David P. Kao

Left Ventricular Dysfunction in Patients Receiving Cardiotoxic Cancer Therapies: Are Clinicians Responding Optimally?

OBJECTIVES The purpose of this study was to examine treatment practices for cancer therapy-associated decreased left ventricular ejection fraction (LVEF) detected on echocardiography and whether management was consistent with American College of Cardiology/American Heart Association guidelines. BACKGROUND Patients treated with anthracyclines or trastuzumab are at risk of cardiotoxicity. Decreased LVEF represents a Class I indication for drug intervention according to American College of Cardiology/American Heart Association guidelines. METHODS Patients receiving anthracycline or trastuzumab at Stanford University from October 2005 to October 2007 and who had undergone echocardiography before and after receiving an anthracycline or trastuzumab were identified. Chart review examined chemotherapy regimens, cardiac risk factors, imaging results, concomitant medications, and cardiology consultations. RESULTS Eighty-eight patients received therapy with an anthracycline or trastuzumab and had a pre-treatment and follow-up echocardiogram. Ninety-two percent were treated with anthracyclines, 17% with trastuzumab after an anthracycline, and 8% with trastuzumab without previous treatment with anthracycline. Mean baseline LVEF was 60%, with 14% having a baseline <55%. Forty percent had decreased LVEF (<55%) after anthracycline and/or trastuzumab treatment. Of these patients, 40% received angiotensin-converting enzyme inhibitor or angiotensin receptor blocker therapy, 51% beta-blocker therapy, and 54% cardiology consultation. Of patients with asymptomatic decreased LVEF, 31% received angiotensin-converting enzyme inhibitor or angiotensin receptor blocker therapy, 35% beta-blocker therapy, and 42% cardiology consultation. Of those with symptomatic decreased LVEF, 67% received angiotensin-converting enzyme inhibitor or angiotensin receptor blocker therapy, 100% beta-blocker therapy, and 89% cardiology consultation. CONCLUSIONS Many cancer survivors are not receiving treatment consistent with heart failure guidelines. There is substantial opportunity for collaboration between oncologists and cardiologists to improve the care of oncology patients receiving cardiotoxic therapy.

Can doctors and nurses recognize depression in patients hospitalized with an acute myocardial infarction in the absence of formal screening

Objective: The objective of this study was to determine the ability of cardiovascular healthcare workers to assess the presence or absence of symptoms of depression in patients hospitalized with acute myocardial infarction (AMI) in the absence of formal screening. Methods: Patients admitted with AMI underwent screening using the Beck Depression Inventory (BDI) administered by a research assistant. The cardiovascular nurse, medicine resident or intern, and attending cardiologist caring for the patient were then approached (blinded to the BDI results) and asked to assess, using a visual analog scale, whether the patient had symptoms that would warrant further evaluation for depression. Results: BDI screening and at least one provider assessment were completed for 60 patients with AMI. A total of 18 of 60 patients (30.0%) had a BDI score of ≥10. Symptoms of depression were considered not present in 24 of 32 patient assessments when the BDI was ≥10 (75% false-negatives). The mean BDI score of patients assessed as depressed by at least one provider (6.7 ± 6.3) was no different from the mean BDI score of patients assessed as not depressed (7.5 ± 7.2, p = .67). Overall, there was little correlation between BDI scores and provider assessments, and this was not influenced by provider type or provider gender. Conclusions: Cardiovascular nurses and medicine residents and interns underrecognize depression in patients with AMI in the absence of formal screening. Formal screening for symptoms of depression should be considered part of routine AMI care. AMI = acute myocardial infarction; BDI = Beck Depression Inventory; CPK = creatine phosphokinase; D-VAS = depression–visual analog scale; DIS = Diagnostic Interview Schedule.

Characterization of subgroups of heart failure patients with preserved ejection fraction with possible implications for prognosis and treatment response

Patients with heart failure and preserved ejection fraction (HFpEF) have a poor prognosis, and no therapies have been proven to improve outcomes. It has been proposed that heart failure, including HFpEF, represents overlapping syndromes that may have different prognoses. We present an exploratory study of patients enrolled in the Irbesartan in Heart Failure with Preserved Ejection Fraction Study (I‐PRESERVE) using latent class analysis (LCA) with validation using the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM)‐Preserved study to identify HFpEF subgroups.

Renal failure and rhabdomyolysis associated with sitagliptin and simvastatin use

Background  Sitagliptin is a new oral glucose‐lowering medication that acts via the incretin hormone system. The most common side‐effects are headache and pharyngitis, and few serious adverse events were observed during clinical trials. Dose adjustment is recommended in renal insufficiency, but long‐term safety experience is limited.

