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.

Multi-variable biomarker approach in identifying incident heart failure in chronic kidney disease: results from the Chronic Renal Insufficiency Cohort study.

AIMS: Heart failure (HF) is one of the leading causes of cardiovascular morbidity and mortality in the ever-growing population of patients with chronic kidney disease (CKD). There is a need to enhance early prediction to initiate treatment in CKD. We sought to study the feasibility of a multi-variable biomarker approach to predict incident HF risk in CKD. METHODS AND RESULTS: We examined 3182 adults enrolled in the Chronic Renal Insufficiency Cohort (CRIC) without prevalent HF who underwent serum/plasma assays for 11 blood biomarkers at baseline visit (B-type natriuretic peptide [BNP], CXC motif chemokine ligand 12, fibrinogen, fractalkine, high-sensitivity C-reactive protein, myeloperoxidase, high-sensitivity troponin T (hsTnT), fibroblast growth factor 23 [FGF23], neutrophil gelatinase-associated lipocalin, fetuin A, aldosterone). The population was randomly divided into derivation (n = 1629) and validation (n = 1553) cohorts. Biomarkers that were associated with HF after adjustment for established HF risk factors were combined into an overall biomarker score (number of biomarkers above the Youden's index cut-off value). Cox regression was used to explore the predictive role of a biomarker panel to predict incident HF. A total of 411 patients developed incident HF at a median follow-up of 7 years. In the derivation cohort, four biomarkers were associated with HF (BNP, FGF23, fibrinogen, hsTnT). In a model combining all four biomarkers, BNP (hazard ratio [HR] 2.96 [95% confidence interval 2.14-4.09]), FGF23 (HR 1.74 [1.30-2.32]), fibrinogen (HR 2.40 [1.74-3.30]), and hsTnT (HR 2.89 [2.06-4.04]) were associated with incident HF. The incidence of HF increased with the biomarker score, to a similar degree in both derivation and validation cohorts: from 2.0% in score of 0% to 46.6% in score of 4 in the derivation cohort to 2.4% in score of 0% to 43.5% in score of 4 in the validation cohort. A model incorporating biomarkers in addition to clinical factors reclassified risk in 601 (19%) participants (352 [11%] participants to higher risk and 249 [8%] to lower risk) compared with clinical risk model alone (net reclassification improvement of 0.16). CONCLUSION: A basic panel of four blood biomarkers (BNP, FGF23, fibrinogen, and hsTnT) can be used as a standalone score to predict incident HF in patients with CKD allowing early identification of patients at high-risk for HF. Addition of biomarker score to clinical risk model modestly reclassifies HF risk and slightly improves discrimination.

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.

Thrombosis of native rheumatic mitral valve: A case report.

Spontaneous native mitral valve leaflet thrombosis is an exceedingly rare phenomenon. Here, we describe the case of a 71-year-old woman with rheumatic mitral stenosis who presented with cardiogenic shock. She was found to have a thrombus on her native mitral valve despite being on anticoagulation and without a clear associated hypercoagulable comorbidity. The patient underwent mitral valve replacement with favorable outcomes. This case sheds light on the inflammatory and prothrombotic nature of rheumatic valvular disease.

Inflammatory Markers and Risk of Heart Failure With Reduced to Preserved Ejection Fraction.

Chronic systemic inflammation is associated with an increased risk of heart failure (HF). We sought to determine the association between biomarkers of systemic inflammation interleukin (IL)-6, IL-2, tumor necrosis factor alpha (TNF-α), and C-reactive protein (CRP) with those of HF and its subtypes. We hypothesize that inflammatory biomarkers IL-6, IL-2, TNF-α, and CRP are associated with HF and its subtypes. We included participants from the Multi-Ethnic Study of Atherosclerosis (a prospective population-based cohort study [2000 to 2002]), without a history of HF, and with available baseline inflammatory biomarkers. We explored the association of IL-6, IL-2, TNF-α, and CRP with incident HF, HF with reduced ejection fraction (left ventricular ejection fraction [LVEF] <40%, HFrEF), HF with midrange EF (LVEF 40% to 50%, HFmrEF), and HF with preserved ejection fraction (LVEF >50%, HFpEF). Among 6,814 participants, 195 developed HF over 10.9 years (56 HFrEF, 30 HFmrEF, and 57 HFpEF). In the models adjusted for clinical risk factors of HF, IL-6 (hazard ratio [HR] 1.33 per doubling; 95% confidence interval [CI] 1.10 to 1.60), TNF-α (HR 2.49 per doubling; 95% CI 1.18 to 5.28), and CRP (HR 1.18 per doubling; 95% CI 1.06 to 1.30) were associated with all HF, and IL-6 (HR 1.51 per doubling; 95% CI 1.09 to 2.10) and CRP (HR 1.21 per doubling; 95% CI: 1.01 to 1.45) were associated with incident HFpEF, whereas none of the examined biomarkers were associated with HFmrEF or HFrEF. In conclusion, inflammatory biomarkers (IL-6, TNF-α, and CRP) are independently associated with incident HF. IL-6 and CRP are associated with incident HFpEF but not HFrEF or HFmrEF. These findings suggest that activation of the IL-6/CRP pathway (as cause, consequence, or epiphenomenon) may be unique to HFpEF.

