Early Assessment of Cardiac Allograft Vasculopathy Risk Among Recipients of Hepatitis C Virus-infected Donors in the Current Era.

BACKGROUND: Transplantation of hearts from hepatitis C virus (HCV)-positive donors has increased substantially in recent years following development of highly effective direct-acting antiviral therapies for treatment and cure of HCV. Although historical data from the pre-direct-acting antiviral era demonstrated an association between HCV-positive donors and accelerated cardiac allograft vasculopathy (CAV) in recipients, the relationship between the use of HCV nucleic acid test-positive (NAT+) donors and the development of CAV in the direct-acting antiviral era remains unclear. METHODS AND RESULTS: We performed a retrospective, single-center observational study comparing coronary angiographic CAV outcomes during the first year after transplant in 84 heart transplant recipients of HCV NAT+ donors and 231 recipients of HCV NAT- donors. Additionally, in a subsample of 149 patients (including 55 in the NAT+ cohort and 94 in the NAT- cohort) who had serial adjunctive intravascular ultrasound examination performed, we compared development of rapidly progressive CAV, defined as an increase in maximal intimal thickening of ≥0.5 mm in matched vessel segments during the first year post-transplant. In an unadjusted analysis, recipients of HCV NAT+ hearts had reduced survival free of CAV ≥1 over the first year after heart transplant compared with recipients of HCV NAT- hearts. After adjustment for known CAV risk factors, however, there was no significant difference between cohorts in the likelihood of the primary outcome, nor was there a difference in development of rapidly progressive CAV. CONCLUSIONS: These findings support larger, longer-term follow-up studies to better elucidate CAV outcomes in recipients of HCV NAT+ hearts and to inform post-transplant management strategies.

Outcomes of Heart Transplant Donation After Circulatory Death.

BACKGROUND: Heart transplantation using donation after circulatory death (DCD) allografts is increasingly common, expanding the donor pool and reducing transplant wait times. However, data remain limited on clinical outcomes. OBJECTIVES: We sought to compare 6-month and 1-year clinical outcomes between recipients of DCD hearts, most of them recovered with the use of normothermic regional perfusion (NRP), and recipients of donation after brain death (DBD) hearts. METHODS: We conducted a single-center retrospective observational study of all adult heart-only transplants from January 2020 to January 2023. Recipient and donor data were abstracted from medical records and the United Network for Organ Sharing registry, respectively. Survival analysis and Cox regression were used to compare the groups. RESULTS: During the study period, 385 adults (median age 57.4 years [IQR: 48.0-63.7 years]) underwent heart-only transplantation, including 122 (32%) from DCD donors, 83% of which were recovered with the use of NRP. DCD donors were younger and had fewer comorbidities than DBD donors. DCD recipients were less often hospitalized before transplantation and less likely to require pretransplantation temporary mechanical circulatory support compared with DBD recipients. There were no significant differences between groups in 1-year survival, incidence of severe primary graft dysfunction, treated rejection during the first year, or likelihood of cardiac allograft vasculopathy at 1 year after transplantation. CONCLUSIONS: In the largest single-center comparison of DCD and DBD heart transplantations to date, outcomes among DCD recipients are noninferior to those of DBD recipients. This study adds to the published data supporting DCD donors as a safe means to expand the heart donor pool.

Randomized controlled trial of urinE chemiStry guided aCute heArt faiLure treATmEnt (ESCALATE): Rationale and design.

Diuresis to achieve decongestion is a central aim of therapy in patients hospitalized for acute decompensated heart failure (ADHF). While multiple clinical trials have investigated initial diuretic strategies for a designated period of time, there is a paucity of evidence to guide diuretic titration strategies continued until decongestion is achieved. The use of urine chemistries (urine sodium and creatinine) in a natriuretic response prediction equation accurately estimates natriuresis in response to diuretic dosing, but a randomized clinical trial is needed to compare a urine chemistry-guided diuresis strategy with a strategy of usual care. The urinE chemiStry guided aCute heArt faiLure treATmEnt (ESCALATE) trial is designed to test the hypothesis that protocolized diuretic therapy guided by spot urine chemistry through completion of intravenous diuresis will be superior to usual care and improve outcomes over the 14 days following randomization. ESCALATE will randomize and obtain complete data on 450 patients with acute heart failure to a diuretic strategy guided by urine chemistry or a usual care strategy. Key inclusion criteria include an objective measure of hypervolemia with at least 10 pounds of estimated excess volume, and key exclusion criteria include significant valvular stenosis, hypotension, and a chronic need for dialysis. Our primary outcome is days of benefit over the 14 days after randomization. Days of benefit combines patient symptoms captured by global clinical status with clinical state quantifying the need for hospitalization and intravenous diuresis. CLINICAL TRIAL REGISTRATION: NCT04481919.

