Mark C. Haigney

Diuretic use, progressive heart failure, and death in patients in the studies of left ventricular dysfunction (SOLVD)

OBJECTIVES We sought to determine whether non-potassium-sparing diuretics (PSDs) in the absence of a PSD may result in progressive heart failure (HF). BACKGROUND Angiotensin-converting enzyme (ACE) inhibitors incompletely suppress ACE activity in HF patients. Furthermore, non-PSDs are activators of aldosterone secretion. We reasoned that non-PSDs, in the absence of a PSD, might result in progressive HF. METHODS In the 6,797 patients in the Studies Of Left Ventricular Dysfunction (SOLVD), we compared the risk of hospitalization for, or death from, HF between those taking a PSD and those who were not, adjusting for known covariates. RESULTS The risk of hospitalization from worsening HF in those taking a PSD relative to those taking only a non-PSD was 0.74 (95% confidence interval [CI] 0.55 to 0.99; p = 0.047). The relative risk for cardiovascular death was 0.74 (95% CI 0.59 to 0.93; p = 0.011), for death from all causes 0.73 (95% CI 0.59 to 0.90; p = 0.004), and for hospitalization for, or death from, HF 0.75 (95% CI 0.58 to 0.97; p = 0.030). Compared with patients not taking any diuretic, the risk of hospitalization or death due to worsening HF in patients taking non-PSDs alone was significantly increased (risk ratio [RR] = 1.31, 95% CI 1.09 to 1.57; p = 0.0004); this was not observed in patients taking PSDs with or without a non-PSD (RR = 0.99, 95% CI 0.76 to 1.30; p = 0.95). CONCLUSIONS The use of PSDs in HF patients is associated with a reduced risk of death from, or hospitalization for, progressive HF or all-cause or cardiovascular death, compared with patients taking only a non-PSD.

Protein Kinase A Hyperphosphorylation Increases Basal Current but Decreases β-Adrenergic Responsiveness of the Sarcolemmal Na+-Ca2+ Exchanger in Failing Pig Myocytes

Abstract— The sodium-calcium exchanger (NCX) protein is the major cardiac calcium extrusion mechanism and is upregulated in heart failure (HF). NCX expression level and functional activity as regulated by &bgr;-adrenergic receptor (&bgr;-AR) stimulation in swine with and without tachycardia-induced heart failure were studied. The Ni2+-sensitive NCX current was measured in myocytes from HF and control animals in the basal state or in the presence of isoproterenol, forskolin, 8-Br-cAMP, okadaic acid, or protein phosphatase type 1. Western blot analysis revealed a significant increase in both the 120-kDa (29%) and 80-kDa (69%) fragments in HF (P <0.05 versus control). Despite this modest increase in protein, the basal peak outward NCX current was increased almost 5-fold in HF (P <0.05 versus control). Stimulation with isoproterenol, however, increased the control currents to a significantly greater extent than HF (500% increase in control versus 100% increase in HF, P <0.01); peak stimulated current was not different in HF and control. This reduction in responsiveness to &bgr;-AR stimulation was refractory to forskolin, 8-Br-cAMP, or okadaic acid stimulation. In vitro protein kinase A back-phosphorylation revealed higher phosphorylation capacity of NCX protein in control versus HF, consistent with increased phosphorylation in vivo (hyperphosphorylation) in HF. Protein phosphatase type 1 exposure resulted in a significant reduction (73%) in peak basal current in HF (compared with no significant difference in controls), confirming that the increased basal NCX current in HF is predominately attributable to hyperphosphorylation. NCX expression and activity are thus increased in HF, although &bgr;-AR responsiveness is decreased because of NCX hyperphosphorylation.

Methadone Safety: A Clinical Practice Guideline From the American Pain Society and College on Problems of Drug Dependence, in Collaboration With the Heart Rhythm Society

