Stabilization of Rapidly Progressive Cardiac Allograft Vasculopathy Using mTOR Inhibition After Heart Transplantation.

BACKGROUND: Inhibition of the mammalian target of rapamycin (mTor) pathway after heart transplantation has been associated with reduced progression of coronary allograft vasculopathy (CAV). The application of low-dose mTOR inhibition in the setting of modern immunosuppression, including tacrolimus, remains an area of limited exploration. METHODS: This retrospective study included patients who received heart transplantation between January 2009 and January 2019 and had baseline, 1-year and 2-3-year coronary angiography with intravascular ultrasound (IVUS). Intimal thickness in 5 segments along the left anterior descending artery was compared across imaging time points in patients who were transitioned to low-dose mTOR inhibitor (sirolimus) vs standard treatment with mycophenolate on a background of tacrolimus. Long-term adverse cardiovascular outcomes (revascularization, severe CAV, retransplant, and cardiovascular death) were also assessed. RESULTS: Among 216 patients (mean age 51.5 ± 11.9 years, 77.8% men, 80.1% white), 81 individuals (37.5%) were switched to mTOR inhibition. mTOR inhibition was associated with a reduction in intimal thickness by 0.05 mm (95% CI 0.02-0.07; P < 0.001). This reduction was driven by patients who met the criteria for rapidly progressive CAV 1-year post-transplant (0.12 mm; P = 0.016 for interaction). After a median follow-up of 8.6 (IQR 6.6-11) years, 40 patients had major adverse cardiovascular outcomes. The use of mTOR inhibitors was not significantly associated with cardiovascular outcomes (P = 0.669). CONCLUSION: Transitioning patients after heart transplantation to an immunosuppression regimen composed of low-dose mTOR inhibition and tacrolimus was associated with a lack of progression of CAV, particularly in those with rapidly progressive CAV at 1 year, but not with long-term cardiovascular outcomes.

Dapagliflozin Improves Heart Failure Symptoms and Physical Limitations Across the Full Range of Ejection Fraction: Pooled Patient-Level Analysis From DEFINE-HF and PRESERVED-HF Trials.

BACKGROUND: Patients with heart failure (HF) have a high burden of symptoms and physical limitations, regardless of ejection fraction (EF). Whether the benefits of SGLT2 (sodium-glucose cotransporter-2) inhibitors on these outcomes vary across the full range of EF remains unclear. METHODS: Patient-level data were pooled from the DEFINE-HF trial (Dapagliflozin Effects on Biomarkers, Symptoms, and Functional Status in Patients With Heart Failure With Reduced Ejection Fraction) of 263 participants with reduced EF (≤40%), and PRESERVED-HF trial (Effects of Dapagliflozin on Biomarkers, Symptoms and Functional Status in Patients With Preserved Ejection Fraction Heart Failure) of 324 participants with preserved EF (≥45%). Both were randomized, double-blind 12-week trials of dapagliflozin versus placebo, recruiting participants with New York Heart Association class II or higher and elevated natriuretic peptides. The effect of dapagliflozin on the change in the Kansas City Cardiomyopathy Questionnaire (KCCQ) Clinical Summary Score (CSS) at 12 weeks was tested with ANCOVA adjusted for sex, baseline KCCQ, EF, atrial fibrillation, estimated glomerular filtration rate, and type 2 diabetes. Interaction of dapagliflozin effects on KCCQ-CSS by EF was assessed using EF both categorically and continuously with restricted cubic spline. Responder analyses, examining proportions of patients with deterioration, and clinically meaningful improvements in KCCQ-CSS were conducted using logistic regression. RESULTS: Of 587 patients randomized (293 dapagliflozin, 294 placebo), EF was ≤40, >40-≤60, and >60% in 262 (45%), 199 (34%), and 126 (21%), respectively. Dapagliflozin improved KCCQ-CSS at 12 weeks (placebo-adjusted difference 5.0 points [95% CI, 2.6-7.5]; P<0.001). This was consistent in participants with EF≤40 (4.6 points [95% CI, 1.0-8.1]; P=0.01), >40 to ≤60 (4.9 points [95% CI, 0.8-9.0]; P=0.02) and >60% (6.8 points [95% CI, 1.5-12.1]; P=0.01; Pinteraction=0.79). Benefits of dapagliflozin on KCCQ-CSS were also consistent when analyzing EF continuously (Pinteraction=0.94). In responder analyses, fewer dapagliflozin-treated patients had deterioration and more had small, moderate, and large KCCQ-CSS improvements versus placebo; these results were also consistent regardless of EF (all Pinteractionvalues nonsignificant). CONCLUSIONS: In patients with HF, dapagliflozin significantly improves symptoms and physical limitations after 12 weeks of treatment, with consistent and clinically meaningful benefits across the full range of EF. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifiers: NCT02653482 and NCT03030235.

