Cardiovascular and Noncardiovascular Prescribing and Mortality After Takotsubo Comparison With Myocardial Infarction and General Population.

Background: Takotsubo syndrome is an increasingly common cardiac emergency with no known evidence-based treatment. Objectives: The purpose of this study was to investigate cardiovascular mortality and medication use after takotsubo syndrome. Methods: In a case-control study, all patients with takotsubo syndrome in Scotland between 2010 and 2017 (n = 620) were age, sex, and geographically matched to individuals in the general population (1:4, n = 2,480) and contemporaneous patients with acute myocardial infarction (1:1, n = 620). Electronic health record data linkage of mortality outcomes and drug prescribing were analyzed using Cox proportional hazard regression models. Results: Of the 3,720 study participants (mean age, 66 years; 91% women), 153 (25%) patients with takotsubo syndrome died over the median of 5.5 years follow-up. This exceeded mortality rates in the general population (N = 374 [15%]; HR: 1.78 [95% CI: 1.48-2.15], P < 0.0001), especially for cardiovascular (HR: 2.47 [95% CI: 1.81-3.39], P < 0.001) but also noncardiovascular (HR: 1.48 [95% CI: 1.16-1.87], P = 0.002) deaths. Mortality rates were lower for patients with takotsubo syndrome than those with myocardial infarction (31%, 195/620; HR: 0.76 [95% CI: 0.62-0.94], P = 0.012), which was attributable to lower rates of cardiovascular (HR: 0.61 [95% CI: 0.44-0.84], P = 0.002) but not non-cardiovascular (HR: 0.92 [95% CI: 0.69-1.23], P = 0.59) deaths. Despite comparable medications use, cardiovascular therapies were consistently associated with better survival in patients with myocardial infarction but not in those with takotsubo syndrome. Diuretic (P = 0.01), anti-inflammatory (P = 0.002), and psychotropic (P < 0.001) therapies were all associated with worse outcomes in patients with takotsubo syndrome. Conclusions: In patients with takotsubo syndrome, cardiovascular mortality is the leading cause of death, and this is not associated with cardiovascular therapy use.

Impaired Cardiac and Skeletal Muscle Energetics Following Anthracycline Therapy for Breast Cancer.

BACKGROUND: Anthracycline-related cardiac toxicity is a recognized consequence of cancer therapies. We assess resting cardiac and skeletal muscle energetics and myocyte, sarcomere, and mitochondrial integrity in patients with breast cancer receiving epirubicin. METHODS: In a prospective, mechanistic, observational, longitudinal study, we investigated chemotherapy-naive patients with breast cancer receiving epirubicin versus sex- and age-matched healthy controls. Resting energetic status of cardiac and skeletal muscle (phosphocreatine/gamma ATP and inorganic phosphate [Pi]/phosphocreatine, respectively) was assessed with 31P-magnetic resonance spectroscopy. Cardiac function and tissue characterization (magnetic resonance imaging and 2D-echocardiography), cardiac biomarkers (serum NT-pro-BNP and high-sensitivity troponin I), and structural assessments of skeletal muscle biopsies were obtained. All study assessments were performed before and after chemotherapy. RESULTS: Twenty-five female patients with breast cancer (median age, 53 years) received a mean epirubicin dose of 304 mg/m2, and 25 age/sex-matched controls were recruited. Despite comparable baseline cardiac and skeletal muscle energetics with the healthy controls, after chemotherapy, patients with breast cancer showed a reduction in cardiac phosphocreatine/gamma ATP ratio (2.0±0.7 versus 1.1±0.5; P=0.001) and an increase in skeletal muscle Pi/phosphocreatine ratio (0.1±0.1 versus 0.2±0.1; P=0.022). This occurred in the context of increases in left ventricular end-systolic and end-diastolic volumes (P=0.009 and P=0.008, respectively), T1 and T2 mapping (P=0.001 and P=0.028, respectively) but with preserved left ventricular ejection fraction, mass and global longitudinal strain, and no change in cardiac biomarkers. There was preservation of the mitochondrial copy number in skeletal muscle biopsies but a significant increase in areas of skeletal muscle degradation (P=0.001) in patients with breast cancer following chemotherapy. Patients with breast cancer demonstrated a reduction in skeletal muscle sarcomere number from the prechemotherapy stage compared with healthy controls (P=0.013). CONCLUSIONS: Contemporary doses of epirubicin for breast cancer treatment result in a significant reduction of cardiac and skeletal muscle high-energy 31P-metabolism alongside structural skeletal muscle changes. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT04467411.

Ultrafiltration versus Diuretics on Prognostic Cardiac and Renal Biomarkers in Acute Decompensated Heart Failure: A Systematic Review and Meta-Analysis.