Early Blood Pressure Variables Associated With Improved Outcomes in VA-ECLS: The ELSO Registry Analysis.

BACKGROUND: As utilization of veno-arterial extracorporeal life support (VA-ECLS) in treatment of cardiogenic shock (CS) continues to expand, clinical variables that guide clinicians in early recognition of myocardial recovery and therefore, improved survival, after VA-ECLS are critical. There remains a paucity of literature on early postinitiation blood pressure measurements that predict improved outcomes. OBJECTIVES: The objective of this study is to help identify early blood pressure variables associated with improved outcomes in VA-ECLS. METHODS: The authors queried the ELSO (Extracorporeal Life Support Organization) registry for cardiogenic shock patients treated with VA-ECLS or venovenous arterial ECLS between 2009 and 2020. Their inclusion criteria included treatment with VA-ECLS or venovenous arterial ECLS; absence of pre-existing durable right, left, or biventricular assist devices; no pre-ECLS cardiac arrest; and no surgical or percutaneously placed left ventricular venting devices during their ECLS runs. Their primary outcome of interest was the survival to discharge during index hospitalization. RESULTS: A total of 2,400 CS patients met the authors' inclusion criteria and had complete documentation of blood pressures. Actual mortality during index hospitalization in their cohort was 49.5% and survivors were younger and more likely to be Caucasian, intubated for >30 hours pre-ECLS initiation, and had a favorable baseline SAVE (Survival After Veno-arterial ECMO) score (P < 0.05 for all). Multivariable regression analyses adjusting for SAVE score, age, ECLS flow at 4 hours, and race showed that every 10-mm Hg increase in baseline systolic blood pressure (HR: 0.92 [95% CI: 0.89-0.95]; P < 0.001), and baseline pulse pressure (HR: 0.88 [95% CI: 0.84-0.91]; P < 0.001) at 24 hours was associated with a statistically significant reduction in mortality. CONCLUSIONS: Early (within 24 hours) improvements in pulse pressure and systolic blood pressure from baseline are associated with improved survival to discharge among CS patients treated with VA-ECLS.

Modification of ventriculo-arterial coupling by spironolactone in nonischemic dilated cardiomyopathy.

AIMS: We sought to clarify the role of ventriculo-arterial (V-A) coupling in the treatment of nonischemic dilated cardiomyopathy (NIDCM) by adding a mineralocorticoid receptor antagonist (MRA) to conventional anti-failure therapy. METHODS AND RESULTS: We employed cardiac magnetic resonance imaging to quantify left ventricular (LV) contractility and V-A coupling in normal subjects at rest (n = 11) and in patients with NIDCM (n = 12) before and after long term anti-failure therapy, in which MRA was added to conventional anti-failure therapy. After ≥6 months' treatment in NIDCM patients, LV volumes and mass decreased, and the LV ejection fraction increased from a median of 24% (17, 27) (interquartile range IQR) to 47 (42, 52) (P < 0.002), with a marked reduction in arterial elastance (Ea) from 2.89 mmHg/mL (2.34, 4.0) to 1.50 (1.29, 1.95) (P < 0.002), similar to Ea of normal subjects, 1.53 (1.34, 1.67) (P > 0.05). The V-A coupling ratio, Ea/end-systolic elastance (single-beat method), decreased by -1.08 (-1.96, -0.55), (P = 0.003), as did Ea/end-systolic pressure/end-systolic pressure ratio, -0.54 (0.35, 0.87), (P = 0.002). The preload recruitable stroke work (PRSW) increased as did PRSW indexed for Ea (both P = 0.002), which reflected 'total circulatory performance'. CONCLUSIONS: In NIDCM, adding MRA to conventional anti-failure therapy markedly improved LV ejection fraction and reduced peripheral vascular resistance, due to both improved LV contractility and especially to enhanced V-A coupling, as Ea decreased to normal. Total circulatory performance was a sensitive indicator of both LV pump performance and the arterial loading conditions.