MELD score is predictive of 90-day mortality after veno-arterial extracorporeal membrane oxygenation support.

BACKGROUND: The Model for End-Stage Liver Disease (MELD) score was originally described as a marker of survival in chronic liver disease. More recently, MELD and its derivatives, MELD excluding INR (MELD-XI) and MELD with sodium (MELD-Na), have been applied more broadly as outcome predictors in heart transplant, left ventricular assist device placement, heart failure, and cardiogenic shock, with additional promising data to support the use of these scores for prediction of survival in those undergoing veno-arterial extracorporeal membrane oxygenation (VA ECMO). METHODS: This study assessed the prognostic impact of MELD in patients with cardiogenic shock undergoing VA ECMO via a single-center retrospective review from January 2014 to March 2020. MELD, MELD-XI, and MELD-Na scores were calculated using laboratory values collected within 48 h of VA ECMO initiation. Multivariate Cox regression analyses determined the association between MELD scores and the primary outcome of 90-day mortality. Receiver operating characteristics (ROC) were used to estimate the discriminatory power for MELD in comparison with previously validated SAVE score. RESULTS: Of the 194 patients, median MELD was 20.1 (13.7-26.2), and 90-day mortality was 62.1%. There was a significant association between MELD score and mortality up to 90 days (hazard ratio (HR) = 1.945, 95% confidence interval (95% CI) = 1.244-3.041, p = 0.004) after adjustment for age, indication for VA ECMO, and sex. The prognostic significance of MELD score for 90-day mortality revealed an AUC of 0.645 (95% CI = 0.565-0.725, p < 0.001). MELD-Na score and MELD-XI score were not associated with mortality. CONCLUSION: MELD score accurately predicts long-term mortality and may be utilized as a valuable decision-making tool in patients undergoing VA ECMO.

Myeloperoxidase is Independently Associated with Incident Heart Failure in Patients with Coronary Artery Disease and Kidney Disease.

Chronic kidney disease (CKD) is associated with high cardiovascular risk and mortality. Myeloperoxidase (MPO) has been linked to adverse events in patients with mild-moderate CKD. We sought to investigate whether MPO levels are associated with adverse outcomes in patients with CKD. We studied participants with mild to moderate CKD in the prospective chronic renal insufficiency cohort (CRIC). We followed patients for incident heart failure (HF), death, and composite outcome (myocardial infarction, incident peripheral arterial disease, cerebrovascular accident and death). A total of 3872 patients were included (2702 without CVD, 1170 with CVD). After multiple adjustments, doubling of MPO in patients with prior CAD was associated with risk of HF (HR 1.15 [1.01-1.30], P = 0.032) and mortality (HR 1.16 [1.05-1.30], P = 0.005), and composite outcome of MI, PAD, CVA and death (HR 1.12 [1.01-1.25], P = 0.031). In this cohort of patients with mild to moderate CKD and CAD, MPO levels are independently associated with incident HF, all-cause mortality, and a composite outcome.

Benign Metastasizing Leiomyoma in the Heart of a 45-Year-Old Woman.

We report a rare case of benign metastasizing leiomyoma in the heart of a 45-year-old woman 2 years after a uterine leiomyoma had been discovered during hysterectomy. Computed tomograms at presentation showed a large mixed cystic mass in the pelvis and bilateral lung nodules suggestive of metastatic disease. A large cardiac mass, attached to the chordae of the tricuspid valve and later shown to be histopathologically consistent with uterine leiomyoma, was successfully resected through a right atriotomy. This case suggests that benign metastasizing leiomyoma should be considered in the differential diagnosis of right-sided cardiac tumors.

Gerbode defect following surgical mitral valve replacement and tricuspid valve repair: a case report.

BACKGROUND: Gerbode defect is a congenital or acquired communication between the left ventricle and right atrium. While the defect is becoming a more well-recognized complication of cardiac surgery, it presents a diagnostic and therapeutic challenge for providers. This case highlights the predisposing factors and imaging features that may assist in the diagnosis of Gerbode defect, as well as potential approaches to treatment. CASE SUMMARY: We report a patient with severe mitral stenosis as a result of remote mediastinal radiation who underwent extensive decalcification during surgical mitral valve replacement and tricuspid valve repair. Following the procedure, he developed progressive heart failure refractory to medical management. Extensive workup ultimately led to the diagnosis of iatrogenic acquired Gerbode defect. Close collaboration between adult cardiology, cardiothoracic surgery, and the congenital cardiology services led to an optimal treatment plan involving percutaneous closure of the defect. DISCUSSION: Gerbode defect is a rare complication of invasive procedures involving the interventricular septum or its nearby structures. An understanding of the key echocardiographic features will aid providers in timely diagnosis. Percutaneous repair should be strongly considered for patients who may be poor surgical candidates.