Existing systematic reviews have insufficiently delineated the differing cardiac and renal profile of ultrafiltration compared to diuretics as a method of decongestion in acute decompensated heart failure. This meta-analysis will investigate the impact of ultrafiltration compared to diuretics on prognostic cardiac and renal biomarkers. We searched PubMed Central, Ovid MEDLINE®, Ovid Embase, all EBM reviews, and Web of Science Core Collection for randomised controlled trials published before 21 July 2022. Our main outcome measures were cardiac (brain natriuretic peptide and N-terminal pro-brain natriuretic peptide) and renal biomarkers (serum creatinine, serum sodium, and blood urea nitrogen). A total of 10 randomised trials were included in our analysis after screening. An inverse-variance random effects meta-analysis of the pooled results demonstrated no significant difference between ultrafiltration and diuretics for brain natriuretic peptide, N-terminal pro-brain natriuretic peptide, creatinine, sodium and long-term blood urea nitrogen. However, ultrafiltration produced statistically greater increases in blood urea nitrogen in the short-term (mean difference, 3.88; 95% confidence interval 0.59-7.17 mg/dL). Overall, ultrafiltration produces a similar impact on prognostic cardiac and renal biomarkers when compared to diuretic therapy. We highlight ultrafiltration's significant impact on short-term BUN and recommend further research to investigate more optimal protocols of ultrafiltration administration.

Structural and Functional Brain Changes in Acute Takotsubo Syndrome.

BACKGROUND: Takotsubo syndrome mimics an acute myocardial infarction, typically in the aftermath of mental or physical stress. OBJECTIVES: The mechanism by which emotional processing in the context of stress leads to significant cardiac injury is poorly understood, so a full exploration of brain structure and function in takotsubo syndrome patients merits investigation. METHODS: Twenty-five acute (<5 days) takotsubo patients and 25 control subjects were recruited into this observational cross-sectional study. Surface-based morphometry was carried out on magnetic resonance imaging (MRI) brain scans to extract cortical morphology based on volume, thickness, and surface area with the use of Freesurfer. Cortical morphology general linear models were corrected for age, sex, photoperiod, and total brain volume. Resting-state functional MRI and diffusion tensor tractography images were preprocessed and analyzed with the use of the Functional Magnetic Resonance Imaging of the Brain Diffusion Toolbox and Functional Connectivity Toolbox. RESULTS: There was significantly smaller total white matter and subcortical gray matter volumes in takotsubo (P < 0.001), with smaller total brain surface area but increased total cortical thickness (both P < 0.001). Individual gray matter regions (hippocampus and others) were significantly smaller in takotsubo (P < 0.001); only thalamus and insula were larger (P < 0.001). There was significant hyperfunctional and hypofunctional connectivity in multiple areas, including thalamus-amygdala-insula and basal ganglia (P < 0.05). All structural tractography connections were increased in takotsubo (P < 0.05). CONCLUSIONS: The authors showed smaller gray and white matter volumes driven by smaller cortical surface area, but increased cortical thickness and structural tractography connections with bidirectional changes in functional connectivity linked to emotion, language, reasoning, perception, and autonomic control. These are interventional targets in takotsubo patients' rehabilitation.

Renin-Angiotensin and Endothelin Systems in Patients Post-Takotsubo Cardiomyopathy.

Background We investigate if renin-angiotensin and endothelin-1 response pathways follow the same pattern of recovery as left ventricular ejection fraction in patients with takotsubo cardiomyopathy. Methods and Results Ninety patients with takotsubo cardiomyopathy (n=30 in each of "acute," "convalescent" [3-5 months] and "recovered" [>1 year] groups) who were on minimal or no medication and were free of any significant cardiac/metabolic comorbidities, and 30 controls were studied. Serum concentrations of renin, angiotensin-converting enzyme, angiotensin II, big endothelin-1, endothelin-1 were measured using commercially available ELISA, and B-type natriuretic peptide was measured using an immunoassay. Mean left ventricular ejection fraction was <40% during the acute phase in all groups, but recovered to 63% in convalescent and 64% in the recovered groups, respectively. Serum renin concentrations remain persistently elevated after a episode of takotsubo cardiomyopathy (P=0.03 versus controls). Angiotensin converting enzyme levels are significantly depressed during the acute phase compared with convalescent (P=0.004), recovered takotsubo cardiomyopathy (P=0.02) or controls (P=0.03). Angiotensin II is increased in patients with takotsubo cardiomyopathy (P<0.001 versus controls) remaining persistently elevated in the chronically recovered group alone (P=0.03 versus controls). Big endothelin-1 levels are unchanged, but endothelin-1 is significantly lower after takotsubo cardiomyopathy compared with controls (P=0.03). Conclusions Despite "normalization" of the left ventricular ejection fraction, there is long-term maladaptive activation of renin-angiotensin system in patients with takotsubo cardiomyopathy. Registration URL: https://www.clinicaltrials.gov; Unique identifiers: NCT02897739, NCT02989454.

