Paul Anaya

Increased mortality among patients taking digoxin—analysis from the AFFIRM study

AIMS Digoxin is frequently used for rate control of atrial fibrillation (AF). It has, however, been associated with increased mortality. It remains unclear whether digoxin itself is responsible for the increased mortality (toxic drug effect) or whether it is prescribed to sicker patients with inherently higher mortality due to comorbidities. The goal of our study was to determine the relationship between digoxin and mortality in patients with AF. METHODS AND RESULTS The association between digoxin and mortality was assessed in patients enrolled in the AF Follow-Up Investigation of Rhythm Management (AFFIRM) trial using multivariate Cox proportional hazards models. Analyses were conducted in all patients and in subsets according to the presence or absence of heart failure (HF), as defined by a history of HF and/or an ejection fraction <40%. Digoxin was associated with an increase in all-cause mortality [estimated hazard ratio (EHR) 1.41, 95% confidence interval (CI) 1.19-1.67, P < 0.001], cardiovascular mortality (EHR 1.35, 95% CI 1.06-1.71, P = 0.016), and arrhythmic mortality (EHR 1.61, 95% CI 1.12-2.30, P = 0.009). The all-cause mortality was increased with digoxin in patients without or with HF (EHR 1.37, 95% CI 1.05-1.79, P = 0.019 and EHR 1.41, 95% CI 1.09-1.84, P = 0.010, respectively). There was no significant digoxin-gender interaction for all-cause (P = 0.70) or cardiovascular (P = 0.95) mortality. CONCLUSION Digoxin was associated with a significant increase in all-cause mortality in patients with AF after correcting for clinical characteristics and comorbidities, regardless of gender or of the presence or absence of HF. These findings call into question the widespread use of digoxin in patients with AF.

Enhanced proliferation and migration of vascular smooth muscle cells in response to vascular injury under hyperglycemic conditions is controlled by β3 integrin signaling

Atheroma formation and restenosis following percutaneous vascular intervention involve the growth and migration of vascular smooth muscle cells (SMCs) into neointimal lesions, in part due to changes in the extracellular matrix. While some clinical studies have suggested that, in comparison to non-diabetics, beta3 integrin inhibition in diabetic patients confers protection from restenosis, little is known regarding the role of beta3 integrin inhibition on SMC responses in this context. To understand the molecular mechanisms underlying integrin-mediated regulation of SMC function in diabetes, we examined SMC responses in diabetic mice deficient in integrin beta3 and observed that the integrin was required for enhanced proliferation, migration and extracellular regulated kinase (ERK) activation. Hyperglycemia-enhanced membrane recruitment and catalytic activity of PKCbeta in an integrin beta3-dependent manner. Hyperglycemia also promoted SMC filopodia formation and cell migration, both of which required alphaVbeta3, PKCbeta, and ERK activity. Furthermore, the integrin-kinase association was regulated by the alphaVbeta3 integrin ligand thrombospondin and the integrin modulator Rap1 under conditions of hyperglycemia. These results suggest that there are differences in SMC responses to vascular injury depending on the presence or absence of hyperglycemia and that SMC response under hyperglycemic conditions is largely mediated through beta3 integrin signaling.

QRS duration predicts death and hospitalization among patients with atrial fibrillation irrespective of heart failure: evidence from the AFFIRM study