UNLABELLED Methadone is used for the treatment of opioid addiction and for treatment of chronic pain. The safety of methadone has been called into question by data indicating a large increase in the number of methadone-associated overdose deaths in recent years that has occurred in parallel with a dramatic rise in the use of methadone for chronic pain. The American Pain Society and the College on Problems of Drug Dependence, in collaboration with the Heart Rhythm Society, commissioned an interdisciplinary expert panel to develop a clinical practice guideline on safer prescribing of methadone for treatment of opioid addiction and chronic pain. As part of the guideline development process, the American Pain Society commissioned a systematic review of various aspects related to safety of methadone. After a review of the available evidence, the expert panel concluded that measures can be taken to promote safer use of methadone. Specific recommendations include the need to educate and counsel patients on methadone safety, use of electrocardiography to identify persons at greater risk for methadone-associated arrhythmia, use of alternative opioids in patients at high risk of complications related to corrected electrocardiographic QTc interval prolongation, careful dose initiation and titration of methadone, and diligent monitoring and follow-up. Although these guidelines are based on a systematic review, the panel identified numerous research gaps, most recommendations were based on low-quality evidence, and no recommendations were based on high-quality evidence. PERSPECTIVE This guideline, based on a systematic review of the evidence on methadone safety, provides recommendations developed by a multidisciplinary expert panel. Safe use of methadone requires clinical skills and knowledge in use of methadone to mitigate potential risks, including serious risks related to risk of overdose and cardiac arrhythmias.

Myocyte Adaptation to Chronic Hypoxia and Development of Tolerance to Subsequent Acute Severe Hypoxia

Studies in animal models and humans suggest that myocardium may adapt to chronic or intermittent prolonged episodes of reduced coronary perfusion. Stable maintenance of partial flow reduction is difficult to achieve in experimental models; thus, in vitro cellular models may be useful for establishing the mechanisms of adaptation. Since moderate hypoxia is likely to be an important component of the low-flow state, isolated adult rat cardiac myocytes were exposed to 1% O2 for 48 hours to study chronic hypoxic adaptation. Hypoxic culture did not reduce cell viability relative to normoxic controls but did enhance glucose utilization and lactate production, which is consistent with an anaerobic pattern of metabolism. Lactate production remained transiently increased after restoration of normal O2 tension. Myocyte contractility was reduced (video-edge analysis), as was the amplitude of the intracellular Ca2+ transient (indo 1 fluorescence) in hypoxic cells. Relaxation was slowed and was accompanied by a slowed decay of the Ca2+ transient. These changes were not due to alterations in the action potential. Tolerance to subsequent acute severe hypoxia occurred in cells cultured in 1% O2 and was manifested as a delay in the time to full ATP-depletion rigor contracture during severe hypoxia and enhanced morphological recovery of myocytes at reoxygenation. The latter was still seen after normalization of the data for the prolonged time to rigor, suggesting a multifactorial basis for tolerance. An intervening period of normoxic exposure before subsequent acute severe hypoxia did not result in loss of tolerance but rather increased the delay to subsequent ATP depletion rigor. Cellular glycogen was preserved during chronic hypoxic exposure and increased after the restoration of normal O2 tension. As mitochondrial cytochromes should be fully oxygenated at levels well below 1% O2, hypoxic adaptation may be mediated by a low-affinity O2-sensing process. Thus, adaptations that occur during prolonged periods of moderate hypoxia are proposed to poise the myocyte in a better position to tolerate impending episodes of severe O2 deprivation.

Gender differences and risk of ventricular tachycardia or ventricular fibrillation

BACKGROUND Healthy women have longer QT intervals and more drug-induced proarrhythmia compared to men, yet those given implantable cardioverter-difibrillators (ICDs) for ischemic cardiomyopathy have fewer episodes of ventricular tachycardia/ventricular fibrillation (VT/VF) than men. The role of repolarization duration and stability in arrhythmogenesis in men and women with structural heart disease has not been explored. OBJECTIVES The purpose of this study was to analyze repolarization differences between men and women and their relation to the risk of VT/VF. METHODS Multicenter Automatic Defibrillator Trial II study patients underwent 10-minute, resting digitized recordings at study entry. QT and heart rate were measured for each beat with a semiautomated method. QT variance was normalized for mean QT (QTVN) or for heart rate variance (QTVI). Spectral analysis of heart rate and QT time series was performed; coherence was indexed to quantify consistency of heart rate and QT power spectra. The incidence of VT/VF was determined by ICD interrogation. RESULTS There were 805 usable recordings (142 females); 463 received ICDs (86 females). There was no gender difference in mean or median QT, QTc, or heart rate. QTVN and QTVI were slightly (but significantly) higher, and the mean coherence was lower in women. In a Cox multivariate analysis, increased QTVN or QTVI (top quartile) was associated with a significantly higher risk for VT/VF in men (QTVN hazard ratio (HR) 2.2; confidence interval [CI] 1.4-3.4; P = .001; QTVI HR 1.9; CI 1.2-3.0; P = .006) but not in women, while reduced coherence (bottom quartile) predicted VT/VF in women (HR 3.3; CI 1.2-9.0; P = .021) but not in men. CONCLUSIONS In post-myocardial infarcation patients with depressed ejection fraction, both women and men manifest increased temporal variability in the QT interval. In men, QT variability by itself raised arrhythmic risk. In women, however, QT variability dissociated from HR variability (low coherence) appeared to be a uniquely significant predictor of arrhythmic events.