Psilocybin-induced takotsubo cardiomyopathy.

We present a case of takotsubo cardiomyopathy following recreational ingestion of Psilocybe semilanceata (known as 'magic mushrooms'). The patient presented with respiratory distress and pulmonary oedema responding to standard medical measures. Investigations included: echocardiogram, cardiac MRI and angiogram. Based on our search, we suggest this is only the second recognised case in the published literature.

Takotsubo Syndrome: Pathophysiology, Emerging Concepts, and Clinical Implications.

Takotsubo syndrome is a condition characterized by acute transient left ventricular systolic dysfunction, which at presentation can be challenging to distinguish from acute myocardial infarction. Although previously thought to be a benign, self-limiting condition, recent studies have confirmed that patients with takotsubo syndrome have persistent subtle ongoing cardiac dysfunction, and many continue to have limiting symptoms despite restoration of left ventricular ejection fraction. Moreover, these patients have a substantial burden of morbidity and mortality, as well, with high rates of subsequent major adverse cardiovascular events that approach those of patients with acute coronary syndrome. The mechanisms behind this condition remain elusive. Despite substantial research, the medical community continues to have an incomplete understanding of its underlying pathogenesis and pathophysiology. Catecholamine-induced myocardial injury is the most established and well-known theory, but this does not explain all the clinical features and presentations of the condition, and numerous other pathways and abnormalities are emerging. Because of the poor understanding of its underlying pathophysiology, there is a lack of evidence-based interventions to treat the acute episode, to avoid recurrences, and to prevent major adverse cardiovascular events. This highlights the need for further research to gain a better understanding of the underlying pathophysiology to inform appropriate randomized controlled trials of interventions targeting the causative pathways. Only then can evidence-based management strategies be established to improve clinical outcomes of this potentially lethal condition.

Novel case of takotsubo cardiomyopathy following COVID-19 vaccination.

We present an unusual case of takotsubo cardiomyopathy (TTC) following administration of the second dose of the DNA ChadOX1 nCOV-19 (AZD122) vaccination. This woman in her early 50s presented to the emergency department 8 days following her vaccine with central chest pain. Initial investigations revealed a raised troponin and evolving T wave inversion on ECG. Acute coronary syndrome management was commenced. Further investigations revealed non-obstructive coronary arteries on coronary angiography and imaging revealed hypokinesia of the anterior and anterior-septal walls in the apex and midcavity level, myocardial oedema and no infarction, all in keeping with TTC. Given the large-scale roll out of vaccinations during the COVID-19 pandemic better understanding of potential adverse events is essential. This is the first case report of TTC following a second dose of the DNA ChadOX1 nCOV-19 (AZD122) vaccination.

An Ecological Study Assessing the Relationship between Public Health Policies and Severity of the COVID-19 Pandemic.

Reliance on government-led policies have heightened during the COVID-19 pandemic. Further research on the policies associated with outcomes other than mortality rates remains warranted. We aimed to determine associations between government public health policies on the severity of the COVID-19 pandemic. This ecological study including countries reporting ≥25 daily COVID-related deaths until end May 2020, utilised public data on policy indicators described by the Blavatnik school of Government. Associations between policy indicators and severity of the pandemic (mean mortality rate, time to peak, peak deaths per 100,000, cumulative deaths after peak per 100,000 and ratio of mean slope of the descending curve to mean slope of the ascending curve) were measured using Spearman rank-order tests. Analyses were stratified for age, income and region. Among 22 countries, containment policies such as school closures appeared effective in younger populations (rs = -0.620, p = 0.042) and debt/contract relief in older populations (rs = -0.743, p = 0.009) when assessing peak deaths per 100,000. In European countries, containment policies were generally associated with good outcomes. In non-European countries, school closures were associated with mostly good outcomes (rs = -0.757, p = 0.049 for mean mortality rate). In high-income countries, health system policies were generally effective, contrasting to low-income countries. Containment policies may be effective in younger populations or in high-income or European countries. Health system policies have been most effective in high-income countries.

Country-level determinants of the severity of the first global wave of the COVID-19 pandemic: an ecological study.

