Paraganglioma-induced reverse takotsubo syndrome treated with extracorporeal membrane oxygenation in a young patient with a history of malignancy: a case report.

Background: Reverse takotsubo-like cardiomyopathy (rTCC) is a rare type of stress-induced cardiomyopathy associated with catecholamine surges. Reverse takotsubo-like cardiomyopathy is characterized by basal and mid-ventricular hypokinesis with apical sparing. Paragangliomas are catecholamine-secreting neuroendocrine tumours outside the adrenal gland that can cause palpitations, hypertension, and rarely cardiomyopathy. In cases of occult paraganglioma, catecholamine-induced rTCC can be rapidly reversed with adequate haemodynamic support. Case summary: A 28-year-old woman with a history of cervical cancer, ovarian insufficiency, and preeclampsia presented to the emergency department with nausea, vomiting, and chest pain. The patient was initially tachycardic, tachypnoeic, and hypotensive. On exam, she was in distress with diffuse rales and cool extremities. Electrocardiogram showed sinus tachycardia to 147 b.p.m. and lateral ST depression in V4 and V5. Troponin was elevated to 13 563 ng/L. An echocardiogram showed severely reduced left ventricular ejection fraction (LVEF) with hypokinesis of the basal segments and apical sparing, identified as rTCC. Computed tomography of the abdomen showed a 3.6 × 2.7 cm right adrenal mass. The patient rapidly developed respiratory failure and was subsequently intubated, sedated, and initiated on vasopressors. In the setting of cardiogenic shock refractory to vasopressor support, the decision was made to cannulate for venoarterial extracorporeal membrane oxygenation (VA-ECMO). Plasma and urine metanephrines were elevated. After 5 days, the patient's LVEF recovered to her baseline, and the rTCC had resolved. The patient's hypertension was managed with gradual alpha-blockade, and she subsequently underwent successful adrenalectomy on Day 44. Discussion: An occult paraganglioma should be considered when rTCC pattern is identified. The pathophysiology of paraganglioma-mediated catecholamine surges predisposing to rTCC is unclear. Potential mechanisms for rTCC include oestrogen deficiency, catecholamine cardiotoxicity, and coronary artery spasm. The VA-ECMO is an increasingly used modality to provide haemodynamic support to patients with refractory cardiogenic shock.

Asthma and incident coronary heart disease: an observational and Mendelian randomisation study.

BACKGROUND: Observational studies suggest asthma is a risk factor for coronary heart disease (CHD) and sex modifies the risk, but they may suffer from methodological limitations. To overcome these, we applied a "triangulation approach", where different methodologies, with different potential biases, were leveraged to enhance confidence in findings. METHODS: First, we conducted an observational study using UK medical records to match asthma patients 1:1, by age, sex and general practitioner (GP) practice, to the general population. We measured the association between asthma and incident CHD (myocardial infarction: hospitalisation/death) by applying minimal sufficient adjustment: model 1, smoking, body mass index, oral corticosteroids, atopy and deprivation; model 2, additionally adjusting for healthcare behaviour (GP consultation frequency). Second, we conducted a Mendelian randomisation (MR) study using data from the UK Biobank, Trans-National Asthma Genetic Consortium (TAGC) and Coronary Artery Disease Genome-wide Replication and Meta-analysis consortium (CARDIoGRAM). Using 64 asthma single nucleotide polymorphisms, the effect of asthma on CHD was estimated with inverse variance-weighted meta-analysis and methods that adjust for pleiotropy. RESULTS: In our observational study (n=1 522 910), we found asthma was associated with 6% increased risk of CHD (model 1: HR 1.06, 95% CI 1.01-1.13); after accounting for healthcare behaviour, we found no association (model 2: HR 0.99, 95% CI 0.94-1.05). Asthma severity did not modify the association, but sex did (females: HR 1.11, 95% CI 1.01-1.21; males: HR 0.91, 95% CI 0.84-0.98). Our MR study (n=589 875) found no association between asthma and CHD (OR 1.01, 95% CI 0.98-1.04) and no modification by sex. CONCLUSIONS: Our findings suggest that asthma is not a risk factor for CHD. Previous studies may have suffered from detection bias or residual confounding.