AIMS The association of QRS duration (QRSd) with morbidity and mortality is understudied in patients with atrial fibrillation (AF). We sought to assess any association of prolonged QRS with increased risk of death or hospitalization among patients with AF. METHODS AND RESULTS QRS duration was retrieved from the baseline electrocardiograms of patients enroled in the Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) study and divided into three categories: <90, 90-119, ≥120 ms. Cox models were applied relating the hazards of mortality and hospitalizations to QRSd. Among 3804 patients with AF, 593 died and 2305 were hospitalized. Compared with those with QRS < 90 ms, patients with QRS ≥ 120 ms, had an increased mortality [hazard ratio (HR) 1.61, 95% confidence interval (CI): 1.29-2.03, P < 0.001] and hospitalizations (HR 1.14, 95% CI: 1.07-1.34, P = 0.043) over an average follow-up of 3.5 years. Importantly, for patients with QRS 90-119 ms, mortality and hospitalization were also increased (HR 1.31, P = 0.005 and 1.11, P = 0.026, respectively). In subgroup analysis based on heart failure (HF) status (previously documented or ejection fraction <40%), mortality was increased for QRS ≥ 120 ms patients with (HR 1.87, P < 0.001) and without HF (HR 1.63, P = 0.02). In the QRS 90-119 ms group, mortality was increased (HR 1.38, P = 0.03) for those with HF, but not significantly among those without HF (HR 1.23, P = 0.14). CONCLUSION Among patients with AF, QRSd ≥ 120 ms was associated with a substantially increased risk for mortality (all-cause, cardiovascular, and arrhythmic) and hospitalization. Interestingly, an increased mortality was also observed among those with QRS 90-119 ms and concomitant HF.

The Evolving Role of Cardiac Troponin in the Evaluation of Cardiac Disorders

Due to their tissue specificity and ease of detection, the cardiac troponins (cTn) have emerged as the most important and most utilized biomarkers for the diagnosis of acute myocardial infarction (AMI). The recent achievement of greater sensitivity by cTn assay systems, however, has resulted in the detection of cTn in a wide array of medical conditions, highlighting myocardial cellular necrosis as a feature in several, seemingly unrelated medical conditions, yet complicating the interpretation of a positive test. Since elevated cTn levels are associated with worse clinical outcomes and, thereby, influence medical decisions, careful consideration should be given to the method by which these biomarkers are measured, the patient population on which the test is being applied, and applicable thresholds based on particular clinical conditions. The objective of this review is to trace the clinical evolution of the cTn biomarker from a test for AMI to a general marker of myocardial cellular necrosis with clinically important prognostic information.

Coronary artery calcification in CKD-5D patients is tied to adverse cardiac function and increased mortality .

Background: Coronary artery calcification (CAC) is common in patients with chronic kidney disease on hemodialysis (CKD-5D) and is an important predictor of mortality. However, cardiac functional links between CAC and mortality have not been well established. This study tested the hypothesis that CAC increases mortality by adversely affecting cardiac function. Methods: Patients were recruited from 37 regional dialysis centers. 2-D and Doppler echocardiographic analyses were performed, and CAC was measured using 64-slice computed tomography. Relationships between CAC and echocardiographic measures of left ventricular (LV) function were analyzed. Survival was assessed with median follow-up of 37 months. Results: There were 157 patients: 59% male, 46% Caucasian, 48% diabetic. Median age was 55 years, and median duration of CKD-5D was 45 months. Agatston CAC scores > 100 were found in 69% of patients, with 51% having a score > 400. CAC was associated with measures of LV systolic and diastolic function (global longitudinal strain (GLS; rho = 0.270, p = 0.004)), peak LV systolic velocity (rho = –0.259, p = 0.004), and estimate of LV filling pressure (E:E’; rho = 0.286, p = 0.001). Multivariate regression confirmed these relationships after adjustment for age, gender, LV ejection fraction, and coronary artery disease. Valvular calcification varied linearly with CAC (p < 0.05). Both LV diastolic and systolic functional measures were significant predictors of mortality, the strongest of which was LV diastolic dysfunction. Conclusions: These findings show a link between CAC, cardiac function, and mortality in CKD-5D. LV diastolic function (E:E’), peak LV systolic velocity, and GLS are independent predictors of mortality. Valvular calcification may be an important marker of CAC in CKD-5D. These effects on cardiac function likely explain the high mortality with CKD-5D and describe a potentially-valuable role for echocardiography in the routine management of these patients.

