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INSIDE THIS ISSUE

Inside This Issue

	Quarterly Focus Issue: Heart Failure

Top Quarterly Focus Issue: Heart... Interventional Cardiology Cardiovascular Risk Pre-Clinical Research

Lionel H. Opie, Juhani Knuuti

Opie and Knuuti describe how the hyperadrenergic state caused by heart failure (HF) increases circulating plasma free fatty acids (FFAs), which leads to impaired glucose metabolism and insulin resistance. In the heart, FFAs can induce mitochondrial uncoupling leading to the generation of reactive oxygen species (ROS), inflammatory proteins, and insulin resistance. They propose that these derangements be addressed by metabolic therapy, which has 3 aims: 1) to decrease hyperadrenergic drive; 2) to inhibit lipotoxicity and glucotoxicity; and 3) to increase glucose uptake by muscle. These aims are respectively achieved by: 1) beta-adrenergic blockade and other measures that reduce the mechanical load on the heart; 2) drugs that inhibit fatty acid oxidation (trimetazidine, perhexiline); and 3) increasing the transport of glucose into the cells by exercise training and metformin. The data behind these recommendations is reviewed and is found to be sparse for hard clinical outcomes, but it does provide reasons for hope and further study.

State-of-the-Art Paper.   Outpatient Management of Ventricular Assist Devices

1647

Sean R. Wilson, Michael M. Givertz, Garrick C. Stewart, Gilbert H. Mudge, Jr

Over the last few decades, much progress has been made in the development and refinement of ventricular assist devices (VADs), medical devices capable of maintaining circulatory output of the diseased ventricle. Initially designed as a temporary support to allow ventricular recovery or bridge patients to cardiac transplant, these devices are now being used as a permanent form of "destination" therapy; this means that patients with VADs are returning to their communities. In this paper, Wilson and colleagues discuss: 1) the spectrum of VADs for outpatient therapy, including their basic physiology and hemodynamics; 2) the multidisciplinary approach required to care for a patient with such a device; 3) routine general cardiac issues that are encountered; 4) associated long-term device and nondevice-related complications; and 5) the reported overall improvements in quality of life.

Viewpoint.   Micronutrient Supplementation May Improve HF Outcomes

1660

Victor Soukoulis, Jamil B. Dihu, Michael Sole, Stefan D. Anker, John Cleland, Gregg C. Fonarow, Marco Metra, Evasio Pasini, Theresa Strzelczyk, Heinrich Taegtmeyer, Mihai Gheorghiade

Soukoulis and colleagues propose that one of the reasons that morbidity and mortality remain high for patients with heart failure (HF) is that current pharmacological regimens do not fully address some unique requirements of the heart for energy metabolism. The heart requires a continuous supply of energy-providing substrates and amino acids, and HF appears to cause defects in cardiac substrate metabolism and utilization. These alterations may be related to deficiencies in key micronutrients, which theoretically could be reversed by micronutrient supplementation. This review explores the evidence that supplementation of coenzyme Q10, L-carnitine, thiamine, and taurine improves outcomes, and it concludes that there is justification for a prospective trial to examine the effects of micronutrient supplementation on morbidity and mortality in patients with HF.

Clinical Research.   Eplerenone May Reduce Cardiac Collagen Turnover and Reduce the Increase in Cardiac Stiffness
1674

George J. Mak, Mark T. Ledwidge, Chris J. Watson, Dermot M. Phelan, Ian R. Dawkins, Niamh F. Murphy, Anil K. Patle, John A. Baugh, Kenneth M. McDonald

Serum levels of markers of collagen turnover correlate with myocardial fibrosis and clinical outcomes. It is currently unknown if collagen metabolism can be beneficially modulated to result in improvements in diastolic function and clinical status in subjects with heart failure and preserved ejection fraction (HFPEF). Mak and colleagues randomized 44 patients with HFPEF to control or eplerenone at escalating doses. Serum markers of collagen turnover and inflammation were analyzed at baseline and at 6 and 12 months. Doppler echocardiographic assessment of diastolic filling indexes were also obtained. In control patients, there were steady increases in these markers over time, but eplerenone attenuated the increase at 12 months and was associated with modest improvements in diastolic function. This study demonstrates progressive increases in markers of collagen turnover and inflammation in HFPEF, and these markers may serve as surrogates for worsening diastolic dysfunction.