Trends in Renal Function Among Heart Transplant Recipients of Donor-Derived Hepatitis C Virus.

Donor-derived hepatitis C (dd-HCV) infection may increase the risk of renal impairment (RI) among heart transplantation (HT) recipients. Sofosbuvir, an integral component of HCV direct-acting antivirals (DAAs) has also been linked to RI. To date, no study has examined the trends in renal function for HT recipients of dd-HCV infection and assessed safety and efficacy of Sofosbuvir-based DAAs. Between September 2016 and June 2018, 46 HCV-naive patients and one patient with a history of HCV treated pretransplant, underwent HT from HCV-positive donors (follow-up available through October 10, 2018). Patients were treated with Ledipasvir-Sofosbuvir (genotype 1) or Sofosbuvir-Velpatasvir (genotype 3) for 12 or 24 weeks; no dose adjustments were made for renal function. Data on renal function were available for 23 patients who achieved a sustained virologic response at 12 weeks after the treatment (SVR12; cohort A) and 18 patients who completed 1 year of follow-up (cohort B). Treatment of dd-HCV infection was initiated at a median of 6 weeks post-HT. In both cohorts, a nonsignificant reduction in median estimated glomerular filtration rate (eGFR; ml/min/1.73 m) was noted (cohort A: pretransplant eGFR: 62 [interquartile range {IQR}: 1-84] to SVR12 eGFR: 49 [IQR: 37-82]; p = 0.43; cohort B: pretransplant eGFR: 65 [IQR: 54-84] to 1 year post-HT eGFR: 56 [IQR: 39-75]; p = 0.29). Pretreatment renal function had no significant impact on changes in renal function during treatment. All patients tolerated DAAs well with 100% completion rate to the assigned therapy and duration and 100% success at achieving SVR12. In this first and largest reported case series to date of HT recipients with dd-HCV infection, we observed that neither the dd-HCV infection nor its treatment with Sofosbuvir-based DAAs increased the risk of RI. Sofosbuvir-based DAAs appear safe, tolerable, and effective for HCV treatment even in presence of severe RI.

Expanding Heart Transplant in the Era of Direct-Acting Antiviral Therapy for Hepatitis C.

Importance: For patients awaiting heart transplant, hepatitis C-positive donors offer an opportunity to expand the donor pool, shorten wait times, and decrease wait-list mortality. While early reported outcomes among few heart transplant recipients have been promising, knowledge of 1-year outcomes in larger cohorts of patients is critical to shared decision-making with patients about this option. Objective: To better define the association of hepatitis C-positive donors with heart transplant volumes, wait-list duration, the transmission and cure of donor-derived hepatitis C, and morbidity and mortality at 1 year. Design, Setting, and Participants: This was a prospective, single-center observational study of 80 adult (age 18 years or older) patients who underwent heart transplant using hearts from hepatitis C-positive donors between September 2016 and April 2019 at a large academic medical center. Among donors, who were considered hepatitis C-positive if results from hepatitis C antibody and/or nucleic acid testing were positive, 70 had viremia and 10 were seropositive but did not have viremia. Follow-up was available through May 15, 2019. Comparisons were drawn with patients who underwent transplant with hearts from hepatitis C-negative donors during the same period. Exposures: In addition to standard posttransplant management, transplant recipients who developed donor-derived hepatitis C infection were treated with direct-acting antivirals. Main Outcomes and Measures: The main outcomes included wait-list duration and 1-year survival in all patients, and for those who developed donor-derived hepatitis C, the response to direct-acting antiviral treatment. Results: Of 80 patients, 57 (71.3%) were men, 55 (68.7%) were white, and 17 (26.3%) were black; the median age at transplant was 54.5 years (interquartile range, 46-62 years). Following consent to accept hearts from hepatitis C-exposed donors, the median days to heart transplant was 4 (interquartile range, 1-18). No recipients of donors with negative nucleic acid testing results (10 [12.5%]) developed donor-derived hepatitis C. Of 70 patients who were recipients of donors with positive nucleic acid testing results, 67 (95.7%) developed donor-derived hepatitis C over a median follow-up of 301 days (interquartile range, 142-617). Treatment with direct-acting antivirals was well tolerated and yielded sustained virologic responses in all treated patients. Within the cohort with infection, 1-year patient survival was 90.4%, which was not significantly different compared with the cohort without infection or with patients who received transplants from hepatitis C-negative donors during the same period. Conclusions and Relevance: In the era of direct-acting antivirals, hepatitis C-positive donors are a viable option to expand the donor pool, potentially reducing wait-list duration and mortality. In heart transplant recipients with donor-derived hepatitis C, infection is well-tolerated and curable, and 1-year survival is equivalent to that in recipients of hepatitis C-negative donors.