Carcinoembryonic Antigen Family Receptor Recognition by Gonococcal Opa Proteins Requires Distinct Combinations of Hypervariable Opa Protein Domains

ABSTRACT Neisserial Opa proteins function as a family of adhesins that bind heparan sulfate proteoglycan (HSPG) or carcinoembryonic antigen family (CEACAM) receptors on human host cells. In order to define the CEACAM binding domain on Opa proteins, we tested the binding properties of a series of gonococcal (strain MS11) recombinants producing mutant and chimeric Opa proteins with alterations in one or more of the four surface-exposed loops. Mutagenesis demonstrated that the semivariable domain, present in the first loop, was completely dispensable for CEACAM binding. In contrast, the two hypervariable (HV) regions present in the second and third loops were essential for binding; deletion of either domain resulted in loss of receptor recognition. Deletion of the fourth loop resulted in a severe decrease in Opa expression at the cell surface and could therefore not be tested for CEACAM binding. Chimeric Opa variants, containing combinations of HV regions derived from different CEACAM binding Opa proteins, lost most of their receptor binding activity. Some chimeric variants gained HSPG binding activity. Together, our results indicate that full recognition of CEACAM receptors by Opa proteins requires a highly coordinate interplay between both HV regions. Furthermore, shuffling of HV regions may result in novel HSPG receptor binding activity.

Safety of Ventricular Tachycardia Ablation in Clinical Practice

Background—Outcomes of ventricular tachycardia (VT) ablation have been described in clinical trials and single-center studies. We assessed the safety of VT ablation in clinical practice. Methods and Results—Using administrative hospitalization data between 1994 and 2011, we identified hospitalizations with primary diagnosis of VT (International Classification of Diseases-9 Clinical Modification code: 427.1) and cardiac ablation (International Classification of Diseases-9 Clinical Modification code: 37.34). We quantified in-hospital adverse events (AEs), including death, stroke, intracerebral hemorrhage, pericardial complications, hematoma or hemorrhage, blood transfusion, or cardiogenic shock. Secondary outcomes included major AEs (stroke, tamponade, or death) and death. Multivariable mixed effects models identified patient and hospital characteristics associated with AEs. Of 9699 hospitalizations with VT ablations (age, 56.5±17.6; 60.1% men), AEs were reported in 825 (8.5%), major AEs in 295 (3.0%), and death in 110 (1.1%). Heart failure had the strongest association with death (odds ratio, 5.52; 95% confidence interval, 2.97–10.3) and major AE (odds ratio, 2.99; 95% confidence interval, 2.15–4.16). Anemia (odds ratio, 4.84; 95% confidence interval, 3.79–6.19) and unscheduled admission (odds ratio, 1.64; 95% confidence interval, 1.37–1.97) were associated with AEs. During the study period, incidence of AEs increased from 9.2% to 12.8% as did the burden of AE risk factors (0.034 patient/y; P<0.001). Hospital volume >25 cases/y was associated with fewer AEs compared with lower volume centers (6.4% versus 8.8%; P=0.008). Conclusions—VT ablation–associated AE rates in clinical practice are similar to those reported in the literature. Over time rates have increased as have the number of AE risk factors per patient. Ablations done electively and at hospitals with higher procedural volume are associated with lower incidence of AEs.

Effect of bucindolol on heart failure outcomes and heart rate response in patients with reduced ejection fraction heart failure and atrial fibrillation

There is little evidence of beta‐blocker treatment benefit in patients with heart failure and reduced left ventricular ejection fraction (HFREF) and atrial fibrillation (AF). We investigated the effects of bucindolol in HFREF patients with AF enrolled in the Beta‐blocker Evaluation of Survival Trial (BEST).

Therapeutic Molecular Phenotype of β-Blocker–Associated Reverse-Remodeling in Nonischemic Dilated Cardiomyopathy

Background—When &bgr;-blockers produce reverse-remodeling in idiopathic dilated cardiomyopathy, they partially reverse changes in fetal–adult/contractile protein, natriuretic peptide, SR-Ca2+-ATPase gene program constituents. The objective of the current study was to further test the hypothesis that reverse-remodeling is associated with favorable changes in myocardial gene expression by measuring additional contractile, signaling, and metabolic genes that exhibit a fetal/adult expression predominance, are thyroid hormone-responsive, and are regulated by &bgr;1-adrenergic receptor signaling. A secondary objective was to identify which of these putative regulatory networks is most closely associated with observed changes. Methods and Results—Forty-seven patients with idiopathic dilated cardiomyopathy (left ventricular ejection fraction, 0.24±0.09) were randomized to the adrenergic-receptor blockers metoprolol (&bgr;1-selective), metoprolol+doxazosin (&bgr;1/&agr;1), or carvedilol (&bgr;1/&bgr;2/&agr;1). Serial radionuclide ventriculography and endomyocardial biopsies were performed at baseline, 3, and 12 months. Expression of 50 mRNA gene products was measured by quantitative polymerase chain reaction. Thirty-one patients achieved left ventricular ejection fraction reverse-remodeling response defined as improvement by ≥0.08 at 12 months or by ≥0.05 at 3 months (&Dgr; left ventricular ejection fraction, 0.21±0.10). Changes in gene expression in responders versus nonresponders were decreases in NPPA and NPPB and increases in MYH6, ATP2A2, PLN, RYR2, ADRA1A, ADRB1, MYL3, PDFKM, PDHX, and CPT1B. All except PDHX involved increase in adult or decrease in fetal cardiac genes, but 100% were concordant with changes predicted by inhibition of &bgr;1-adrenergic signaling. Conclusions—In addition to known gene expression changes, additional calcium-handling, sarcomeric, adrenergic signaling, and metabolic genes were associated with reverse-remodeling. The pattern suggests a fetal–adult paradigm but may be because of reversal of gene expression controlled by a &bgr;1-adrenergic receptor gene network. Clinical Trial Registration—URL: www.clinicaltrials.gov. Unique Identifier: NCT01798992.