Clinical Research.   Meta-Analysis of Remote Monitoring for HF Patients Confirms Benefits
1683

Catherine Klersy, Annalisa De Silvestri, Gabriella Gabutti, François Regoli, Angelo Auricchio

Klersy and colleagues performed a meta-analysis of studies that compared remote patient monitoring (RPM) versus standard care for patients with chronic heart failure (HF). RPM could occur via regularly scheduled structured telephone contacts between patients and health care providers or via electronic transfer of physiological data using external, wearable, or implantable electronic devices. There were 20 articles reporting outcomes of randomized controlled trials (RCTs) and 12 papers describing cohort studies totaling almost 9,000 patients. Both RCTs and cohort studies showed that RPM was associated with a significantly lower mortality (RCTs relative risk [RR]: 0.83, cohort RR: 0.53) and hospitalizations (RCTs RR: 0.93, cohort RR: 0.52). This analysis demonstrates that RPM confers a significant protective clinical effect in patients with chronic HF compared with usual care.

Clinical Research.   Hospitalization Frequent in Patients With a History of HF, But Is Often for Non-HF Conditions

1695

Shannon M. Dunlay, Margaret M. Redfield, Susan A. Weston, Terry M. Therneau, Kirsten Hall Long, Nilay D. Shah, Véronique L. Roger

Dunlay and colleagues sought to determine the lifetime burden and risk factors for hospitalization after a diagnosis of heart failure (HF) using a random sample of incident HF cases in Olmsted County, Minnesota, over nearly 20 years. Among 1,077 HF patients, 4,359 hospitalizations occurred. Over 80% of patients were hospitalized at least once, and 43% were hospitalized 4 times. However, the primary reason for hospitalization was HF in only 17% of hospitalizations and other cardiovascular conditions in an additional 22%. Sixty-two percent of subsequent hospitalizations were for noncardiovascular reasons. Multiple hospitalizations are common after HF diagnosis, although less than one-half are due to cardiovascular causes.

Editorial Comment: Soko Setoguchi, Lynne Warner Stevenson, p. 1703

Clinical Research.   Hypoxia, Not the Frequency of Sleep Apnea, Raises BNP
1706

Joshua D. Gottlieb, Alan R. Schwartz, Joanne Marshall, Pamela Ouyang, Linda Kern, Veena Shetty, Maria Trois, Naresh M. Punjabi, Cynthia Brown, Samer S. Najjar, Stephen S. Gottlieb

Sleep apnea is strongly associated with heart failure (HF), and could conceivably worsen HF through increased sympathetic activity, hemodynamic stress, hypoxemia, and oxidative stress. Gottlieb and colleagues hypothesized that if apneic activity causes acute cardiac stress, it should increase B-type natriuretic peptide (BNP). This hypothesis was tested by serially measuring BNP at 20-min intervals while subjects with HF were being monitored for evidence of sleep apnea. There was no relationship between BNP and the number of apneic/hypopneic episodes or the number of arousals. However, the burden of hypoxemia, the time spent with oxygen saturation below 90%, predicted BNP concentrations. Hypoxemia appears to be an important factor that underlies the impact of sleep abnormalities on hemodynamic stress in patients with HF.

Editorial Comment: Lee R. Goldberg, p. 1713

Clinical Research.   Mildly Elevated Cardiac Troponin T Predicts Poor Outcomes in Patients With HF

1715

Wayne L. Miller, Karen A. Hartman, Mary F. Burritt, Diane E. Grill, Allan S. Jaffe

Miller and colleagues measured cardiac troponin T (cTnT) every 3 months in stable outpatients with a history of New York Heart Association functional class III to IV heart failure (HF). The primary end point was long-term clinical outcome, specifically death or cardiac transplantation after at least 1 year of stability. Of the 172 patients, 13% experienced death or transplantation during the first year. The remaining patients were divided into 3 groups: 1) those who never had a cTnT elevation (defined as <0.01 ng/ml); 2) those with 1 or more but not all cTnT values elevated; and 3) those who had persistently elevated cTnT values. The event rate was 11% in subjects with persistently normal cTnT levels, 19% in those with intermittent elevations, and 33% in those with persistently elevated cTnT levels. These findings show that elevations in cTnT, even using a low threshold of 0.01 ng/ml, detected during routine clinical follow-up of ambulatory patients are highly predictive of poor outcomes.

