This document summarizes several studies related to advanced heart failure: 1) A study of 2,816 patients found that initial strategy (bridge to transplant vs. destination therapy) impacted outcomes, with bridge to transplant having better survival rates. Strategies often changed over time. 2) A study of 50 patients found that placing an intra-aortic balloon pump through the left axillary artery allowed mobility and was a feasible strategy to bridge patients to heart transplantation. 3) A study comparing everolimus to mycophenolate mofetil in preventing cardiac allograft vasculopathy after heart transplant found everolimus was more effective in reducing intimal thickening and cases of vasculopathy.

1. october 2013
volume 1, no. 5 Inside This Issue
MINI FOCUS ISSUE:
ADVANCED HEART
FAILURE
Implant Strategies Change Over Time and Impact Outcomes: Insights
From the INTERMACS (Interagency Registry for Mechanically Assisted
Circulatory Support)
369
Jeffrey J. Teuteberg, Garrick C. Stewart, Mariell Jessup, Robert L. Kormos, Benjamin Sun,
O. H. Frazier, David C. Naftel, Lynne W. Stevenson
In this study the authors investigated how the initial intended strategy at left
ventricular assist device (LVAD) implantation influenced patient outcomes. Left
ventricular assist device implantation strategy impacts candidate selection, reim-
bursement, and clinical trial design; however, concepts of device strategy are
continuing to evolve. For patients entered in the Interagency Registry for
Mechanically Assisted Circulatory Support receiving a primary continuous flow
LVAD between March 2006 and March 2011, initial strategies were bridge to
transplant (BTT), bridge to candidacy (BTC) for transplant, and destination
therapy (DT). Primary analyses compared BTT, BTC, and DT outcomes at 6, 12,
and 24 months. Among 2,816 primary LVAD recipients, implant strategy was
1,060 (38%) BTT, 1,162 (42%) BTC (likely to be listed 796, moderately likely 282,
unlikely 84), and 553 (20%) DT. Compared with BTC/DT, those listed at implant
(BTT) had similar degrees of ventricular dysfunction and hemodynamic status but
generally less comorbidity. Survival (alive with LVAD or transplanted) was superior
at 24 months for BTT versus BTC versus DT (77.7% vs.70.1% vs. 60.7%,
respectively, p < 0.0001). Strategic intent changed over time, at 2 years 43.5% of
BTT patients were no longer listed for transplant, but 29.3% of BTC patients were
listed for transplant. The currently accepted indications only account for 58% of
LVAD implants. Across indications, patients differ by the number and types of
comorbidities rather than the need for hemodynamic support. Regardless of initial
implant strategy, patients often have long durations of support, and strategies often
change over time, challenging the regulatory categorization of LVAD recipients as
either BTT or DT.
EDITORIAL COMMENT
Moving Beyond “Bridges” 379
James C. Fang, Joseph Stehlik
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2. Percutaneous Placement of an Intra-Aortic Balloon Pump in the Left Axillary/
Subclavian Position Provides Safe, Ambulatory Long-Term Support as Bridge
to Heart Transplantation
382
Jerry D. Estep, Andrea M. Cordero-Reyes, Arvind Bhimaraj, Barry Trachtenberg,
Nashwa Khalil, Matthias Loebe, Brian Bruckner, Carlos M. Orrego, Jean Bismuth,
Neal S. Kleiman, Guillermo Torre-Amione
See additional content in the online version of this issue.
The authors evaluated the feasibility, tolerability, and efficacy of a strategy for
percutaneous intra-aortic balloon pump (IABP) placement through the left axillary-
subclavian artery to provide mechanical circulatory support in patients with end-
stage heart failure as a bridge to heart transplantation. The transfemoral approach to
IABP placement is associated with major disadvantages, including the risk for
infection and limitation of patient mobility in those requiring extended support.
Estep and colleagues developed a percutaneous technique for placing IABPs in the
left axillary artery that permits upright sitting and ambulation. They performed
a retrospective review of data from patients who had undergone left axillary IABP
implantation between 2007 and 2012. Fifty patients who received a left axillary
IABP as bridge to transplantation were identified, of whom 42 (84%) underwent
heart or heart–multiorgan transplantation. Cumulative survival on IABP support
was 92%, and post-transplant 90-day survival was 90%. Median duration of support
was 18 days. Four of 50 patients (8%) died while on IABP support, and 3 (6%)
received greater mechanical circulatory support. Four patients (8%) had clinically
significant thromboembolic or bleeding events without long-term sequelae. The
most common minor adverse event was IABP malposition, in 22 patients (44%).
Prolonged IABP support in the heart-transplantation cohort was associated with
significant improvements in mean pulmonary artery pressure and in creatinine and
total bilirubin concentrations. Percutaneous insertion of an IABP through the left
axillary artery is a feasible and relatively well-tolerated strategy to bridge patients
with end-stage heart failure to heart transplantation. This form of mechanical-
device treatment permits upright sitting and ambulation in those requiring extended
support.