Arrhythmia associated with buprenorphine and methadone reported to the food and drug administration

AIM To assess the relative frequency of reporting of adverse events involving ventricular arrhythmia, cardiac arrest, corrected QT interval (QTc) prolongation or torsade de pointes to the US Food and Drug Administration (FDA) between buprenorphine and methadone. DESIGN Retrospective pharmacoepidemiological study. SETTING Adverse drug events reported spontaneously to the FDA between 1969 and June 2011 originating in 196 countries (71% events from the United States). CASES Adverse event cases mentioning methadone (n = 14 915) or buprenorphine (n = 7283) were evaluated against all other adverse event cases (n = 4 796 017). MEASUREMENTS The primary outcome was the composite of ventricular arrhythmia or cardiac arrest. The secondary outcome was the composite of QTc prolongation or torsade de pointes. The proportional reporting ratio (PRR) was used to identify disproportionate reporting defined as a PRR > 2, χ(2) error > 4, with ≥ 3 cases. FINDINGS There were 132 (1.8%) ventricular arrhythmia/cardiac arrest and 19 (0.3%) QTc prolongation/torsade de pointes cases associated with buprenorphine compared with 1729 (11.6%) ventricular arrhythmia/cardiac arrest and 390 (2.6%) QTc prolongation/torsade de pointes cases involving methadone. PRRs associated with buprenorphine were not significant for ventricular arrhythmia/cardiac arrest (1.10, 95%, confidence interval (0.93-1.31, χ(2)  = 1.2) or QTc prolongation/torsade de pointes (1.03, 95% CI = 0.66-1.62, χ(2)  = 0.01), but were for methadone (7.20, 95% CI = 6.88-7.52, χ(2)  = 8027; 10.7, 95% CI = 9.66-11.8, χ(2)  = 1538, respectively). CONCLUSION In spontaneously reported adverse events, methadone is associated with disproportionate reporting of cardiac arrhythmias, whereas buprenorphine is not. Although these findings probably reflect clinically relevant differences, a causal connection cannot be presumed and disproportionality analysis cannot quantify absolute risk per treatment episode. Population-based studies to definitively quantify differential incidence rates are warranted.

Trends in reporting methadone-associated cardiac arrhythmia, 1997-2011: an analysis of registry data.

BACKGROUND Long-acting opioids are a leading cause of accidental death in the United States, and methadone is associated with greater mortality rates. Whether this increase is related to the proarrhythmic properties of methadone is unclear. OBJECTIVE To describe methadone-associated arrhythmia events reported in the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS). DESIGN Description of national adverse event registry data before and after publication of a 2002 report describing an association between methadone and arrhythmia. SETTING FAERS, November 1997 and June 2011. PATIENTS Adults with QTc prolongation or torsade de pointes and ventricular arrhythmia or cardiac arrest. MEASUREMENTS FAERS reports before and after the 2002 report. RESULTS 1646 cases of ventricular arrhythmia or cardiac arrest and 379 cases of QTc prolongation or torsade de pointes were associated with methadone. Monthly reports of QTc prolongation or torsade de pointes increased from a mean of 0.3 (95% CI, 0.1 to 0.5) before the 2002 publication to a mean of 3.5 (CI, 2.5 to 4.8) after it. After 2000, methadone was the second-most common primary suspect in cases of QTc prolongation or torsade de pointes after dofetilide (a known proarrhythmic drug) and was associated with disproportionate reporting similar to that of antiarrhythmic agents known to promote torsade de pointes. Antiretroviral drugs for HIV were the most common coadministered drugs. LIMITATION Reports to FAERs are voluntary and selective, and incidence rates cannot be determined from spontaneously reported data. CONCLUSION Since 2002, reports to FAERS of methadone-associated arrhythmia have increased substantially and are disproportionately represented relative to other events with the drug. Coadministration of methadone with antiretrovirals in patients with HIV may pose particular risk. PRIMARY FUNDING SOURCE Colorado Clinical and Translational Sciences Institute, National Institutes of Health, and Agency for Healthcare Research and Quality.