Anticoagulation Reversal and Risk of Thromboembolic Events Among Heart Transplant Recipients Bridged with Durable Mechanical Circulatory Support Devices.

Anticoagulation reversal agents (ARAs) can minimize bleeding complications associated with mechanical circulatory support devices (MCSDs) explantation at the time of heart transplantation (HT); data on thromboembolic (TE) risk associated with ARAs are limited in this patient population. In this single-center study, we retrospectively analyzed 118 consecutive adults who were supported with durable MCSDs and underwent HT between May 2013 and October 2016. Patients were categorized based on intraoperative use of ARAs (recombinant factor VIIa [n=23], 4-factor prothrombin complex concentrate [n=48], or factor IX complex [n=2]) at the time of HT; these agents were used at discretion of implanting surgeons for bleeding control. The primary outcome of interest was presence of venous or systemic TE events within 3 months of HT. Multivariable logistic regression analyses were used to assess association between TE events and use of ARAs. A total of 71 (60%) patients received ARAs, and a total of 32 patients (27.1%) had TE events (25 venous [median time to diagnosis: 11.5 days; interquartile range {IQR}: 9-31 days], and 10 systemic [median time to diagnosis: 5.5 days; IQR: 4-8 days]); 26 (81.2%) of those with TE events had ARAs used at the time of HT. Multivariable analysis identified use of ARAs as an independent predictor of TE events (multivariable odds ratio: 3.06; 95% CI: 1.09-8.58; p = 0.034). Unplanned intraoperative use of ARAs to control bleeding was associated with a significantly higher risk of TE events among HT recipients bridged with durable MCSD. Future studies are required to further assess safety of these agents and their impact on patient outcomes.

Timing of Left Ventricular Remodeling in Nonischemic Dilated Cardiomyopathy.

BACKGROUND: Mineralocorticoid receptor antagonist (MRA) treatment produces beneficial left ventricular (LV) remodeling in nonischemic dilated cardiomyopathy (NIDCM). This study addressed the timing of maximal beneficial LV remodeling in NIDCM when adding MRA. MATERIALS AND METHODS: We studied 12 patients with NIDCM on stable ß-blocker and angiotensin-converting enzyme inhibitor/angiotensin receptor-blocking therapy who underwent cardiac magnetic resonance imaging before and after 6-31 months of continuous MRA therapy. RESULTS: At baseline, the LV ejection fraction (LVEF) was 24% (19-27); median [interquartile range]. The LV end-systolic volume index (LVESVI) was 63 ml (57-76) and the LV stroke volume index (LVSVI) was 19 ml (14-21), all depressed. After adding MRA to the HF regimen, the LVEF increased to 47% (42-52), with a decrease in LVESVI to 36 ml (33-45) and increase in LVSVI to 36 ml (28-39) (for each, P < 0 .0001). Using generalized least squares analysis, the maximal beneficial remodeling (defined by maximal increase in LVEF, the maximal decrease in LVESVI and maximal increase in LVSVI) was achieved after approximately 12-16 months of MRA treatment. CONCLUSIONS: Adding MRA to a standard medical regimen for NIDCM resulted in beneficial LV remodeling. The maximal beneficial remodeling was achieved with 12-16 months of MRA therapy. These results have implications for the timing of other advanced therapies, such as placing internal cardioverter-defibrillators.