OBJECTIVE: We aimed to identify the country-level determinants of the severity of the first wave of the COVID-19 pandemic. DESIGN: Ecological study of publicly available data. Countries reporting >25 COVID-19 related deaths until 8 June 2020 were included. The outcome was log mean mortality rate from COVID-19, an estimate of the country-level daily increase in reported deaths during the ascending phase of the epidemic curve. Potential determinants assessed were most recently published demographic parameters (population and population density, percentage population living in urban areas, population >65 years, average body mass index and smoking prevalence); economic parameters (gross domestic product per capita); environmental parameters (pollution levels and mean temperature (January-May); comorbidities (prevalence of diabetes, hypertension and cancer); health system parameters (WHO Health Index and hospital beds per 10 000 population); international arrivals; the stringency index, as a measure of country-level response to COVID-19; BCG vaccination coverage; UV radiation exposure; and testing capacity. Multivariable linear regression was used to analyse the data. PRIMARY OUTCOME: Country-level mean mortality rate: the mean slope of the COVID-19 mortality curve during its ascending phase. PARTICIPANTS: Thirty-seven countries were included: Algeria, Argentina, Austria, Belgium, Brazil, Canada, Chile, Colombia, the Dominican Republic, Ecuador, Egypt, Finland, France, Germany, Hungary, India, Indonesia, Ireland, Italy, Japan, Mexico, the Netherlands, Peru, the Philippines, Poland, Portugal, Romania, the Russian Federation, Saudi Arabia, South Africa, Spain, Sweden, Switzerland, Turkey, Ukraine, the UK and the USA. RESULTS: Of all country-level determinants included in the multivariable model, total number of international arrivals (beta 0.033 (95% CI 0.012 to 0.054)) and BCG vaccination coverage (-0.018 (95% CI -0.034 to -0.002)), were significantly associated with the natural logarithm of the mean death rate. CONCLUSIONS: International travel was directly associated with the mortality slope and thus potentially the spread of COVID-19. Very early restrictions on international travel should be considered to control COVID-19 outbreaks and prevent related deaths.

Hypertensive Disorders of Pregnancy (HDP) and the Risk of Common Cancers in Women: Evidence from the European Prospective Investigation into Cancer (EPIC)-Norfolk Prospective Population-Based Study.

PURPOSE: The purpose was to determine the association between HDP and cancer in a UK cohort. METHODS: Between 1993 and 1997, participants from the EPIC-Norfolk cohort attended baseline health-checks and completed questionnaires, where a history of HDP was collected. Incident cancer cases were identified through NHS record linkage until March 2016. Univariable and multivariable logistic regression analyses were employed to determine the association between HDP and odds of cancer, with adjustment for potential confounders including co-morbidities, sociodemographic, lifestyle and reproductive factors. RESULTS: 13,562 women were included after excluding prevalent cancer cases and women with no pregnancies. 2919 (21.5%) reported HDP and 2615 incident cancers occurred during mean follow up of 19 years. Median age (IQR) at baseline for incident cancer was 60.8 (±14.8) years. Among incident cancer cases, 578 (22.1%) had HDP. In multivariable analyses, HDP had odds ratio (OR) 1.06; 95% CI 0.95-1.18 for incident cancer. The ORs (95% CIs) for common site-specific cancers including breast, colorectal, lung, ovarian and endometrial cancers were 1.06 (0.88-1.28), 1.15 (0.92-1.45), 0.96 (0.68-1.35), 1.30 (0.93-1.83) and 1.16 (0.80-1.67). CONCLUSION: We found no association between HDP and cancer risk. Further studies are required to confirm and account for any underlying genetic factors involved in pregnancy-related exposures and cancer risk.

Does prior antithrombotic therapy influence recurrence and bleeding risk in stroke patients with atrial fibrillation or atrial flutter?

BACKGROUND: Whilst antithrombotic therapy is recommended in people with atrial fibrillation, little is known about the survival benefits of antithrombotic treatment in those with both high ischaemic and bleeding risk scores. We aim to describe the distribution of these risk scores in those with a prior diagnosis of atrial fibrillation who have suffered stroke and to determine the net clinical benefit of antithrombotic treatment. METHODS: We used regional stroke register data in the UK. Patients with a prior diagnosis of atrial fibrillation and ischaemic or haemorrhagic stroke patients were selected and their ischaemic stroke risk score (CHA2DS2-VASc) and bleeding risk score (HEMORR2HAGES) scores retrospectively calculated. Logistic regression and Cox proportional hazards models were constructed to determine the association between antithrombotic therapy prior to stroke and in-hospital and long-term mortality. RESULTS: A total of 1928 stroke patients (mean age 81.3 years (standard deviation 8.5), 56.8% women) with prior atrial fibrillation were included. Of these, 1761 (91.3%) suffered ischaemic stroke. The most common phenotype (64%) was of those with both high CHA2DS2-VASc (≥2) and high HEMORR2HAGES score (≥4). In our fully adjusted model, patients on antithrombotic treatment with both high ischaemic and bleeding risk had a significant reduction in odds of 31% for in-hospital mortality (odds ratio 0.69 (95% confidence interval 0.48-1.00: p = 0.049)) and 17% relative risk reduction for long-term mortality (hazard ratio 0.83 (95% confidence interval 0.71-0.97: p = 0.02)). CONCLUSIONS: Our study suggests that antithrombotic treatment has a prognostic benefit following incident stroke in those with both high ischaemic risk and high bleeding risk. This should be considered when choosing treatment options in this group of patients.