Loss of cardiac magnesium in experimental heart failure prolongs and destabilizes repolarization in dogs.

OBJECTIVES We sought to determine whether heart failure results in loss of cardiac magnesium sufficient to alter cellular electrophysiology. BACKGROUND Free magnesium has numerous intracellular roles affecting metabolism, excitability and RNA synthesis. Total cardiac magnesium content is reduced in heart failure, but it is unclear whether magnesium loss is primary or iatrogenic. Furthermore, it is unknown whether free magnesium levels are affected or whether a change in free magnesium would alter cellular electrophysiology. METHODS Eight mongrel dogs underwent demand ventricular pacing (VVI) at 250 beats/min for 3 weeks to induce heart failure. Sublingual epithelial magnesium was measured before pacing and at death. Left ventricular myocytes were isolated and loaded with Mag-Indo-1 to measure free magnesium ([Mg2+]i); myocytes from eight normal dogs served as controls. To test whether changes in [Mg2+]i in this range could alter cellular repolarization, current-clamped myocytes were dialyzed with 0.5 or 1.0 mmol/liter MgCl2. RESULTS Mean sublingual epithelial magnesium fell significantly in the paced animals, from 36.9 +/- 0.5 to 33.9 +/- 0.7 mEq/liter (p < 0.01). Mean cardiac [Mg2+]i was significantly lower in the dogs with heart failure--0.49 +/- 0.06 versus 1.06 +/- 0.15 mmol/liter (p < 0.003). Time to 90% repolarization was significantly shorter in cells dialyzed with 1.0 mmol/liter compared with 0.5 mmol/liter MgCl2 in myocytes from normal dogs or dogs with heart failure (596 +/- 34 vs. 760 +/- 58 ms in normal dogs and 586 +/- 29 vs. 838 +/- 98 ms in dogs with heart failure; p < 0.05 for each). CONCLUSIONS Experimental heart failure results in both tissue and cardiac magnesium loss in the absence of drug therapy. Free cardiac magnesium is significantly reduced, possibly contributing to abnormal repolarization in heart failure.

Association between Symptoms of Depression and Anxiety with Heart Rate Variability in Patients with Implantable Cardioverter Defibrillators

Objective: This study investigated whether depression and anxiety symptoms are associated with measures of autonomic nervous system dysfunction in patients with implantable cardioverter defibrillators who are at high risk of cardiac rhythm disturbances. Depression and anxiety are associated with autonomic nervous system dysfunction, which may promote the risk of malignant cardiac arrhythmias. Methods: Patients with an implantable cardioverter defibrillator (ICD) underwent ambulatory electrocardiographic (ECG) monitoring (n = 44, mean age = 62.1 ± 9.3 years). Depression was assessed using the Beck Depression Inventory and anxiety was evaluated using the Taylor Manifest Anxiety Scale. Heart rate variability was assessed using time (RMSSD, pNN50, and SDNN) and frequency domain measures derived from 24-hour R-R intervals. Multivariate models were adjusted for age, sex, hypertension, diabetes, and smoking status. Results: Defibrillator patients with elevated depression symptoms (n = 12) had significantly lower RMSSD (15.25 ± 1.66 ms versus 24.97 ± 2.44 ms, p = .002) and pNN50 (1.83 ± 0.77 versus 5.61 ± 1.04, p = .006) than defibrillator patients with low depression symptoms (n = 32). These associations remained significant after multivariate adjustment for covariates. ICD patients with high anxiety levels (n = 10) displayed lower RMSSD (p = .013), which became marginally significant when adjusting for covariates (p = .069). Conclusions: Depression and anxiety in defibrillator patients are associated with autonomic nervous system dysfunction indices of reduced parasympathetic control. Autonomic nervous system dysfunction may partially explain the association between depression and anxiety with life-threatening cardiac outcomes in vulnerable patients. ICD = implantable cardioverter defibrillators; HRV = heart rate variability; BDI = Beck Depression Inventory; BMI = body mass index.

