast Cancer Survivors: Understanding Biological Mechanisms and Risk Factors

Thesis (Ph.D.)--University of Washington, 2021Although survival rates have improved, many breast cancer survivors experience adverse effects related to the physiologic consequences of cancer treatment including an increased risk cardiovascular disease (CVD) and symptoms, such as fatigue. Currently, it is not known how to best identify breast cancer survivors at risk for CVD and fatigue. Cancer treatments are known to be associated with both CVD and fatigue independently. At the same time, cardiotoxicity and fatigue may share common physiologic mechanisms such as chronic inflammation and oxidative stress, which directly target cardiac tissue to produce CVD and produce circulating inflammatory markers that may lead to fatigue. It is hypothesized that cancer treatments, through the complex relationship with oxidative stress and inflammation, create a pro-fibrotic environment, which contributes to heart disease and heart failure. While cancer treatments can independently cause fatigue, fatigue is also a commonly reported symptom in patients with heart failure, coronary artery disease, pericardial disease, and valvular disease, which are all potential cardiovascular outcomes associated with radiation treatment. Therefore, it is not only important to examine the association between inflammatory and oxidative stress biomarkers and fatigue but also look at cardiac damage and fibrosis markers in persons who have received radiation treatment. Additionally, there is evidence in non-cancer populations that fatigue itself, and other symptoms associated with cancer treatments, are associated with the risk of CVD. Therefore, the overall purpose of this dissertation is to better understand risk factors for CVD and symptoms after cancer treatment in breast cancer survivors and to better understand how these factors relate to one another. Specifically, this dissertation has the following aims: 1) to assess the association of post-cancer biomarkers and CVD events in breast cancer survivors treated with radiation; 2) to examine the associations of post-cancer biomarkers and post-cancer fatigue in breast cancer survivors treated with radiation; and 3) examine whether physical and mental health-related quality of life (which incorporates a measure of fatigue) or sleep disturbances scores are associated with CVD risk in breast cancer survivors

Angiotensin-Converting Enzyme Inhibitors, Angiotensin II Receptor Blockers, and Outcomes in Patients Hospitalized for COVID-19

BACKGROUND: Use of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers (ACEi/ARB) is thought to affect COVID-19 through modulating levels of angiotensin-converting enzyme 2, the cell entry receptor for SARS-CoV2. We sought to assess the association between ACEi/ARB, biomarkers of inflammation, and outcomes in patients hospitalized for COVID-19. METHODS AND RESULTS: We leveraged the ISIC (International Study of Inflammation in COVID-19), identified patients admitted for symptomatic COVID-19 between February 1, 2020 and June 1, 2021 for COVID-19, and examined the association between in-hospital ACEi/ARB use and all-cause death, need for ventilation, and need for dialysis. We estimated the causal effect of ACEi/ARB on the composite outcomes using marginal structural models accounting for serial blood pressure and serum creatinine measures. Of 2044 patients in ISIC, 1686 patients met inclusion criteria, of whom 398 (23.6%) patients who were previously on ACEi/ARB received at least 1 dose during their hospitalization for COVID-19. There were 215 deaths, 407 patients requiring mechanical ventilation, and 124 patients who required dialysis during their hospitalization. Prior ACEi/ARB use was associated with lower levels of soluble urokinase plasminogen activator receptor and C-reactive protein. In multivariable analysis, in-hospital ACEi/ARB use was associated with a lower risk of the composite outcome of in-hospital death, mechanical ventilation, or dialysis (adjusted hazard ratio 0.49, 95% CI [0.36- -0.65]). CONCLUSIONS: In patients hospitalized for COVID-19, ACEi/ARB use was associated with lower levels of inflammation and lower risk of in-hospital outcomes. Clinical trials will define the role of ACEi/ARB in the treatment of COVID-19

Lack of Association Between Neurohormonal Blockade and Survival in Transthyretin Cardiac Amyloidosis