Outpatient Management of Guideline-Directed Medical Therapy for Heart Failure Using Telehealth: A Comparison of In-Office, Video, and Telephone Visits.

BACKGROUND: There are limited data regarding the management of guideline-directed medical therapy (GDMT) for heart failure with reduced ejection fraction (HFrEF) with virtual visits in comparison with in-office visits. We sought to compare the changes in GDMT (angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, angiotensin receptor neprilysin inhibitors, mineralocorticoid receptor antagonists, and sodium glucose cotransporter-2 inhibitors) and loop diuretics across visit types. METHODS AND RESULTS: This study included 13,481 outpatient visits performed for 5439 unique patients with HFrEF between March 16, 2020, and March 15, 2021. The rates of initiation and discontinuation of GDMT were documented, and multivariable logistic regression was performed to test associations with outcomes between modes of visit. The rates of medication initiation were higher in office (11.7%) compared with video (9.6%) or telephone (7.2%) visits. In multivariable adjusted analysis, the initiation of at least 1 GDMT class was similar between in-office visits and video visits (adjusted odds ratio [OR] 0.97, 95% confidence interval [CI] 0.82-1.14, P = .703). Telephone visits were associated with less frequent initiation of at least 1 class of GDMT in comparison with in-office visits (adjusted OR 0.64, 95% CI 0.55-0.75; P < .001) and video visits (adjusted OR 0.67, 95% CI 0.55-0.81, P < .001). Despite similar rates of baseline loop diuretic use, patients seen with both video visits (adjusted OR 0.70, 95% CI 0.52-0.94, P = .018) and telephone visits (adjusted OR 0.64, 95% CI 0.49-0.83, P < .001) were less likely to have a loop diuretic initiated when compared with in-office visits. CONCLUSIONS: The initiation of GDMT for HFrEF was similar between in-office and video visits and lower with telephone visits, whereas the initiation of a loop diuretic was less frequent in both types of virtual visits. These data suggest that video streaming capabilities should be encouraged for virtual visits.

Outpatient Management of Heart Failure During the COVID-19 Pandemic After Adoption of a Telehealth Model.

OBJECTIVES: This study sought to determine whether the increased use of telehealth was associated with a difference in outcomes for outpatients with heart failure. BACKGROUND: The COVID-19 pandemic led to dramatic changes in the delivery of outpatient care. It is unclear whether increased use of telehealth affected outcomes for outpatients with heart failure. METHODS: In March 2020, a large Midwestern health care system, encompassing 16 cardiology clinics, 16 emergency departments, and 12 hospitals, initiated a telehealth-based model for outpatient care in the setting of the COVID-19 pandemic. A propensity-matched analysis was performed to compare outcomes between outpatients seen in-person in 2018 and 2019 and via telemedicine in 2020. RESULTS: Among 8,263 unique patients with heart failure with 15,421 clinic visits seen from March 15 to June 15, telehealth was employed in 88.5% of 2020 visits but in none in 2018 or 2019. Despite the pandemic, more outpatients were seen in 2020 (n = 5,224) versus 2018 and 2019 (n = 5,099 per year). Using propensity matching, 4,541 telehealth visits in 2020 were compared with 4,541 in-person visits in 2018 and 2019, and groups were well matched. Mortality was similar for telehealth and in-person visits at both 30 days (0.8% vs 0.7%) and 90 days (2.9% vs 2.4%). Likewise, there was no excess in hospital encounters or need for intensive care with telehealth visits. CONCLUSIONS: A telehealth model for outpatients with heart failure allowed for distanced encounters without increases in subsequent acute care or mortality. As the pressures of the COVID-19 pandemic abate, these data suggest that telehealth outpatient visits in patients with heart failure can be safely incorporated into clinical practice.

PCSK9 Inhibitors in Heart Transplant Patients: Safety, Efficacy, and Angiographic Correlates.