Obesity in Heart Failure with Reduced Ejection Fraction: Time to Address the Elephant in the Room.

Obesity has been long recognized as a risk factor for the development of heart failure, but recent evidence suggests obesity is more typically associated with heart failure with preserved ejection fraction as opposed to heart failure with reduced ejection fraction (HFrEF). Nevertheless, numerous studies have found that obesity modulates the presentation and progression of HFrEF and may contribute to the development of HFrEF in some patients. Although obesity has definite negative effects in HFrEF patients, the effects of intentional weight loss in HFrEF patients with obesity have been poorly studied.

Epicardial Fat in Heart Failure with Preserved Ejection Fraction: Bad Actor or Just Lying Around?

Heart failure with preserved ejection fraction (HFpEF) is increasingly recognised to be strongly associated with obesity and abnormalities in fat distribution. Epicardial fat has been associated with abnormal haemodynamics in HFpEF, with potential for direct mechanical effects on the heart causing constriction-like physiology and local myocardial remodelling effects from secretion of inflammatory and profibrotic mediators. However, patients with epicardial fat generally have more systemic and visceral adipose tissue making determination of causality between epicardial fat and HFpEF complex. In this review, we will summarise the evidence for epicardial fat being either directly causal in HFpEF pathogenesis or merely being a correlate of worse systemic inflammatory and generalised adiposity. We will also discuss therapies that directly target epicardial fat and may have potential for treating HFpEF and elucidating the independent role of epicardial fat in its pathogenesis.

Outcomes of coronary artery bypass grafting in patients with heart failure with a midrange ejection fraction.

BACKGROUND: Coronary artery bypass grafting (CABG) improves survival in patients with heart failure and severely reduced left ventricular systolic function (LVEF). Limited data exist regarding adverse cardiovascular event rates after CABG in patients with heart failure with midrange ejection fraction (HFmrEF; LVEF > 40% and < 55%). METHODS: We analyzed data on isolated CABG patients from the Veterans Affairs national database (2010-2019). We stratified patients into control (normal LVEF and no heart failure), HFmrEF, and heart failure with reduced LVEF (HFrEF) groups. We compared all-cause mortality and heart failure hospitalization rates between groups with a Cox model and recurrent events analysis, respectively. RESULTS: In 6533 veterans, HFmrEF and HFrEF was present in 1715 (26.3%) and 566 (8.6%) respectively; the control group had 4252 (65.1%) patients. HFrEF patients were more likely to have diabetes mellitus (59%), insulin therapy (36%), and previous myocardial infarction (31%). Anemia was more prevalent in patients with HFrEF (49%) as was a lower serum albumin (mean, 3.6 mg/dL). Compared with the control group, a higher risk of death was observed in the HFmrEF (hazard ratio [HR], 1.3 [1.2-1.5)] and HFrEF (HR, 1.5 [1.2-1.7]) groups. HFmrEF patients had the higher risk of myocardial infarction (subdistribution HR, 1.2 [1-1.6]; P = .04). Risk of heart failure hospitalization was higher in patients with HFmrEF (HR, 4.1 [3.5-4.7]) and patients with HFrEF (HR, 7.2 [6.2-8.5]). CONCLUSIONS: Heart failure with midrange ejection fraction negatively affects survival after CABG. These patients also experience higher rates myocardial infarction and heart failure hospitalization.

Development of algorithms for determining heart failure with reduced and preserved ejection fraction using nationwide electronic healthcare records in the UK.