Sildenafil in heart failure with reactive pulmonary hypertension (Sildenafil HF) clinical trial (rationale and design)

In this article, we present the rationale and design of the Sildenafil HF trial (ClinicalTrials.gov identifier: NCT02304705). We will randomize patients with heart failure and reactive pulmonary hypertension (pulmonary capillary wedge pressure > 15 mmHg, pulmonary vascular resistance > 3 Wood units) into two groups: the treatment group receiving sildenafil 20 mg 3 times a day and a matching placebo group. The duration of intervention will be 3 months. The primary outcome is 6-minute walk distance. Key features of this trial include (1) that reactive pulmonary hypertension is an inclusion criterion, (2) that patients will be enrolled regardless of left ventricular ejection fraction, and (3) that clinical stability in the 3 months preceding enrollment is not required.

CT Angiography for Emergency Decision Making in Acute Coronary Syndromes: Applying Future Vision Now

infarction (AMI) from the ED, physicians have to err on the side of admitting patients to rule out AMI. Strategies to streamline this process, including the utilization of chest pain centers, have been shown to be effective at reducing unnecessary hospital admissions, but have not been widely adopted [3–6]. Consequently, more efficient means of risk stratifying patients presenting to the ED with chest pain are needed. Cardiac CTangiography allows for the noninvasive, anatomic assessment of the presence of coronary artery disease. It is associatedwith a negative predictive value of nearly 100% for intermediate-term cardiovascular events and represents a potentially cost-effective tool for the risk stratification of patients presenting to the ED with a suspected ACS [2, 7]. The American College of Radiology Imaging Network (ACRIN) PA 4005 clinical trial is the latest published comparativeeffectiveness trial undertaken to determine whether cardiac CTangiography (CCTA) can be applied to expedite discharge from the ED by more efficiently identifying chest-pain patients presenting to the ED who do not have significant coronary artery disease (CAD).

Diagnosis of subclinical coronary atherosclerosis: challenges and insight

BACKGROUND In the last 30 years, significant progress has been made in our ability to stratify individuals on the basis of cardiovascular (CV) risk, allowing those at the highest risk of CV disease to be more aggressively treated. In the US, this has resulted in a gradual decline in CV mortality. Whether medical interventions in individuals at low-to-intermediate risk for CV disease translate into improved outcomes remains an open question, and depends largely on our ability to diagnose atherosclerosis at an earlier stage than is possible at present. OBJECTIVE The objective of this paper is to review current literature on the diagnosis of subclinical atherosclerosis. METHODS Medline searches for peer-reviewed publications using search terms relevant to the diagnosis of subclinical atherosclerosis were performed. RESULTS Data from these references are discussed and grouped into three broad categories, including biomarkers, imaging and genomics. CONCLUSION The recent identification of new biomarkers and genes associated with atherosclerosis combined with recent advances in cardiovascular imaging has enhanced our understanding of atherosclerosis. These techniques show promise in their ability to detect subclinical atherosclerosis indepenedent of conventional clinical CV risk factors. Further research is needed better to define roles for these technologies in the diagnosis of atherosclerosis among asymptomatic individuals.

CAN THE VENTRICULAR-ARTERIAL COUPLING RATIO PREDICT RESPONSE TO CARDIAC RESYNCHRONIZATION THERAPY FOR PATIENTS MEETING CLASS IIA INDICATIONS?

Background: Cardiac Resynchronization Therapy (CRT) improves outcomes in low EF patients with left bundle branch block (LBBB) ≥ 150 ms, yet predicting CRT response among patients with shorter QRS durations or non-LBBB patterns remains a clinical challenge. Ventricular-arterial coupling (VAC) is a

Old Dog, New Tricks - Usefulness of the ECG in Monitoring Acute Rejection Post Cardiac Transplantation

Electrocardiographic abnormalities have been described in the setting of acute rejection following orthotopic cardiac transplantation. The following is a brief commentary related to an interesting case report by Goldraich et al. which was recently published in the VAD Journal.