Hypertensive Disorders of Pregnancy and Subsequent Cardiovascular Disease: Current National and International Guidelines and the Need for Future Research.

Background: It is well-established that hypertensive disorders of pregnancy (HDP) are associated with an increased risk of cardiovascular disease (CVD) in later life. National and International guidelines recognize this but due to a lack of research in this area few details are provided on how best to risk stratify or when and how to monitor these women. Objectives: This article aims to summarize current guidelines in this area in order to raise awareness of need for further research in this important clinical area. Search Strategy: A review of the published literature was carried out in August 2018 using the databases EMBASE and Medline and the websites of professional societies were searched manually using the search terms "pre-eclampsia," "hypertensive disorders of pregnancy," "management," "guidelines," "long term follow up" and "cardiovascular risk." Guidelines published in English were included and articles that provided guidance on follow up post-partum of women with HDP. Main Results: The search identified 360 records. Of these, 16 guidelines mentioned the follow up of women with HDP; their reported years ranges from 2010 to 2018. Only 8 (50%) provided some level of recommendation for follow up beyond the immediate post-partum period. These recognized the future risk of CVD to women from HDP and provide detailed recommendations for the management of these conditions during pregnancy and in the immediate post-partum period. Guidelines recommended that women and primary care clinicians are made aware of this risk and some suggest yearly BP monitoring, and at least 5 yearly monitoring of renal functions, urinalysis and lipid profile testing alongside lifestyle modifications and control of CVD risk factors. Guidelines used a combination of meta-analysis, individual cohort studies and expert opinions to inform their recommendations. Conclusions: There is a need for future studies of women with a history of HDP to define their trajectory for the development of CVD and candidate biomarkers in order to develop screening, risk stratification, and preventive measures to reduce the significant CV burden associated with HDP in women.

Baseline anticholinergic burden from medications predicts incident fatal and non-fatal stroke in the EPIC-Norfolk general population.

Background: Stroke is primarily a disease of older age, with a substantial impact on global mortality and morbidity. Medications with anticholinergic effects are widely used, but no studies have been conducted to examine the relationship between anticholinergic burden (ACB) and stroke in a general population. Method: The sample was drawn from the EPIC-Norfolk cohort. Baseline assessments were carried out during 1993-97 and participants were followed up until March 2016. Participants were divided into four groups according to their total ACB score at baseline; these groups were those with a total ACB score of 0, 1, 2-3 and >3. After exclusion, Cox proportional hazards models were constructed to determine the associations between the ACB score groups and the risk of incident stroke and stroke mortality. Sensitivity analysis and propensity score matched analyses were performed. Results: In total 25 639 participants attended the first health check; 3917 participants were excluded, leaving 21 722 participants to be included. Participants had a mean age [standard deviation (SD)] of 58.9 (9.2) years (54.4% women). Of these, 2131 suffered incident stroke and 562 died from stroke. Mean follow-up was approximately 18 years for both outcomes. In the fully adjusted model, those with an ACB of >3 had 59% relative risk of incident stroke {hazard ratio [HR] [95% confidence interval (CI) 1.59 [1.34-1.89]} and 86% relative risk of stroke mortality [1.86 (1.37-2.53)] compared with those in ACB 0 category. Sensitivity analyses and propensity score matched analyses showed similar results. Conclusions: Our results provide an incentive for the cautious use of medications with anticholinergic properties, to help reduce the global burden of stroke.

Takotsubo cardiomyopathy with severe bradyarrhythmia following epidural insertion.

We present a case of takotsubo cardiomyopathy (TTC) with ventricular stand still and atrioventricular block. TTC can mimic ST elevation myocardial infarction and heart failure, but in this case resulted in a severe cardiac conduction disorder and ventricular standstill. This is a recognised but unusual presentation and serves as a lesson to those undertaking anaesthetics to be vigilant for TTC.