Early outcomes using hepatitis C-positive donors for cardiac transplantation in the era of effective direct-acting anti-viral therapies.

BACKGROUND: Given the shortage of suitable donor hearts for cardiac transplantation, and the favorable safety and efficacy of current agents used to treat hepatitis C virus (HCV), our institution recently piloted transplantation of select patients using HCV-positive donors. METHODS: Between September 2016 and March 2017, 12 HCV-naive patients and 1 patient with a history of treated HCV underwent heart transplantation (HT) using hearts from HCV-positive donors after informed consent. Patients who acquired HCV were referred to hepatology and treated with direct-acting anti-viral therapies (DAAs). Data collection and analysis were performed with institutional review board approval. RESULTS: At the time of HT, mean age of recipients was 53 ± 10 years, and 8 patients (61.5%) were on left ventricular assist device support. After consent to consider an HCV-positive heart, mean time to HT was 11 ± 12 days. Nine of 13 patients (69%) developed HCV viremia after transplant, including 8 who completed DAA treatment and demonstrated cure, as defined by a sustained virologic response 12 weeks after treatment. One patient died during Week 7 of his treatment due to pulmonary embolism. DAAs were well tolerated in all treated patients. CONCLUSIONS: In the era of highly effective DAAs, the use of HCV-positive donors represents a potential approach to safely expand the donor pool. Additional follow-up is needed to elucidate long-term outcomes.

Cardiac rehabilitation and readmissions after heart transplantation.

BACKGROUND: Exercise-based cardiac rehabilitation (CR) is under-utilized. CR is indicated after heart transplantation, but there are no data regarding CR participation in transplant recipients. We characterized current CR utilization among heart transplant recipients in the United States and the association of CR with 1-year readmissions using the 2013-2014 Medicare files. METHODS: The study population included Medicare beneficiaries enrolled due to disability (patients on the transplant list are eligible for disability benefits under Medicare regulations) or age ≥65 years. We identified heart transplant patients by diagnosis codes and cumulative CR sessions occurring within 1 year after the transplant hospitalization. RESULTS: There were 2,531 heart transplant patients in the USA in 2013, of whom 595 (24%) received Medicare coverage and were included in the study. CR utilization was low, with 326 patients (55%) participating in CR programs. The Midwest had the highest proportion of transplant recipients initiating CR (68%, p = 0.001). Patients initiating CR attended a mean of 26.7 (standard deviation 13.3) sessions, less than the generally prescribed program of 36 sessions. Transplant recipients age 35 to 49 years were less likely to initiate CR (odds ratio [OR] 0.39, 95% confidence interval [CI] 0.23 to 0.66, p < 0.001) and attended 8.2 fewer sessions (95% CI 3.5 to 12.9, p < 0.001) than patients age ≥65 years. CR participation was associated with a 29% lower 1-year readmission risk (95% CI 13% to 42%, p = 0.001). CONCLUSIONS: Only half of cardiac transplant recipients participate in CR, and those who do have a lower 1-year readmission risk. These data invite further study on barriers to CR in this population.

Myocardial T1 Measurement Predicts Beneficial LV Remodeling After Long-Term Heart Failure Therapy.