BACKGROUND: Determining heart failure (HF) phenotypes in routine electronic health records (EHR) is challenging. We aimed to develop and validate EHR algorithms for identification of specific HF phenotypes, using Read codes in combination with selected patient characteristics. METHODS: We used The Healthcare Improvement Network (THIN). The study population included a random sample of individuals with HF diagnostic codes (HF with reduced ejection fraction (HFrEF), HF with preserved ejection fraction (HFpEF) and non-specific HF) selected from all participants registered in the THIN database between 1 January 2015 and 30 September 2017. Confirmed diagnoses were determined in a randomly selected subgroup of 500 patients via GP questionnaires including a review of all available cardiovascular investigations. Confirmed diagnoses of HFrEF and HFpEF were based on four criteria. Based on these data, we calculated a positive predictive value (PPV) of predefined algorithms which consisted of a combination of Read codes and additional information such as echocardiogram results and HF medication records. RESULTS: The final cohort from which we drew the 500 patient random sample consisted of 10 275 patients. Response rate to the questionnaire was 77.2%. A small proportion (18%) of the overall HF patient population were coded with specific HF phenotype Read codes. For HFrEF, algorithms achieving over 80% PPV included definite, possible or non-specific HF HFrEF codes when combined with at least two of the drugs used to treat HFrEF. Only in non-specific HF coding did the use of three drugs (rather than two) contribute to an improvement of the PPV for HFrEF. HFpEF was only accurately defined with specific codes. In the absence of specific coding for HFpEF, the PPV was consistently below 50%. CONCLUSIONS: Prescription for HF medication can reliably be used to find HFrEF patients in the UK, even in the absence of a specific Read code for HFrEF. Algorithms using non-specific coding could not reliably find HFpEF patients.

The importance of randomization in clinical research.

Studies evaluating average treatment effects (ATE) of an intervention could broadly be classified into those with observational and randomized designs. Observational studies are limited by confounding, in addition to selection and information bias, making the evaluation of ATE hypothesis generating and not hypothesis testing. Randomization attempts to reduce the systemic error introduced by observational studies by ensuring equal distribution of prognostic factors between the treatment and control groups, thereby confirming that any difference in outcomes observed between the two groups is attributable to the treatment. While randomized controlled trials (RCT) remain the gold standard in estimating ATE of therapeutic interventions, they do have inherent limitations due to uncertain external validity. Observational studies can have a complementary role in enhancing RCTs' ability to inform routine clinical practice. In this review, we focus on the limitations of observational studies, the need for randomization, interpretation, and the limitations of RCTs.

Association between status epilepticus and cardiorespiratory comorbidity in patients with epilepsy: A population-based study.

PURPOSE: This study aimed to evaluate the relationship between status epilepticus (SE) and cardiorespiratory comorbidity in patients with epilepsy. METHODS: We conducted a population-based study using cloud-based aggregated electronic medical records from >53 million patients in the US (Explorys, IBM Watson; January 1999 to November 2020). During the study period, we identified patients with epilepsy with SE. Patients with a history of cardiac arrest, anoxic encephalopathy, and/or cerebrovascular disease were excluded. We reported the prevalences and prevalence ratios of cardiorespiratory and medical comorbidities using age- and sex-adjusted standardization. RESULTS: We identified 494,790 patients with epilepsy and 19,190 had SE. Cardiovascular and respiratory diseases were statistically significantly more prevalent in patients with epilepsy with SE than in those without SE (adjusted prevalence ratio (APR) 1.13, prevalence 68.7% [95% confidence interval (CI): 67.6-69.9] vs 60.9% [95% CI: 60.7-61.1]) and (APR 1.25, 73.1% [95% CI: 71.8-74.3] vs 58.4% [95% CI: 58.1-58.6]), respectively. Aspiration pneumonia (APR 3.12, 0.47% [95% CI: 0.37-0.57] vs 0.15% [95% CI: 0.14-0.16]) and acute respiratory distress syndrome (APR 2.40, 0.47% [95% CI: 0.37-0.57] vs 0.20% [95% CI: 0.18-0.21]) were more prevalent in patients with epilepsy with SE. Common cardiovascular risk factors such as diabetes mellitus (APR 1.13, 17.1% [95% CI: 16.5-17.6] vs 15.1% [95% CI: 1.50-15.2]) and hypertension (APR 1.28, 10.6% [95% CI: 10.2-11.0] vs 8.31% [95% CI: 8.23-8.39]) were also more common in patients with epilepsy with SE. CONCLUSION: In this population-based study, patients with epilepsy with SE had a statistically significantly higher prevalence of cardiorespiratory comorbidities than in those without SE.