BACKGROUND: Statins are recommended in heart transplant patients, but are sometimes poorly tolerated. Alternative agents are often considered including proprotein convertase subtilisin/kexin type-9 inhibitors (PCSK9i). We sought to investigate the use of PCSK9i after heart transplantation. METHODS AND RESULTS: We identified patients who received a heart transplant from 1999 to 2019 and were started on PCSK9i at our institution. Clinical, laboratory, and coronary angiography with intravascular ultrasound results were compared. Among 65 patients initiated on PCSK9i (48 for statin intolerance and 17 for refractory hyperlipidemia), the median time from transplant was 5.5 years (interquartile range [IQR], 2.8-9.9 years) with a median PCSK9 treatment duration of 1.6 years (IQR, 0.8-3.2 years) and 80% still on treatment. Evolocumab was used in 73.8%, alirocumab in 12.3%, and both in 13.8% owing to insurance coverage. All patients required prior authorization; initial denial occurred in 18.5% and 32.3% had denials in subsequent years. The median low-density lipoprotein cholesterol decreased from 130 mg/dL (IQR, 102-148 mg/dL) to 55 mg/dL (IQR, 35-74 mg/dL) after starting PCSK9i (P < .001), with 72% of patients achieving a low-density lipoprotein cholesterol of <70 mg/dL after treatment. There were also significant reductions of total cholesterol, non-high-density lipoprotein cholesterol, total/high-density lipoprotein cholesterol ratio, and triglycerides, with a modest increase in high-density lipoprotein cholesterol. These changes were durable at latest follow-up. In 33 patients with serial coronary angiography and intravascular ultrasound, PCSK9i were associated with stable coronary plaque thickness and lumen area. CONCLUSIONS: Among heart transplant recipients, PCSK9i are effective in lowering cholesterol levels and stabilizing coronary intimal hyperplasia with minimal side effects. Despite favorable effects, access and affordability remain a challenge.

Single-center utilization of donor-derived cell-free DNA testing in the management of heart transplant patients.

BACKGROUND: Gene expression profiling (GEP) and donor-derived cell-free DNA (dd-cfDNA) are useful in acute rejection (AR) surveillance in orthotopic heart transplant (OHT) patients. We report a single-center experience of combined GEP and dd-cfDNA testing for AR surveillance. METHODS: GEP and dd-cfDNA are tested together starting at 2 months post-OHT. After 6 months, combined testing was obtained before scheduled endomyocardial biopsy (EMB), and EMB was canceled with a negative dd-cfDNA. This approach was compared to using a GEP-only approach, where EMB was canceled with a negative GEP. We evaluated for frequency of EMB cancellation with dd-cfDNA usage. RESULTS: A total of 153 OHT patients over a 13-month period underwent 495 combined GEP/dd-cfDNA tests. 82.2% of dd-cfDNA tests were below threshold. Above threshold results identified high-risk patients who developed AR. 378 combined tests ≥6 months post-OHT resulted in cancellation of 83.9% EMBs as opposed to 71.2% with GEP surveillance alone. There were 2 acute cellular and 2 antibody-mediated rejection episodes, and no significant AR ≥6 months. CONCLUSION: Routine dd-cfDNA testing alongside GEP testing yielded a significant reduction in EMB volume by re-classifying GEP (+) patients into a lower risk group, without reduction in AR detection. The addition of dd-cfDNA identified patients at higher risk for AR.

Dapagliflozin effects on lung fluid volumes in patients with heart failure and reduced ejection fraction: Results from the DEFINE-HF trial.

Sodium-glucose cotransporter-2 (SGLT2) inhibitors have been shown to reduce the risk of cardiovascular death or worsening heart failure (HF), and improve symptom burden, physical function and quality of life in patients with HF and reduced ejection fraction. The mechanisms of the HF benefits of SGLT2 inhibitors, however, remain unclear. In this substudy of the DEFINE-HF trial, patients randomized to dapagliflozin or placebo had lung fluid volumes (LFVs) measured by remote dieletric sensing at baseline and after 12 weeks of therapy. A significantly greater proportion of dapagliflozin-treated patients (as compared with placebo) experienced improvement in LFVs and fewer dapagliflozin-treated patients had no change or deterioration in LFVs after 12 weeks of treatment. To our knowledge, this is the first study to suggest a direct effect of dapagliflozin (or any SGLT2 inhibitor) on more effective "decongestion", contributing in a meaningful way to the ongoing debate regarding the mechanisms of SGLT2 inhibitor HF benefits.

Influence of Donor Transmitted and Rapidly Progressive Coronary Vascular Disease on Long-Term Outcomes After Heart Transplantation: A Contemporary Intravascular Ultrasound Analysis.