BACKGROUND: The myocardial longitudinal relaxation time (T1) on cardiac magnetic resonance imaging (CMR) can quantify myocardial fibrosis in the presence or absence of visually detectable late gadolinium (Gd) enhancement (LGE). Mineralocorticoid receptor antagonist (MRA) treatment produces beneficial remodeling in nonischemic dilated cardiomyopathy (NIDCM). We assessed the hypothesis that interstitial myocardial fibrosis measured with the use of CMR predicts left ventricular (LV) beneficial remodeling in NIDCM after heart failure (HF) treatment including MRAs. METHODS AND RESULTS: Twelve patients with NIDCM, on stable beta-blocker and angiotensin-converting enzyme inhibitor/angiotensin receptor-blocking therapy, were studied before and after 6-29 months of treatment with MRAs, by means of CMR assessment of LV structure, function, and T1 from standard Look-Locker sequences (T1LL). All patients had depressed cardiac function, dilated left ventricles, and no visual LGE. After adding MRA to HF treatment, the LV ejection fraction increased and the LV end-systolic volume index (LV end-systolic volume/m2) decreased in all patients (P < .0001). This this was inversely proportional to the baseline myocardial T1LL (r = -0.65; P = .02). CONCLUSION: Myocardial T1LL, in the absence of visually detectable LGE, was quantitatively related to the degree of beneficial LV remodeling achieved in response to adding MRA to a HF regimen.

Randomized, Controlled Trial of an Advance Care Planning Video Decision Support Tool for Patients With Advanced Heart Failure.

BACKGROUND: Conversations about goals of care and cardiopulmonary resuscitation (CPR)/intubation for patients with advanced heart failure can be difficult. This study examined the impact of a video decision support tool and patient checklist on advance care planning for patients with heart failure. METHODS: This was a multisite, randomized, controlled trial of a video-assisted intervention and advance care planning checklist versus a verbal description in 246 patients ≥64 years of age with heart failure and an estimated likelihood of death of >50% within 2 years. Intervention participants received a verbal description for goals of care (life-prolonging care, limited care, and comfort care) and CPR/intubation plus a 6-minute video depicting the 3 levels of care, CPR/intubation, and an advance care planning checklist. Control subjects received only the verbal description. The primary analysis compared the proportion of patients preferring comfort care between study arms immediately after the intervention. Secondary outcomes were CPR/intubation preferences and knowledge (6-item test; range, 0-6) after intervention. RESULTS: In the intervention group, 27 (22%) chose life-prolonging care, 31 (25%) chose limited care, 63 (51%) selected comfort care, and 2 (2%) were uncertain. In the control group, 50 (41%) chose life-prolonging care, 27 (22%) selected limited care, 37 (30%) chose comfort care, and 8 (7%) were uncertain (P<0.001). Intervention participants (compared with control subjects) were more likely to forgo CPR (68% versus 35%; P<0.001) and intubation (77% versus 48%; P<0.001) and had higher mean knowledge scores (4.1 versus 3.0; P<0.001). CONCLUSIONS: Patients with heart failure who viewed a video were more informed, more likely to select a focus on comfort, and less likely to desire CPR/intubation compared with patients receiving verbal information only. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01589120.

High reproducibility of adenosine stress cardiac MR myocardial perfusion imaging in patients with non-ischaemic dilated cardiomyopathy.

OBJECTIVE: To evaluate the reproducibility of first-pass contrast-enhanced cardiac MR (CMR) myocardial perfusion imaging in patients with non-ischaemic dilated cardiomyopathy (NIDCM). DESIGN: Prospective observational study. SETTING: Single centre, tertiary care hospital. PARTICIPANTS: 6 outpatient participants with NIDCM. OUTCOME: Reproducibility of semiquantitative myocardial perfusion analysis by CMR. METHOD: 6 patients with NIDCM were studied twice using first-pass of contrast transit through the left ventricular (LV) myocardium with a saturation-recovery gradient echo sequence at rest and during adenosine-induced hyperaemia. The anterior wall was divided into endocardial (Endo) and epicardial (Epi) segments. The Myocardial Perfusion Index (MPI) was calculated as the myocardial signal augmentation rate normalised to the LV cavity rate. The Myocardial Perfusion Reserve Index (MPRI) was calculated as hyperaemic/resting MPI. RESULTS: Between study 1 and 2, median MPI was similar for resting Endo (0.076 vs 0.077), hyperaemic Endo (0.143 vs 0.143), resting Epi (0.073 vs 0.074), and hyperaemic Epi (0.135 vs 0.134). Median MPRI was similar for Endo (1.84 vs 1.87) and Epi (1.90 vs 2.00). Combining Endo and Epi MPI (N=12), there was excellent agreement between Study 1 and 2 for resting MPI (r=0.998, intraclass correlation coefficient (ICC) 0.998, coefficients of variation (CoV) 1.4%), hyperaemic MPI (r=0.979, ICC 0.963, CoV 3.3%) and MPRI (r=0.989, ICC 0.94, CoV 3.8%). CONCLUSIONS: Resting and hyperaemic myocardial perfusion using a normalised upslope analysis during adenosine CMR is a highly reproducible technique in patients with NIDCM. TRIAL REGISTRATION NUMBER: Clinical Trials.Gov ID NCT00574119.

