JACC in a Flash

Is Hospital Admission for Heart Failure Really Necessary?
In a paper published recently in JACC, Sean P. Collins, MD, from Vanderbilt University in Nashville, and colleagues suggest one surefire way to reduce HF readmission rates: reduce HF admission rates. Emergency physicians admit patients with symptomatic HF approximately 800,000 times a year, but, according to the authors, large subsets of HF patients are hospitalized without a clear need for time-sensitive therapies or procedures. To avoid unnecessary inpatient admissions they propose an observation unit (OU) strategy for managing HF, especially when the exact impact of hospitalization on post-discharge events remains unclear.

To select the proper patient for emergency department (ED)-based management, Dr. Collins and colleagues propose a two-level targeted evaluation to determine a patient's risk profile and discharge eligibility.

The first step in identifying discharge-eligible HF patients is a focused initial ED evaluation using readily-available baseline data. The second level of evaluation involves analyzing patients' response to therapy initiated in the ED.

Patients deemed "low-risk" or "intermediate-risk" would undergo a period of examination and treatment in the OU, and would avoid an unnecessary inpatient admission.

OU management for HF, which is designed to simultaneously treat and risk stratify patients, is vastly under-utilized according to the authors, despite the savings in health care costs and resources and the reduction in readmission. Up to 50% of patients triaged to the OU with this method might be sufficiently improved within 24 hours to permit home discharge, the authors argue, asserting that there is a crucial, timely need to compare their proposed risk assessment and disposition strategy with the current approach in a randomized clinical trial.

In an accompanying editorial, Akshay S. Desai, MD, and Lynne W. Stevenson, MD, recognize the need for alternate routes to avoid HF hospitalizations, but also acknowledge the challenges in even testing this new approach. One of the major roadblocks is defining the best way to stratify risk at the initial point of triage and after admission to the OU, as the relative benefits of hospitalization over home discharge vary according to the reason for HF exacerbation.

"Now that HF admission has moved from the profit to the loss column, every hospital is struggling to deploy and enhance available resources effectively to decrease heart failure admissions," Drs. Desai and Stevenson write. "As systems are redesigned, care must be taken to contain excessive aversion to hospitalization that could become detrimental in complex situations for which an inpatient stay will still offer the best setting to integrate care for the rest of the journey."

Collins SP, Pang PS, Fonarow GC, et al. J Am Coll Cardiol. 2013;61:121-6.
Desai AS, Stevenson LW. J Am Coll Cardiol. 2013;61:127-30.

An A-salt on the System: Dietary Sodium and Vascular Function
Reducing sodium intake is a commonly recommended lifestyle modification for lowering blood pressure, and the risk for CV events by extension, but the effect of dietary sodium restriction (DSR) on improving vascular endothelial function, independent of lowering BP, remains unclear.

Kristine L. Jablonski, PhD, from the University of Colorado in Boulder, and colleagues conducted a double-blind, placebo-controlled, randomized, crossover design study in a group of patients with moderately elevated BP to examine this relationship, as well as the underlying pathophysiological mechanisms involved in these changes.

Seventeen middle-aged and older participants (age range, 51-77 years; 11 men and 6 women) with moderately high systolic BP completed the 10-week protocol, which consisted of two 4-week periods: one in which subjects lowered sodium intake to a target of 50 mmol/day (1,500 mg/day, consistent with the DASH diet), and one in which subjects returned their sodium intake to a target of ~150 mmol/day (the average US sodium intake based on recent NHANES dietary data) by taking 10 slow-release sodium chloride tablets throughout the day. Blood pressure, urinary sodium excretion, endothelial nitric oxide synthase (eNOS), and endothelium-dependent dilation (EDD)—determined by forearm blood flow to acetylcholine (FBFACh) and brachial artery flow-mediated dilation (FMDBA)—were measured during each 5th "off week" to determine the effect of DSR on conduit artery (macrovascular) and resistance vessel (microvascular) endothelial function.

At the end of the study period, Jablonski et al. reported an average decrease in systolic BP of 12 mm Hg, as well as a significant improvement in endothelial function. In addition, DSR was associated with a number of beneficial changes in subjects' arterial biology, including greater arterial nitric oxide release, restored bioactivity of tetrahydrobiopterin (BH4), and reduced oxidative stress. They also note that none of these vascular effects was related to changes in BP, other dietary factors, clinical characteristics, or humoral influences, suggesting that maintaining low dietary sodium intake exerts a "vasculo-protective" effect.

While this effect is certainly possible, David S. Celermajer, DSc, and Bruce Neal, PhD, write in an accompanying editorial, the current study is not powered to prove this hypothesis. "Whether via BP or not, however, excess dietary sodium clearly exerts a variety of adverse effects on the systemic vasculature.... Our next challenge is to translate this knowledge derived from vascular biology into effective and appropriate public health strategy."

Celermajer DS, Neal B. J Am Coll Cardiol. 2012 October 25. [Epub ahead of print]
Jablonski KL, Racine ML, Geolfos CJ, et al. J Am Coll Cardiol. 2012 October 25. [Epub ahead of print]

The Balancing Act of Cardio-Oncology: Cardiotoxicity of Cancer Therapeutics
Protein kinases are a common therapeutic target for cancer drug development, but unfortunately, some kinases may be essential for cardiac function; the unexpected cardiotoxicity from approved kinase inhibitors (KIs) necessitates a team approach when developing new cancer drugs. As Hind Lal, PhD, from the Center of Translational Medicine and Cardiology Division of Temple University School of Medicine in Philadelphia, and colleagues report in a paper recently published in JACC, the limited understanding of various kinases' roles in heart function makes predicting cardiotoxicity virtually impossible. Thus, the challenge for cardiologists and oncologists is to develop pre-clinical models to narrow down the kinases involved in cardiac function, as well as possibly identifying these problematic agents prior to use in patients.

Researchers have proposed solutions to deal with on-target cardiotoxicity, in which the targeted kinase also provides an important function in the heart and/or vasculature, such as targeted delivery of the drug specifically to the cancer or targeting unique kinases from the cancer kinome that are not expressed in the heart, but off-target toxicity presents another set of problems.

Off-target toxicity (when inhibition of a target not intended to be inhibited by a KI is responsible for the adverse effects) is directly related to the poor selectivity of a KI—all of the approved KIs bind to multiple kinases, so enhanced selectivity should be a top priority.

Biomarkers have successfully been used to predict cardiotoxicity with antrhacyclines, but, in the setting of KI treatment, it is unclear if these "traditional" biomarkers (such as troponin) will be effective. The same is true for imaging methods—a combination of longitudinal strain and high-sensitivity TnI has had encouraging results in anthracycline-treated patients, but is unproven in KI-treated patients.

KIs, and targeted therapeutics in general, have radically altered cancer treatment, Dr. Lal and colleagues conclude, but a full understanding of the power of these modern cancer therapeutics is still needed. "Given the central role played by kinases in the heart and other organs (leading to on-target toxicity with KIs); the relatively poor selectivity of the current and future crop of KIs (leading to off-target effects); the paucity of verified preclinical models to predict toxicity; the uncertainties as to how effective traditional biomarkers and imaging will be in identifying cardiotoxicity with these agents; our poor understanding of the role played by the majority of kinases expressed in the heart; and the number of new KIs in development, we are heading into uncharted waters."

Lal H, Kolaja KL, Force T. J Am Coll Cardiol. 2013;61:267-74.

Keywords: Protein Kinases, Life Style, Cross-Over Studies, Brachial Artery, Biomarkers, Heart Failure, Blood Pressure, Risk Assessment, Inpatients, Sodium Chloride, Dietary

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