Anticoagulation in new-onset postoperative atrial fibrillation: An analysis from the Society of Thoracic Surgeons Adult Cardiac Surgery Database.

Background: New-onset postoperative atrial fibrillation (POAF) is the most common complication after cardiac surgery and is associated with increased long-term stroke and mortality. Anticoagulation has been suggested as a potential therapy, but data on safety and efficacy are scant. Objectives: To determine the association between anticoagulation for POAF and long-term outcomes. Methods: Adult patients with POAF after isolated coronary artery bypass surgery (CABG) were identified through the Society of Thoracic Surgeons Adult Cardiac Surgery Database and linked to the Medicare Database. Propensity-matched analyses were performed for all-cause mortality, stroke, myocardial infarction, and major bleeding for patients discharged with or without anticoagulation. Interaction between anticoagulation and CHA2DS2-VASc score was also assessed. Results: Of 38,936 patients, 9861 (25%) were discharged on oral anticoagulation. After propensity score matching, discharge anticoagulation was associated with increased mortality (hazard ratio [HR] 1.16, 95% confidence interval [CI] 1.06-1.26). There was no difference in ischemic stroke between groups (HR 0.97, 95% CI 0.82-1.15), but there was significantly higher bleeding (HR 1.60, 95% CI 1.38-1.85) among those discharged on anticoagulation. Myocardial infarction was lower in the first 30 days for those discharged on anticoagulation, but this effect decreased over time. The incidence of all complications was higher for patients with CHA2DS2-VASc scores ≥5 compared to patients with scores of 2-4. Anticoagulation did not appear to benefit either subgroup. Conclusion: Anticoagulation is associated with increased mortality after new-onset POAF following CABG. There was no reduction in ischemic stroke among those discharged on anticoagulation regardless of CHA2DS2-VASc score.

Revascularization in ischaemic heart failure with preserved ejection fraction: a nationwide cohort study.

AIMS: Despite the common occurrence of coronary artery disease (CAD) and heart failure (HF) with preserved ejection fraction (HFpEF), there is limited evidence to guide revascularization. METHODS AND RESULTS: We investigated the long-term outcomes of coronary artery bypass grafting (CABG) in patients with HF and significant CAD across the spectrum of ejection fraction, using a large national cohort of patients from the Veteran Affairs (VA) Medical Centers in the US. Patients with HF were stratified into groups, HFpEF, HF with mid-range ejection fraction (HFmrEF), and HF with reduced ejection fraction (HFrEF) and compared to patients with no preoperative HF. We analysed 10 396 patients. Despite an increased hazard in the first year following revascularization, the long-term survival (median follow-up 6.6 years; interquartile range 3.7-10.1) of HFpEF post-CABG was similar to controls (hazard ratio 0.85, 95% confidence interval 0.68-1.06), but survival progressively declined with HFmrEF and HFrEF. Similar trends were seen with recurrent HF hospitalization with lower risk with baseline HFpEF (43.9 ± 6.9/100 patient-years) compared to HFmrEF (65.9 ± 3.8/100 patient-years) and HFrEF (93.4 ± 4.8/100 patient-years). Although HFpEF patients had lower mortality and HF hospitalization post-CABG compared to patients with a lower ejection fraction, they experienced the highest rates of future myocardial infarction. CONCLUSION: Although HFpEF patients with CAD have greater short-term risk post-CABG, their long-term survival is comparable to controls. However, they are at increased risk for HF hospitalizations and myocardial infarction. These data support the safety of CABG in HFpEF patients and suggest continuum of mortality risk for ischaemic HF when stratified by baseline ejection fraction before revascularization.

Adverse events after coronary artery bypass grafting in patients with preoperative metabolic syndrome: A 10-year follow-up of the Veterans Affairs Database.