Antifailure therapy including spironolactone improves left ventricular energy supply-demand relations in nonischemic dilated cardiomyopathy.

BACKGROUND: Left ventricular (LV) energy supply-demand imbalance is postulated to cause "energy starvation" and contribute to heart failure (HF) in nonischemic dilated cardiomyopathy (NIDCM). Using cardiac magnetic resonance (CMR) and [(11)C] acetate positron emission tomography (PET), we evaluated LV perfusion and oxidative metabolism in NIDCM and the effects of spironolactone on LV supply-demand relations. METHODS AND RESULTS: Twelve patients with NIDCM underwent CMR and PET at baseline and after ≥6 months of spironolactone therapy added to a standard HF regimen. The myocardial perfusion reserve index (MPRI) was calculated after gadolinium injection during adenosine, as compared to rest. The monoexponential clearance rate of [(11)C] acetate (kmono) was used to calculate the work metabolic index (WMI), an index of LV mechanical efficiency, and kmono/RPP (rate-pressure product), an index of energy supply/demand. At baseline, the subendocardium was hypoperfused versus the subepicardium (median MPRI, 1.63 vs. 1.80; P<0.001), but improved to 1.80 (P<0.001) after spironolactone. The WMI increased (P=0.001), as did kmono/RPP (P=0.003). These improvements were associated with reverse remodeling, increased LV ejection fraction, and decreases in LV mass and systolic wall stress (all P<0.002). CONCLUSIONS: NIDCM is associated with subendocardial hypoperfusion and impaired myocardial oxidative metabolism, consistent with energy starvation. Antifailure therapy improves parameters of energy starvation and is associated with augmented LV performance. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov/ Unique identifier: ID NCT00574119.

Impairment of subendocardial perfusion reserve and oxidative metabolism in nonischemic dilated cardiomyopathy.

BACKGROUND: Cardiac magnetic resonance (CMR) and [(11)C]acetate positron emission tomography (PET) were used to assess the hypothesis that patients with nonischemic dilated cardiomyopathy (NIDCM) have decreased subendocardial perfusion reserve and impaired oxidative metabolism, consistent with the concept of "energy starvation" in heart failure (HF). METHODS AND RESULTS: CMR myocardial perfusion was evaluated in 13 NIDCM patients and 15 control subjects with coronary risk factors and normal myocardial perfusion. The NIDCM patients underwent [(11)C]acetate PET. The myocardial perfusion index (MPI) was calculated as the normalized rate of myocardial signal augmentation following gadolinium contrast injection. Hyperemic transmural, subendocardial, and subepicardial MPI were reduced in NIDCM compared with control subjects [0.13 vs 0.18 (P < .001), 0.13 vs 0.17 (P < .001), and 0.13 vs 0.17 (P = .008), respectively]. The subendocardial perfusion reserve was 1.59 ± 0.21 vs 1.86 ± 0.32 for the subepicardium (P = .002), demonstrating reduced perfusion reserve. The myocardial oxidative metabolic rate (kmono) per unit demand (rate-pressure product) was reduced in proportion to perfusion reserve (P = .02) CONCLUSIONS: Impaired subendocardial perfusion reserve in NIDCM confirmed results previously attained only in animal models. Impaired perfusion and impaired oxidative metabolism are consistent with subendocardial energy starvation in HF.

Benefits of ambulatory axillary intra-aortic balloon pump for circulatory support as bridge to heart transplant.