	Interventional Cardiology

Top Quarterly Focus Issue: Heart... Interventional Cardiology Cardiovascular Risk Pre-Clinical Research

 
Interventional Cardiology.   Early Results Show Promise for Transcatheter Implantation of Pulmonary Valve in Patients With RVOT Conduits
1722

Evan M. Zahn, William E. Hellenbrand, James E. Lock, Doff B. McElhinney

This study was designed to evaluate the safety, procedural success, and short-term effectiveness of the Melody transcatheter pulmonary valve (Medtronic, Inc., Minneapolis, Minnesota) in patients with dysfunctional right ventricular outflow tract (RVOT) conduits. Standardized entry criteria, implantation, and follow-up protocols were utilized in this multicenter study, which also used core laboratories to evaluate results. The initial conduit Doppler mean gradient was 29 mm Hg, and 94% of patients had moderate or severe pulmonary regurgitation (PR). Implantation was successful in 29 of 30 attempts. There were significant procedural complications in 3 patients. The peak systolic conduit gradient fell acutely from 37 to 17 mm Hg, and no patient had more than mild PR at the end of the procedure. There were no deaths. At 6-month follow-up, conduit Doppler mean gradient and PR fraction remained significantly improved. Implantation of the Melody valve for RVOT conduit dysfunction has encouraging acute and short-term outcomes.

	Cardiovascular Risk

Top Quarterly Focus Issue: Heart... Interventional Cardiology Cardiovascular Risk Pre-Clinical Research

 
Cardiovascular Risk.   High Central PP Is Independently Associated With Adverse Cardiovascular Outcome
1730

Mary J. Roman, Richard B. Devereux, Jorge R. Kizer, Peter M. Okin, Elisa T. Lee, Wenyu Wang, Jason G. Umans, Darren Calhoun, Barbara V. Howard

Roman and colleagues have previously shown that central pulse pressure (PP) is a better predictor of incident cardiovascular disease (CVD) than brachial PP. In this study, they sought to determine a threshold value that predicts adverse outcomes. Radial applanation tonometry was performed in over 2,000 subjects to determine central blood pressure. Quartiles of central PP predicted a CVD event more strongly than quartiles of brachial PP. Central PP 50 mm Hg predicted higher risk regardless of sex, age, or diabetes status. Central PP 50 mm Hg predicts adverse CVD outcomes and may serve as a target in intervention strategies.

	Pre-Clinical Research

Top Quarterly Focus Issue: Heart... Interventional Cardiology Cardiovascular Risk Pre-Clinical Research

 
Pre-Clinical Research.   Ultrasound-Mediated Destruction of Carrier Microbubbles for Endovascular Gene Delivery

1735

Jeremy Kobulnik, Michael A. Kuliszewski, Duncan J. Stewart, Jonathan R. Lindner, Howard Leong-Poi

Kobulnik and colleagues hypothesized that ultrasound-mediated (UM) destruction of intravenously administered deoxyribonucleic acid-bearing carrier microbubbles during their microcirculatory transit may be a more effective way of transfecting cells to stimulate angiogenesis. In a rat model of hind limb ischemia, UM was compared with intramuscular (IM) injections for the efficiency of transfection with vascular endothelial growth factor (VEGF). Microvascular blood volume and microvascular blood flow (MBF) were measured by contrast-enhanced ultrasound. The increase in MBF was greater in UM-treated animals compared with IM. Immunohistochemistry showed that the VEGF localized to the vascular endothelium after UM delivery. These results demonstrate that UM gene delivery produces a pattern of gene expression that may be more efficacious compared with direct IM injections.

Related Articles

The Adrenergic-Fatty Acid Load in Heart Failure

Lionel H. Opie and Juhani Knuuti
J. Am. Coll. Cardiol. 2009 54: 1637-1646. [Abstract] [Full Text] [PDF]

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