Circulation: Clinical Summaries
Original Research Put Into Perspective for the Practicing Clinician
- Screening for Acute IKr Block Is Insufficient to Detect Torsades de Pointes Liability: Role of Late Sodium Current
- Association Between Antipsychotic Use and Risk of Acute Myocardial Infarction: A Nationwide Case-Crossover Study
- Early Remodeling of Perinuclear Ca2+ Stores and Nucleoplasmic Ca2+ Signaling During the Development of Hypertrophy and Heart Failure
- Randomized, Controlled Trial to Improve Self-Care in Patients With Heart Failure Living in Rural Areas
- Evaluation of Interval Times From Onset to Reperfusion in Patients Undergoing Endovascular Therapy in the Interventional Management of Stroke III Trial
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Screening for Acute IKr Block Is Insufficient to Detect Torsades de Pointes Liability: Role of Late Sodium Current
Most drugs that have been associated with torsades de pointes have been found to reduce the rapid component of the delayed rectifies repolarizing potassium current IKr by direct block or by interfering with cell surface expression of the channel. However, clinicians have long recognized that some drugs, notably QT-prolonging antiarrhythmics, seem to have a high propensity for causing torsades, especially in patients with certain underlying heart diseases, whereas the incidence with others, such as certain antibiotics, is confined to occasional case reports to the US Food and Drug Administration or in the literature. The reasons for this dichotomy remain unexplained.
A recent report showed that the anticancer drug nilotinib, which is labeled as having torsades liability, unexpectedly did not acutely prolong cardiac action potentials but did with hours of exposure. The mechanism was in part an increase in the late inward sodium current that has been recorded under a range of conditions, from some forms of the congenital long QT syndrome to heart failure, and that increase was attributed to phosphoinositide 3-kinase inhibition. Yang et al show here that hours of exposure to multiple drugs with torsades liability, including those considered to be pure IKr blockers such as dofetilide, also increase late sodium current and that phosphoinositide 3-kinase inhibition likely contributes. The clinical implications are that variability in this new arrhythmia pathway may account for variability in torsades liability across drugs and perhaps among individual patients and that the strategy of screening new drug entities for rectifier potassium current block is insufficient to rule out a torsades liability. See p 224.
Association Between Antipsychotic Use and Risk of Acute Myocardial Infarction: A Nationwide Case-Crossover Study
Recent evidence suggests that patients with mental illnesses have a 2- to 5-fold greater risk of coronary heart disease and a 2- to 3-fold greater risk of cardiac mortality than the general population. These patients are at risk not only because of their unfavorable health profiles for cardiovascular disease but also possibly because of the drugs that they are taking. To date, the association between the use of antipsychotics and the risk of acute myocardial infarction (AMI) remains unclear. Studying 56 910 patients with schizophrenia, mood disorders, or dementia first hospitalized or visiting an emergency room for AMI, we found a significant association between AMI risk and the antipsychotic drugs used before the AMI event. The risk was dose dependent and increased in short-term users (≤30 days), male patients, elderly patients, and patients with dementia. We also found dopamine type 3 receptor blockading to be the most likely pharmacological property responsible for AMI associated with antipsychotic use. Because clinicians frequently prescribe antipsychotics for various mental health conditions with little perception of potential risk for AMI, we suggest that antipsychotics be initiated starting with low dosages when such treatment is clearly indicated, followed by a close monitoring for patient signs or symptoms of AMI, especially within the first 30 days of a treatment period. Special caution should be used when prescribing antipsychotics to elderly individuals with dementia. Further research is needed to investigate the underlying biological mechanisms of antipsychotic-related AMI. See p 235.
Early Remodeling of Perinuclear Ca2+ Stores and Nucleoplasmic Ca2+ Signaling During the Development of Hypertrophy and Heart Failure
Hypertrophy and heart failure are severe and widespread cardiac diseases associated with increased morbidity and mortality. Understanding the underlying cellular mechanisms is crucial for developing new treatment strategies and thereby improving prognosis. Numerous studies have identified impaired cytoplasmic Ca2+ handling of cardiomyocytes as underlying contractile failure in hypertrophy and heart failure. Here, we show for the first time how nucleoplasmic Ca2+ homeostasis is altered during this hypertrophy–heart failure transition. We provide compelling evidence that nuclear envelope structure, its molecular composition, and nucleoplasmic Ca2+ transients undergo significant changes as remodeling progresses. These nuclear changes precede the changes in cytoplasmic Ca2+ dysregulation, thus suggesting that altered nucleoplasmic [Ca2+] is an early event during remodeling and may contribute to the development and progression of cardiac hypertrophy and heart failure. Importantly, the changes were observed not only in animal models of hypertrophy and HF but also in nonfailing, moderately failing, and end-stage failing human hearts, hence strengthening their general applicability and clinical relevance. In conclusion, the present work presents a new paradigm for cardiac hypertrophy and failure, in which early remodeling of nuclear calcium homeostasis is an important factor for the development and progression of this common and severe cardiac disease. Normalization of impaired nucleoplasmic Ca2+ regulation may therefore be a novel therapeutic approach for the prevention of adverse cardiac remodeling. See p 244.
Randomized, Controlled Trial to Improve Self-Care in Patients With Heart Failure Living in Rural Areas
Multidisciplinary disease management programs reduce heart failure (HF) hospitalizations and cardiac death. However, patients with HF who live in rural areas have minimal access to such programs and other specialty cardiac services because of geographic distance. In a randomized, clinical trial of 602 rural patients with HF, a single face-to-face educational intervention emphasizing the HF self-care strategies promoted in disease management programs was tested. The intervention included all aspects of HF self-care but focused particularly on teaching patients to monitor daily weights and to identify early signs of hypervolemia. Telephone calls by nurses designed to reinforce the educational content varied in number between the 2 intervention groups. At 3 and 12 months, both intervention groups reported significantly better self-care behaviors than the control group. At 24 months, the improvement in the 2 intervention groups in self-care behaviors was sustained but was no longer significantly different. However, the proportion of patients in the 3 groups experiencing the composite end point of cardiac death or HF hospitalization at 2 years was not significantly different among groups. When the trial results are interpreted, it is important to note that patients’ physicians were blinded to group assignment to reduce potential bias. The results potentially reinforce the important role of collaboration and communication between members of the HF team, particularly among physicians and nurses, in caring for this complex group of chronically ill patients. See p 256.
Evaluation of Interval Times From Onset to Reperfusion in Patients Undergoing Endovascular Therapy in the Interventional Management of Stroke III Trial
The significance of time in hyperacute ischemic stroke behooves the medical team to guarantee rapid work flow until reperfusion is achieved. The numerous and delicate steps involved require well-planned protocols to ensure the safe and smooth transition of patients from one stage to the next. The recent Interventional Management of Stroke (IMS) III randomized, controlled trial is the largest study to date to examine the efficacy of endovascular therapy against the standard treatment of intravenous tissue plasminogen activator. The IMS III study also offers valuable insights into the importance of work flow in ensuring timely reperfusion. In this article, the work flow of patients enrolled in the endovascular arm of IMS III is divided into different time intervals and analyzed to provide a better understanding of the sources and magnitude of delay. These findings will also inform current and future endovascular trials to accomplish an optimized work flow for their patients and thus faster reperfusion. See p 265.
- © 2014 American Heart Association, Inc.
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