BACKGROUND: Donor-transmitted atherosclerosis (DTA) and rapidly progressive cardiac allograft vasculopathy (CAV) at 1 year are intravascular ultrasound (IVUS)-derived measures shown to predict adverse cardiovascular outcomes in the setting of early generation immunosuppressive agents. Given the paucity of data on the prognostic value of IVUS-derived measurements in the current era, we sought to explore their association with adverse outcomes after heart transplantation. METHODS AND RESULTS: This is a retrospective cohort analysis of patients who underwent heart transplantation at our center between January 2009 and June 2016 with baseline and 1-year IVUS. Five IVUS sections were prospectively analyzed for intimal thickness and lumen area. DTA was defined as maximum intimal thickness of 0.5 mm or greater at baseline, and rapidly progressive CAV as an increase in maximum intimal thickness by 0.5 mm or more at 1 year. Our primary analysis assessed the relationship of IVUS and other clinical data on a composite outcome: coronary intervention, CAV stage 2 or 3 (defined by the International Society for Heart and Lung Transplantation 2010 nomenclature), or cardiovascular death. Among 249 patients (mean age 51.0 ± 12.2 years and 74.3% male) included in the analysis, DTA was detected in 118 patients (51.4%). Over a median follow-up of 6.1 years (interquartile range 4.2-8.0 years), 45 patients met the primary end point (23 percutaneous coronary intervention, 11 CAV 2 or 3, and 11 cardiovascular deaths as first event). DTA and rapidly progressive CAV were not associated with the primary end point, all-cause mortality, or retransplantation. In an additional analysis including post-transplant events, incident rejection was strongly associated with poor outcomes, although cytomegalovirus infection was not. CONCLUSIONS: In this contemporary cohort, IVUS-derived DTA and rapidly progressive CAV were not associated with medium- to long-term adverse events after heart transplantation.

Health Status Changes and Outcomes in Patients With Heart Failure and Mitral Regurgitation: COAPT Trial.

BACKGROUND: In the COAPT (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation) trial, transcatheter mitral valve repair (TMVr) with the MitraClip rapidly improved health status and reduced the long-term risks for death and heart failure (HF) hospitalization in patients with HF and severe secondary mitral regurgitation who remained symptomatic despite maximally tolerated guideline-directed medical therapy (GDMT). OBJECTIVES: The aim of this study was to examine if early health status changes were associated with long-term clinical outcomes in the COAPT population. METHODS: The association between change in health status (Kansas City Cardiomyopathy Questionnaire overall summary score [KCCQ-OS]) from baseline to 1 month and the composite rate of death or HF hospitalization between 1 month and 2 years in the COAPT trial were evaluated, and whether treatment (TMVr or GDMT alone) modified this association was tested. RESULTS: Among 551 patients with HF and severe secondary mitral regurgitation who were alive at 1 month, those randomized to TMVr were more likely than those randomized to GDMT alone to achieve a ≥10-point improvement in KCCQ-OS from baseline to 1 month (TMVr, 58%; GDMT alone, 26%). Early improvement in KCCQ-OS was inversely associated with the risk for death or HF hospitalization between 1 month and 2 years (p < 0.001). When analyzed as a continuous variable, a 10-point increase in KCCQ-OS was associated with a 14% lower risk for death or HF hospitalization (hazard ratio: 0.86; 95% confidence interval: 0.81 to 0.92; p < 0.001), with no significant interaction with treatment group (pinteraction = 0.17). After adjusting for demographic and clinical factors, the association between change in KCCQ-OS and outcomes was strengthened (hazard ratio: 0.79; 95% confidence interval: 0.73 to 0.86; p < 0.001). CONCLUSIONS: In patients with HF and severe secondary mitral regurgitation, a short-term change in disease-specific health status was strongly associated with the subsequent long-term risk for death or HF hospitalization. These findings reinforce the prognostic utility of serial KCCQ-OS assessments to identify patients at risk for poor long-term clinical outcomes in this population. (Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients With Functional Mitral Regurgitation [The COAPT Trial]; NCT01626079).

Dapagliflozin Effects on Biomarkers, Symptoms, and Functional Status in Patients With Heart Failure With Reduced Ejection Fraction: The DEFINE-HF Trial.