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3. Cardiac Allograft Vasculopathy by Intravascular Ultrasound in Heart Transplant
Patients: Substudy From the Everolimus Versus Mycophenolate Mofetil
Randomized, Multicenter Trial
389
Jon A. Kobashigawa, Daniel F. Pauly, Randall C. Starling, Howard Eisen, Heather Ross,
Shoei-Shen Wang, Bernard Cantin, James A. Hill, Patricia Lopez, Gaohong Dong,
Stephen J. Nicholls, on behalf of the A2310 IVUS Substudy Investigators
JACC: Heart Failure CME is available online.
Go to http://heartfailure.onlinejacc.org/ to participate.
See additional content in the online version of this issue.
In a pre-planned substudy of a multicenter randomized trial, the efficacy of ever-
olimus in the prevention of cardiac allograft vasculopathy (CAV) after heart
transplantation was compared to that of mycophenolate mofetil (MMF). Study
patients were a subgroup of the 553-patient A2310 study who underwent heart
transplants and received everolimus or MMF. Intravascular ultrasound was per-
formed at baseline and 12 months. Increase in mean maximal intimal thickness was
smaller in the everolimus group (0.03 mm) compared with the MMF group (0.07
mm; p < 0.001). Incidence of CAV was 12.5% with everolimus versus 26.7% with
MMF (p ¼ 0.018). Everolimus was significantly more efficacious than MMF in
preventing CAV by IVUS criteria.
CLINICAL RESEARCH The STICH Trial (Surgical Treatment for Ischemic Heart Failure):
Mode-of-Death Results
400
Peter Carson, John Wertheimer, Alan Miller, Christopher M. O’Connor, Ileana L. Pina,
Craig Selzman, Carla Sueta, Lilin She, Deborah Greene, Kerry L. Lee, Robert H. Jones,
Eric J. Velazquez, for the STICH Investigators
See additional content in the online version of this issue.
This paper examines the effect of coronary artery bypass grafting added to medical
therapy on committee-adjudicated mode of death in an ischemic cardiomyopathy
population from the STICH (Surgical Treatment for Ischemic Heart Failure) trial.
Compared with medical therapy alone, the results demonstrated that bypass surgery
reduced the 2 most common modes of death: sudden death and fatal pump failure
events. These effects were principally seen after 2 years. A reduction was also seen in
myocardial infarction–related deaths, and there was an increase in cardiovascular
procedure deaths. Noncardiovascular deaths did not differ between treatment
groups.
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4. Characteristics, Adverse Events, and Racial Differences Among Delivering
Mothers With Peripartum Cardiomyopathy
409
David P. Kao, Eileen Hsich, JoAnn Lindenfeld
See additional content in the online version of this issue.
The authors sought to identify clinical features associated with peripartum
cardiomyopathy (PPCM) and possible racial differences and to quantify in-hospital
outcomes in delivering mothers with PPCM. Investigation of patient characteristics
and outcomes in PPCM has been limited to small cohorts. Hospital discharge data
allow assembly of the largest number of PPCM cases to date. Hospital records from
6 states were screened for PPCM. Clinical profiles, maternal, and fetal outcomes in
delivering mothers with and without PPCM were compared and stratified by race.
A maternal major adverse event (MAE) was defined as death, cardiac arrest, heart
transplantation, or mechanical circulatory support. Logistic regression was used to
identify variables associated with PPCM. In total, 535 of 4,003,914 records of
delivering mothers specified a diagnosis of PPCM. Prevalence of PPCM was
highest among African Americans and similar in Caucasians and Hispanics.
Established risk factors including age !30 years, African-American race, hyper-
tension, preeclampsia/eclampsia, and multigestational status were associated with
PPCM, and novel associations such as anemia and asthma were identified. Auto-
immune disease and substance abuse, which can cause cardiomyopathy indepen-
dently, were also associated with PPCM. The prevalence of PPCM at the time of
delivery in Hispanics was similar to Caucasians and lower than African Americans
Maternal MAE and stillbirth occurred more frequently among women with
PPCM.
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5. Tubular Damage and Worsening Renal Function in Chronic Heart Failure 417
Kevin Damman, Serge Masson, Hans L. Hillege, Adriaan A. Voors, Dirk J. van Veldhuisen,
Patrick Rossignol, Gianni Proietti, Savino Barbuzzi, Gian Luigi Nicolosi, Luigi Tavazzi,
Aldo P. Maggioni, Roberto Latini
See additional content in the online version of this issue.
This study sought to investigate the relationship between tubular damage and
worsening renal function (WRF) in chronic heart failure (HF). WRF is associated
with poor outcome in chronic HF. It is unclear whether urinary tubular markers
may identify patients at risk for WRF. In 2,011 patients with chronic HF, the
authors evaluated using urinary tubular markers (N-acetyl-beta-D-glucosaminidase
(NAG), kidney injury molecule (KIM)-1, and neutrophil gelatinase-associated
lipocalin (NGAL) to predict WRF. They assessed the prognostic importance of
WRF. A total of 290 patients (14.4%) experienced WRF during follow-up. Patients
with WRF had lower baseline glomerular filtration rate (GFR) and higher KIM-1,
NAG, and NGAL levels. In a multivariable-adjusted model, KIM-1 was the
strongest independent predictor of WRF independent of GFR and albuminuria.