OBJECTIVE: Axillary intra-aortic balloon pump therapy has been described as a bridge to transplant. Advantages over femoral intra-aortic balloon pump therapy include reduced incidence of infection and enhanced patient mobility. We identified the patients who would benefit most from this therapy while awaiting heart transplantation. METHODS: We conducted a single-center, retrospective observational study to evaluate outcomes from axillary intra-aortic balloon pump therapy. These included hemodynamic parameters, duration of support, and success in bridging to transplant. We selected patients on the basis of history of sternotomy, elevated panel-reactive antibody, and small body habitus. Patients were made to ambulate aggressively beginning on postoperative day 1. RESULTS: Between September 2007 and September 2010, 18 patients underwent axillary intra-aortic balloon pump therapy. All patients had the devices placed through the left axillary artery with a Hemashield side graft (Boston Scientific, Natick, Mass). Before axillary placement, patients underwent femoral placement to demonstrate hemodynamic benefit. Duration of support ranged from 5 to 63 days (median = 19 days). There was marked improvement in ambulatory potential and hemodynamic parameters, with minimal blood transfusion requirements. There were no device-related infections. Some 72% of the patients (13/18) were successfully bridged to transplantation. CONCLUSIONS: Axillary intra-aortic balloon pump therapy provides excellent support for selected patients as a bridge to transplant. The majority of the patients were successfully bridged to transplant and discharged. Although this therapy has been described in previous studies, this is the largest series to incorporate a regimen of aggressive ambulation with daily measurements of distances walked.

Episodes of acute heart failure syndrome are associated with increased levels of troponin and extracellular matrix markers.

BACKGROUND: Increased myocyte loss and extracellular matrix (ECM) turnover are central mechanisms that contribute to pathological myocardial remodeling in chronic heart failure (HF). We tested the hypothesis that episodes of acute HF syndrome (AHFS) are associated with transient increases in markers of myocyte injury and ECM turnover beyond those observed in chronic stable HF. METHODS AND RESULTS: Markers of myocyte injury and ECM turnover were assessed in 80 patients prospectively divided into 3 groups: AHFS (n=39); chronic stable systolic HF (n=21); and control subjects without HF (n=20). Myocyte injury was assessed by measuring plasma troponin I. ECM turnover was assessed by measuring plasma matrix metalloproteinases, tissue inhibitors of matrix metalloproteinases, and procollagen N-terminal type I and procollagen type III N-terminal peptides. In the AHFS group, biomarkers were obtained (1) at the time of hospital admission for an episode of HF decompensation, (2) at the time of hospital discharge, and (3) several weeks after discharge in patients who had returned to a chronic stable compensated state. In patients with stable HF (versus non-HF controls), there was a small increase in troponin I and little or no difference in any marker of ECM turnover. In patients with AHFS, troponin I and 3 markers of ECM turnover (matrix metalloproteinases-2, tissue inhibitors of matrix metalloproteinases-1, and procollagen type III N-terminal peptides) were elevated (versus chronic stable HF), and all fell toward chronic HF levels in patients who returned to a compensated state. CONCLUSIONS: Episodes of AHFS are associated with transient increases in markers of myocyte injury and ECM turnover that may reflect an acceleration of pathological myocardial remodeling during AHFS.

Arterial stiffness and vascular load in heart failure.

Vascular load is an important determinant of ventricular function. This is particularly true of the failing heart, which is exquisitely load-sensitive. Vascular load comprises 2 major components: resistive load, which arises primarily at the arteriolar resistance vessels, and pulsatile load, which is primarily determined by aortic stiffness and early return of reflected waves from the periphery to the heart. Assessment of pulsatile load is gaining increasing prominence as evidence grows of a significant pathophysiologic role for arterial stiffness in cardiovascular disease, including heart failure. Assessment of arterial stiffness and vascular load is reviewed here. The importance of optimal ventricular-vascular coupling to maximize the efficiency of cardiac ejection is discussed. Current knowledge of arterial stiffness, vascular load, and ventricular-vascular coupling in systolic heart failure and in heart failure with a normal ejection fraction ("diastolic failure") is described. Reducing aortic stiffness may form an important future therapeutic target in patients with heart failure.