Randomized, Double-Blind, Placebo-Controlled Clinical Trial of a Two-Day Regimen of Dihydroartemisinin-Piperaquine for Malaria Prevention Halted for Concern over Prolonged Corrected QT Interval

ABSTRACT Dihydroartemisinin-piperaquine, the current first-line drug for uncomplicated malaria caused by Plasmodium falciparum and Plasmodium vivax in Cambodia, was previously shown to be of benefit as malaria chemoprophylaxis when administered as a monthly 3-day regimen. We sought to evaluate the protective efficacy of a compressed monthly 2-day treatment course in the Royal Cambodian Armed Forces. The safety and efficacy of a monthly 2-day dosing regimen of dihydroartemisinin-piperaquine were evaluated in a two-arm, randomized, double-blind, placebo-controlled cohort study with 2:1 treatment allocation. Healthy military volunteers in areas along the Thai-Cambodian border where there is a high risk of malaria were administered two consecutive daily doses of 180 mg dihydroartemisinin and 1,440 mg piperaquine within 30 min to 3 h of a meal once per month for a planned 4-month period with periodic electrocardiographic and pharmacokinetic assessment. The study was halted after only 6 weeks (69 of 231 projected volunteers enrolled) when four volunteers met a prespecified cardiac safety endpoint of QTcF (Fridericias formula for correct QT interval) prolongation of >500 ms. The pharmacodynamic effect on the surface electrocardiogram (ECG) peaked approximately 4 h after piperaquine dosing and lasted 4 to 8 h. Unblinded review by the data safety monitoring board revealed mean QTcF prolongation of 46 ms over placebo at the maximum concentration of drug in serum (Cmax) on day 2. Given that dihydroartemisinin-piperaquine is one of the few remaining effective antimalarial agents in Cambodia, compressed 2-day treatment courses of dihydroartemisinin-piperaquine are best avoided until the clinical significance of these findings are more thoroughly evaluated. Because ECG monitoring is often unavailable in areas where malaria is endemic, repolarization risk could be mitigated by using conventional 3-day regimens, fasting, and avoidance of repeated dosing or coadministration with other QT-prolonging medications. (This study has been registered at ClinicalTrials.gov under registration no. NCT01624337.)

Electrocardiographic Studies of Romidepsin Demonstrate Its Safety and Identify a Potential Role for KATP Channel

Purpose: Romidepsin is a histone deacetylase inhibitor (HDI) approved for the treatment of both cutaneous and peripheral T-cell lymphoma (CTCL and PTCL). During development, a thorough assessment of cardiac toxicity was conducted. Experimental Design: A phase II single-agent nonrandomized study of romidepsin was conducted in patients with CTCL or PTCL who had progressed after at least 1 prior systemic therapy. Results: Results for the first 42 patients enrolled on the NCI 1312 phase II study of romidepsin in CTCL or PTCL showed no cardiac toxicity based on serial electrocardiograms (ECG), troponins, and MUGA scans/echocardiograms. The cardiac assessments reported herein confirm the safety of romidepsin among 131 enrolled patients, while supporting a role for electrolyte replacement. Heart rate increased an average 11 bpm following romidepsin infusion; there was no evidence of increased arrhythmia. Criteria for potassium/magnesium replacement were met before 55% of 1365 romidepsin doses; an association with hypoalbuminemia was confirmed. We propose a mechanism for ST segment flattening and depression, the most common ECG abnormalities observed: HDI-induced alteration of the activity or expression of KATP channels. In addition, examination of the variants of the active transporter of romidepsin, ABCB1, showed a trend toward smaller heart rate changes in the peri-infusion period among wild-type than variant diplotypes. Conclusions: We conclude that in the context of appropriate attention to electrolyte levels, the data support the cardiac safety of romidepsin. Clin Cancer Res; 19(11); 3095–104. ©2013 AACR.

Intravenous Cocaine and QT Variability

Background: Dynamic instability in cardiac repolarization may contribute to drug‐induced arrhythmogenesis. We hypothesized that intravenous cocaine would significantly destabilize repolarization as measured by QT variability.