WRF was a strong and independent predictor of all-cause mortality and HF
hospitalizations. KIM-1 was the strongest independent predictor of WRF and
could therefore be used to identify patients at risk for WRF and poor clinical
outcome.
EDITORIAL COMMENT
Biomarkers of Acute Kidney Injury in Chronic Heart Failure:
What Do the Signals Mean?
425
Jeffrey M. Testani, W. H. Wilson Tang
Effects of Respiratory Exchange Ratio on the Prognostic Value of
Peak Oxygen Consumption and Ventilatory Efficiency in Patients With
Systolic Heart Failure
427
Paul J. Chase, Aarti Kenjale, Lawrence P. Cahalin, Ross Arena, Paul G. Davis,
Jonathan Myers, Marco Guazzi, Daniel E. Forman, Euan Ashley, Mary Ann Peberdy,
Erin West, Christopher T. Kelly, Daniel R. Bensimhon
The purpose of this analysis was to evaluate the prognostic characteristics of peak
oxygen consumption (VO2) and the minute ventilation/carbon dioxide (VE/VCO2)
slope of different peak respiratory exchange ratios obtained from the cardiopul-
monary exercise testing in 1,728 patients with heart failure. Subsequently, the
patients were followed for up to 3 years for major cardiac-related events. Two
hundred seventy major events occurred, with no significant proportional differences
across respiratory exchange ratio subgroups. Univariate and multivariate Cox
regression analysis demonstrated that the VE/VCO2 slope and peak VO2 remained
prognostic within each subgroup; the VE/VCO2 slope was the strongest predictor.
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6. Urocortin-2 Infusion in Acute Decompensated Heart Failure:
Findings From the UNICORN Study (Urocortin-2 in the Treatment of Acute Heart
Failure as an Adjunct Over Conventional Therapy)
433
W. Y. Wandy Chan, Christopher M. Frampton, Ian G. Crozier, Richard W. Troughton,
A. Mark Richards
Urocortin-2 produced favorable integrated hemodynamic, hormonal, and renal
effects in experimental heart failure but there were no equivalent human data. The
authors investigated the effects of urocortin-2 as an adjunct therapy in acute
decompensated heart failure (ADHF). In this randomized, double-blind, placebo-
controlled trial, 53 patients with ADHF were randomly assigned to a 4-h infusion
of urocortin-2 at 5 ng/kg/min or placebo. Ten patients in each study arm also
underwent invasive hemodynamic measurements. Changes in vital signs and
plasma neurohormonal and renal indices during treatment were compared using
repeated-measures analysis of covariance. Urocortin-2 produced greater falls in
systolic blood pressure compared to placebo (16 Æ 5.8 mm Hg, p < 0.001).
Cardiac output was significantly augmented with an associated 47% reduction in
calculated total peripheral resistance (p = 0.015) but without significant reflex
tachycardia. B-type natriuretic peptide levels fell significantly over 24 h with
urocortin-2 (p < 0.01) but not with placebo. There was a transient reduction in
urine volume and creatinine clearance and a rise in plasma renin activity with
urocortin-2 infusion concurrently with fall in blood pressure. These indices
returned to baseline in the post infusion phase when blood pressure improved. The
renal and hormonal effects of urocortin-2 might be masked by the response
induced by hypotension. Further investigations are required to uncover the full
potential of urocortin-2 in treating ADHF.
EDITORIAL COMMENT
The Challenge of Drug Development in Acute Heart Failure:
Balancing Mechanisms, Targeting Patients, and Gambling on Outcomes
442
Peter S. Pang, Michael M. Givertz
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7. Associations Between Use of the Hospitalist Model and Quality of Care
and Outcomes of Older Patients Hospitalized for Heart Failure
445
Robb D. Kociol, Bradley G. Hammill, Gregg C. Fonarow, Paul A. Heidenreich, Alan S. Go,
Eric D. Peterson, Lesley H. Curtis, Adrian F. Hernandez
See additional content in the online version of this issue.
The hospitalist model of inpatient care has grown nationally, but its associations
with quality of care and outcomes of patients hospitalized with heart failure are not
known. In this large study linking data from the American Heart Association’s
Get With the Guidelines-Heart Failure registry to Medicare claims, the use of
hospitalists was associated with shorter length of stay and better adherence but was
not associated with improved patient outcomes at 30 days. Comanagement by
hospitalists and cardiologists may help to improve adherence to some quality
measures, but it remains unclear what care model improves 30-day clinical
outcomes.
CORRESPONDENCE
Research
Correspondence
Is Dual Renin-Angiotensin-System Blockade Associated With Increased
Risk of Stroke?
454
Harikrishna Makani, Sripal Bangalore, Peter Sever, Franz H. Messerli
EDITOR'S PAGE JACC: Heart Failure Fellows Program: Training the Next Generation 458
Christopher O’Connor
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