Background Despite the belief that heart failure therapies are not effective in transthyretin cardiac amyloidosis, data are limited. We tested the association of neurohormonal blockade use with survival. Methods and Results A total of 309 consecutive patients with transthyretin cardiac amyloidosis were identified. Medication inventory was obtained at baseline and subsequent visits. Exposure included a neurohormonal blockade class (β‐blocker [βB], angiotensin‐converting enzyme inhibitor/angiotensin receptor blocker, and mineralocorticoid antagonist) at baseline and subsequent visits. βB was modeled as baseline use, time‐varying use, and in an inverse probability treatment weighted model. Primary outcome was all‐cause mortality analyzed with adjusted Cox proportional hazards models. Continuing compared with stopping βB during follow‐up was tested. Mean age was 73.2 years, 84.1% were men, and 17.2% had atrial fibrillation/flutter at baseline. At the time of study entry, 49.8% were on βBs, 35.0% were on angiotensin‐converting enzyme inhibitors/angiotensin receptor blockers, and 23.9% were on mineralocorticoid antagonists. For the total cohort, there was a trend toward harm in the unadjusted model for baseline βB use, but this was neutral after adjustment. When βB use was analyzed as a time‐varying exposure, there was no association with mortality. βB discontinuation was associated with decreased mortality for the total cohort. Findings were consistent in inverse probability treatment weighted models. For angiotensin‐converting enzyme inhibitor/angiotensin receptor blocker or mineralocorticoid antagonist use, there was no association with mortality after adjustment for the total cohort. Conclusions There was no association of neurohormonal blockade use with survival in transthyretin cardiac amyloidosis. For the total cohort, deprescribing βB may be associated with improved survival. Additional studies are needed to confirm these findings

Inflammatory, Oxidative Stress, and Cardiac Damage Biomarkers and Radiation-Induced Fatigue in Breast Cancer Survivors.

PURPOSE: Studies examining biomarkers associated with fatigue in breast cancer survivors treated with radiation are limited. Therefore, we examined the longitudinal association between serum biomarkers and post-breast cancer fatigue in survivors treated with radiation: [oxidative stress] 8-hydroxyguanosine, myeloperoxidase; [inflammation] interleukin-6 (IL-6), c-reactive protein, growth differentiation factor-15 (GDF-15), placental growth factor, transforming growth factor-beta, [cardiac damage] cystatin-C, troponin-I. METHODS: In a secondary analysis, we included participants from the Womens Health Initiative if they had: a previous breast cancer diagnosis (stages I-III), no prior cardiovascular diseases, pre-and post-breast cancer serum samples drawn approximately 3 years apart, and fatigue measured using the Short-Form 36 vitality subscale at both serum collections. Biomarkers were measured using ELISA or RT-qPCR and modeled as the log2 post-to pre-breast cancer ratio. RESULTS: Overall, 180 women with a mean (SD) age of 67.0 (5.5) years were included. The mean (SD) vitality scores were 66.2 (17.2) and 59.7 (19.7) pre- and post-breast cancer, respectively. Using multivariable weighted linear regression, higher biomarker ratios of cystatin-C, IL-6, and GDF-15 were associated with a lower vitality score (i.e., higher fatigue). For example, for each 2-fold difference in cystatin-C biomarker ratio, the vitality score was lower by 7.31 points (95% CI: -14.2, -0.45). CONCLUSION: Inflammatory and cardiac damage biomarkers are associated with fatigue in breast cancer survivors treated with radiation; however, these findings should be replicated in a larger sample. Biomarkers could be measured in clinical practice or assessed in risk prediction models to help identify patients at high risk for fatigue

Inflammation, Hyperglycemia, and Adverse Outcomes in Individuals With Diabetes Mellitus Hospitalized for COVID-19.