INTRODUCTION: Data regarding 10-year survival and adverse cardiovascular events in patients with metabolic syndrome (MET) after coronary artery bypass grafting (CABG) is limited. METHODS: We compared 10-year events rates for veterans undergoing isolated CABG (January 1, 2005, to December 31, 2014, follow-up October 31, 2019) stratified by presence of metabolic syndrome (MET+) versus without (MET-). A multivariable weighted Cox model was used to analyze all-cause mortality. Competing risk analysis was used to calculate cumulative event rates for congestive heart failure, myocardial infarction, and cerebrovascular events. The Fine-Gray subhazard model was used to determine adjusted association of MET with myocardial infarction and stroke. Congestive heart failure was modeled as a recurrent-event analysis. RESULTS: Nationally, 9615 adults (median age, 60 years; 98.9% men) underwent isolated coronary artery bypass grafting at 41 centers); among them, 3121 out of 9615 (32.5%) had MET. The prevalence of MET increased from (27.88% in 2005 to 34.02% in 2014; P = .02). MET+ group members were likely younger (median age, 63 vs 64 years; P < .01), White (72% vs 68%), and had more peripheral vascular disease (30% vs 28%; P = .04). Multivessel (72% vs 70%; P = .23) and multiarterial (4% vs 4%; P = .14) grafting was performed equally. With a median follow-up of 6.5 years, survival was similar (P = .26); however, MET was associated with higher risks for myocardial infarction (21% vs 16%; hazard ratio, 1.3; P < .01) and recurrent admissions for congestive heart failure. CONCLUSIONS: Patients with metabolic syndrome undergoing coronary artery bypass grafting have higher 10-year cardiovascular event rates.

Hospitalization for Heart Failure in the United States, UK, Taiwan, and Japan: An International Comparison of Administrative Health Records on 413,385 Individual Patients.

BACKGROUND: Registries show international variations in the characteristics and outcome of patients with heart failure (HF), but national samples are rarely large, and case selection may be biased owing to enrolment in academic centers. National administrative datasets provide large samples with a low risk of bias. In this study, we compared the characteristics, health care resource use (HRU) and outcomes of patients with primary HF hospitalizations (HFH) using electronic health records (EHR) from 4 high-income countries (United States, UK, Taiwan, Japan) on 3 continents. METHODS AND RESULTS: We used electronic health record to identify unplanned HFH between 2012 and 2014. We identified 231,512, 10,991, 36,900, and 133,982 patients with a primary HFH from the United States, the UK, Taiwan, and Japan, respectively. HFH per 100,000 population was highest in the United States and lowest in Taiwan. Fewer patients in Taiwan and Japan were obese or had chronic kidney disease. The length of hospital stay was shortest in the United States (median 4 days) and longer in the UK, Taiwan, and Japan (medians of 7, 9, and 17 days, respectively). HRU during hospitalization was highest in Japan and lowest in UK. Crude and direct standardized in-hospital mortality was lowest in the United States (direct standardized rates 1.8, 95% confidence interval 1.7%-1.9%) and progressively higher in Taiwan (direct standardized rates 3.9, 95% CI 3.8%-4.1%), the UK (direct standardized rates 6.4, 95% CI 6.1%-6.7%), and Japan (direct standardized rates 6.7, 95% CI 6.6%-6.8%). The 30-day all-cause (25.8%) and HF (7.2%) readmissions were highest in the United States and lowest in Japan (11.9% and 5.1%, respectively). CONCLUSIONS: Marked international variations in patient characteristics, HRU, and clinical outcomes exist; understanding them might inform health care policy and international trial design.

Under-recognition of heart failure in patients with atrial fibrillation and the impact of gender: a UK population-based cohort study.