Causes and predictors of 30-day readmissions in patients with cardiogenic shock requiring extracorporeal membrane oxygenation support.

BACKGROUND: Cardiogenic shock is associated with significant mortality, morbidity, and healthcare cost. Utilization of extracorporeal membrane oxygenation in cardiogenic shock has increased in the United States. We sought to identify the rates and predictors of hospital readmissions in patients with cardiogenic shock after weaning from extracorporeal membrane oxygenation. METHODS: Using the 2016 Nationwide Readmission Database, we identified all patients (⩾18 years) with cardiogenic shock (ICD-10 CM R57.0) that have been implanted with extracorporeal membrane oxygenation (ICD-10-PSC of 5A15223) and were discharged alive (January-November 2016). We explored the rates, causes, and predictors of all-cause readmissions within 30 days. RESULTS: Out of 69,040 admissions with cardiogenic shock, 1641 (2.4%) underwent extracorporeal membrane oxygenation (581 were implanted during or after cardiac surgery). A total of 734 (44.7%) patients of all extracorporeal membrane oxygenations survived to discharge, and 661 were available for analysis. Out of those, 158 (23.9%) were readmitted within 30 days of discharge. More than 50% of these readmissions happened within the first 11 days. Out of 158 patients who were readmitted, 12 (7.4%) died during the readmission hospitalization. Leading causes of readmission were cardiovascular (31.6%) (heart failure: 24.1%, arrhythmia: 20.6%, neurovascular: 10.3%, hypertension: 10.3%, and endocarditis: 6.8%), followed by complications of medical/device care (17.7%), infection (11.3%), and gastrointestinal/liver (10.1%) complications. Factors associated with readmissions include the following: discharge to skilled nursing facility or with home healthcare (odds ratio: 2.10; 95% confidence interval: 1.18-3.74), durable ventricular assisted device implantation, asthma, and chronic liver disease. CONCLUSION: Patients with cardiogenic shock who underwent extracorporeal membrane oxygenation had a readmission rate. Identifying patients at high risk of readmissions might help improve outcomes.

Linezolid Toxicity and Mitochondrial Susceptibility: A Novel Neurological Complication in a Lebanese Patient.

The recent rise in the use of linezolid to treat a variety of resistant pathogens has uncovered many side effects. Some patients develop lactic acidosis, myelosuppression, optic or peripheral neuropathies, and myopathies. We evaluated an elderly patient who presented to the Emergency Room with linezolid toxicity and a novel neurologic complication characterized by bilateral globi pallidi necrosis. Mitochondrial ribosome inhibition was described to be the predisposing factor. The patient belongs to the mitochondrial J1 haplotype known to be associated with side effects of the drug. We recommend based on the molecular profile of the illness pretreatment considerations and complication management.

Inflammatory Bowel Disease Environmental Risk Factors: A Population-Based Case-Control Study of Middle Eastern Migration to Australia.

BACKGROUND & AIMS: The incidences of the inflammatory bowel diseases (IBDs) Crohn's disease (CD) and ulcerative colitis (UC) are increasing, indicating gene-environment interactions. Migrants from low-IBD-prevalence countries to a high-prevalence country may help identify the relative contribution of environmental risk factors compared with native Caucasians. METHODS: This prospective case-control study evaluated IBD environmental risk factors of Middle Eastern migrants (MEM) in Australia compared with matched Caucasian IBD subjects, MEM controls, Caucasian controls, and controls in the Middle East using adjusted odds ratios (aOR). RESULTS: A total of 795 subjects were recruited: 154 MEM cases (75 CD; 79 UC), 153 MEM controls, 162 Caucasian cases (85 CD; 77 UC), 173 Caucasian controls, and 153 controls in Lebanon. Smoking increased CD risk in MEM and Caucasians and reduced UC risk in Caucasians (aOR, 0.77; 95% CI, 0.41-0.98) but not MEM (aOR, 1.45; 95% CI, 0.80-2.62). Antibiotic use reduced the risk of MEM CD (aOR, 0.27; 95% CI, 0.11-0.67) and UC (aOR, 0.38; 95% CI, 0.18-0.80), but increased the risk in Caucasians (CD: aOR, 5.24; 95% CI, 2.13-12.90; and UC: aOR, 6.82; 95% CI, 2.67-17.38). Most hygiene markers (rural dwelling, pet ownership, pet feeding, and farm animal contact) reduced CD and UC risk in MEM (P < .05). In contrast, in Caucasians these hygiene markers lacked significance. Other significant risk factors include IBD family history, appendectomy, tonsillectomy, and breastfeeding. CONCLUSIONS: Differential IBD environmental risk factors exist between migrants and native Caucasians, indicating a dynamic interplay between environmental factors and IBD risk for immigrants that is distinct to those factors most relevant in native Caucasians.