OBJECTIVE: Diabetes mellitus (DM) is a major risk factor for severe coronavirus disease 2019 (COVID-19) for reasons that are unclear. RESEARCH DESIGN AND METHODS: We leveraged the International Study of Inflammation in COVID-19 (ISIC), a multicenter observational study of 2,044 patients hospitalized with COVID-19, to characterize the impact of DM on in-hospital outcomes and assess the contribution of inflammation and hyperglycemia to the risk attributed to DM. We measured biomarkers of inflammation collected at hospital admission and collected glucose levels and insulin data throughout hospitalization. The primary outcome was the composite of in-hospital death, need for mechanical ventilation, and need for renal replacement therapy. RESULTS: Among participants (mean age 60 years, 58.2% males), those with DM (n = 686, 33.5%) had a significantly higher cumulative incidence of the primary outcome (37.8% vs. 28.6%) and higher levels of inflammatory biomarkers than those without DM. Among biomarkers, DM was only associated with higher soluble urokinase plasminogen activator receptor (suPAR) levels in multivariable analysis. Adjusting for suPAR levels abrogated the association between DM and the primary outcome (adjusted odds ratio 1.23 [95% CI 0.78, 1.37]). In mediation analysis, we estimated the proportion of the effect of DM on the primary outcome mediated by suPAR at 84.2%. Hyperglycemia and higher insulin doses were independent predictors of the primary outcome, with effect sizes unaffected by adjusting for suPAR levels. CONCLUSIONS: Our findings suggest that the association between DM and outcomes in COVID-19 is largely mediated by hyperinflammation as assessed by suPAR levels, while the impact of hyperglycemia is independent of inflammation

Chronic Oxidative Stress as a Marker of Long-term Radiation-Induced Cardiovascular Outcomes in Breast Cancer.

While biomarkers have been proposed to identify individuals at risk for radiation-induced cardiovascular disease (RICVD), little is known about long-term associations with cardiac events. We examined associations of biomarkers of oxidative stress (myeloperoxidase, growth differentiation factor-15, 8-hydroxy-2-deoxyguanosine [8-OH-dG], placental growth factor), cardiac injury (troponin I, cystatin-C), inflammation (interleukin-6, C-reactive protein), and myocardial fibrosis (transforming growth factor-ß) with long-term RICVD in breast cancer (BC) survivors. We conducted a nested case-control study within the Womens Health Initiative of postmenopausal women with incident BC stages I-III, who received radiation and had pre- and post-BC diagnosis serum samples. Cases (n = 55) were defined as developing incident, physician-adjudicated myocardial infarction, coronary heart disease death, other CVD death, heart failure, or stroke after BC. Cases were matched to three controls (n = 158). After adjustment, a higher 8-OH-dG ratio was significantly associated with an elevated long-term risk of RICVD, suggesting oxidative DNA damage may be a putative pathway for RICVD

The association between heart failure and incident cancer in women: an analysis of the Women's Health Initiative

AimsThere is conflicting evidence whether heart failure (HF) is a risk factor for incident cancer. Despite population-based cohorts demonstrating this association, an analysis of the Physician's Health Study found no association in a cohort of mostly healthy males. We investigated the association of HF with incident cancer among a large cohort of post-menopausal women.Methods and resultsA prospective cohort study of 146 817 post-menopausal women age 50 to 79 years enrolled in the Women's Health Initiative from 1993-1998, and followed through 2015. The primary exposure was adjudicated incident HF diagnosis, including preserved and reduced ejection fraction in a sub-cohort. The primary outcome was adjudicated incident total and site-specific cancers. Hazard ratios were calculated using multivariable-adjusted Cox proportional hazard regression models. Over a median follow-up of 8.4 years, 3272 and 17 474 women developed HF and cancer, respectively. HF developed in 235 women prior to cancer. HF was associated with subsequent incident cancer [hazard ratio (HR) 1.28, 95% confidence interval (CI) 1.11-1.48]. Associations were observed for obesity-related cancers (HR 1.24, 95% CI 1.02-1.51), as well as lung and colorectal cancers (HR 1.58, 95% CI 1.09-2.30 and HR 1.52, 95% CI 1.02-2.27, respectively). HF with preserved ejection fraction (HR 1.34, 95% CI 1.06-1.67), but not HF reduced ejection fraction (HR 0.99, 95% CI 0.74-1.34), was associated with total cancer.ConclusionHeart failure was associated with an increase in cancer diagnoses in post-menopausal women. This association was strongest for lung cancer. Further research is needed to appreciate the underlying mechanisms responsible for this association