BACKGROUND: Patients with atrial fibrillation (AF) complicated by heart failure (HF) have a poor prognosis. We investigated whether long term loop-diuretic therapy in patients with AF and no known diagnosis of HF, as a potential surrogate marker of undiagnosed HF, is also associated with worse outcomes. METHODS: Adults with incident AF were identified from UK primary and secondary care records between 2004 and 2016. Repeat prescriptions for loop diuretics, without a diagnosis of HF or documented non-cardiac indication, were classified as 'isolated' loop diuretic use. RESULTS: Amongst 124,256 people with incident AF (median 76 years, 47% women), 22,001 (17.7%) had a diagnosis of HF, and 22,325 (18.0%) had isolated loop diuretic use. During 2.9 (LQ-UQ 1-6) years' follow-up, 12,182 patients were diagnosed with HF (incidence rate 3.2 [95% CI 3.1-3.3]/100 person-years). Of these, 3999 (32.8%) had prior isolated loop diuretic use, including 31% of patients diagnosed with HF following an emergency hospitalisation. The median time from AF to HF diagnosis was 3.6 (1.2-7.7) years in men versus 5.1 (1.8-9.9) years in women (p = 0.0001). In adjusted models, patients with isolated loop diuretic use had higher mortality (HR 1.42 [95% CI 1.37-1.47], p < 0.0005) and risk of HF hospitalisation (HR 1.60 [95% CI 1.42-1.80], p < 0.0005) than patients with no HF or loop diuretic use, and comparably poor survival to patients with diagnosed HF. CONCLUSIONS: Loop diuretics are commonly prescribed to patients with AF and may indicate increased cardiovascular risk. Targeted evaluation of these patients may allow earlier HF diagnosis, timely intervention, and better outcomes, particularly amongst women with AF, in whom HF appears to be under-recognised and diagnosed later than in men.

Model-free estimates that complement information obtained from the hazard ratio.

Understand the limitations of the modeling of survival data, especially as pertains to the Cox proportional hazards model.An introduction to model-free estimates of survival, namely, the restricted mean survival time/restricted mean lost time.Use R (The R Foundation for Statistical Computing, Austria) or STATA® (The STATACorp, College Station, TX, USA) to perform analyses and obtain these parameters from a dataset. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12055-021-01167-4.

Pre-operative glycaemic control and long-term survival in diabetic patients after coronary artery bypass grafting.

OBJECTIVES: We analysed the Veteran Affairs data to evaluate the association of pre-operative glycated haemoglobin (HbA1c) and long-term outcome after isolated coronary artery bypass grafting (CABG). METHODS: Veterans with diabetes mellitus and isolated CABG (2006-2018) were divided into 4 groups (I: HbA1c <6.5%, II: HbA1c 6.5-8, III 8-10% and IV: HbA1c >10%). The relationship of pre-operative HbA1c and long-term survival was evaluated with a multivariable Cox proportional hazards model and reported as hazard ratios (HR). The cumulative incidence of secondary end-points [myocardial infarction (MI) and repeat revascularization (percutaneous intervention)] for each group was modelled as competing events with cause-specific Cox proportional hazards models. RESULTS: Overall, 16 190 patients (mean age 64.9 years, male 98%; insulin dependent 53%) with diabetes mellitus underwent isolated CABG. We observed 19.4%, 45.4%, 27% and 8.2% patients in groups I, II, III and IV, respectively. Patients with HbA1c >10% were the youngest (mean age 60.9 years) and had high rates of Insulin dependence (78%). In patients with HbA1c >10%, improvement in levels was observed in 76%. The median follow-up observed was 5.8 (3.2-8.8) years. Compared to the study mean HbA1c (7.3%), mortality rate increased with HbA1c levels >8%, and especially with pre-operative HbA1c levels >9%. Compared to patients with HbA1c <8%, HbA1c 8-10% and >10% were associated with increased MI (HR 1.24 and HR 1.39, respectively) and need for reintervention (HR 1.20 and HR 1.24, respectively). CONCLUSIONS: In patients undergoing CABG, pre-operative HbA1c >8% is associated with the increased risk of mortality and adverse cardiac events.

Survival analysis-part 3: intermediate events and the importance of competing risks.

LEARNING OBJECTIVES: Understand what events can be labelled as intermediate events in survival analysis.Understand why the Kaplan and Meier method cannot be used in the presence of competing events.Regression analysis in the presence of competing events.

Survival analysis-part 2: Cox proportional hazards model.

Learning objectives: 1. To understand the log-rank test and limitations of the log-rank test in comparing survival between groups. 2. To understand the fundamental concepts of the proportional hazards assumption. 3. To understand basic steps in the development of the Cox proportional hazards model and reported hazard ratios. 4. To understand how results of a Cox model run using STATA© (a commonly used proprietary statistical software) can be understood and interpreted. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12055-020-01108-7.