BACKGROUND: Outcome trials in patients with type 2 diabetes mellitus have demonstrated reduced hospitalizations for heart failure (HF) with sodium-glucose co-transporter-2 inhibitors. However, few of these patients had HF, and those that did were not well-characterized. Thus, the effects of sodium-glucose co-transporter-2 inhibitors in patients with established HF with reduced ejection fraction, including those with and without type 2 diabetes mellitus, remain unknown. METHODS: DEFINE-HF (Dapagliflozin Effects on Biomarkers, Symptoms and Functional Status in Patients with HF with Reduced Ejection Fraction) was an investigator-initiated, multi-center, randomized controlled trial of HF patients with left ventricular ejection fraction ≤40%, New York Heart Association (NYHA) class II-III, estimated glomerular filtration rate ≥30 mL/min/1.73m2, and elevated natriuretic peptides. In total, 263 patients were randomized to dapagliflozin 10 mg daily or placebo for 12 weeks. Dual primary outcomes were (1) mean NT-proBNP (N-terminal pro b-type natriuretic peptide) and (2) proportion of patients with ≥5-point increase in HF disease-specific health status on the Kansas City Cardiomyopathy Questionnaire overall summary score, or a ≥20% decrease in NT-proBNP. RESULTS: Patient characteristics reflected stable, chronic HF with reduced ejection fraction with high use of optimal medical therapy. There was no significant difference in average 6- and 12-week adjusted NT-proBNP with dapagliflozin versus placebo (1133 pg/dL (95% CI 1036-1238) vs 1191 pg/dL (95% CI 1089-1304), P=0.43). For the second dual-primary outcome of a meaningful improvement in Kansas City Cardiomyopathy Questionnaire overall summary score or NT-proBNP, 61.5% of dapagliflozin-treated patients met this end point versus 50.4% with placebo (adjusted OR 1.8, 95% CI 1.03-3.06, nominal P=0.039). This was attributable to both higher proportions of patients with ≥5-point improvement in Kansas City Cardiomyopathy Questionnaire overall summary score (42.9 vs 32.5%, adjusted OR 1.73, 95% CI 0.98-3.05), and ≥20% reduction in NT-proBNP (44.0 vs 29.4%, adjusted OR 1.9, 95% CI 1.1-3.3) by 12 weeks. Results were consistent among patients with or without type 2 diabetes mellitus, and other prespecified subgroups (all P values for interaction=NS). CONCLUSIONS: In patients with heart failure and reduced ejection fraction, use of dapagliflozin over 12 weeks did not affect mean NT-proBNP but increased the proportion of patients experiencing clinically meaningful improvements in HF-related health status or natriuretic peptides. Benefits of dapagliflozin on clinically meaningful HF measures appear to extend to patients without type 2 diabetes mellitus. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02653482.

Implementation of Best Practice Alert in an Electronic Medical Record to Limit Lower-Value Inpatient Echocardiograms.

There are increasing efforts nationally and at our institution to reduce lower-value care, including some use of imaging studies such as transthoracic echocardiography (TTE). In an effort to avoid repeating unnecessary studies on inpatients who recently underwent TTE, we implemented a best practice alert (BPA) in our electronic health record to notify ordering clinicians that a TTE had been performed in the past 6 months. The BPA requires the ordering clinician to acknowledge the alert and provide a reason for proceeding with the order and provides a link to ASE AUC criteria. Data on initial use were reviewed after approximately 6 months (February 16, 2017 to September 12, 2017.) This included review of the number of TTE orders removed, number reordered within the same day, subspecialty of ordering clinician, type of ordering clinician (MD vs NP, and so on), and length of stay in patients with orders that were confirmed versus removed. Independent t tests, Chi-square, and Fisher's exact tests were used for analysis. Over 209 days, the BPA triggered 3,226 times with 20% of these TTEs cancelled by the ordering clinician and remaining cancelled after 24 hours. There were no statistically significant differences in the proportion of removed TTE orders between subspecialties or types of clinician (p = 0.144.) There was no statistically significant difference in the length of stay in patients with orders kept (9.2 days) compared with orders cancelled (10.5 days). An electronic health record alert triggered by an order for an inpatient TTE within 6 months of a previous study effectively reduced study volume by 20%.

Stability of pacing indices and need for pacing in cardiac transplant patients over 1 year of follow-up.

BACKGROUND: A significant minority of cardiac transplant patients require permanent pacemaker (PPM) implant, primarily for sinus node dysfunction. The stability of pacing indices has not been determined in this unique patient population, and data regarding ongoing need for pacing are limited. METHODS: Pacing indices (sensing, threshold, and impedance) as well as the percentage of time patients required pacing were recorded, from 30 cardiac transplant patients that underwent PPM implant, over 1 year of follow-up. Repeated measure ANOVA (analysis of variance) was used to compare pacing indices and the percentage of time patients required pacing in each cardiac chamber (right atrium (RA) and right ventricle (RV)) and at different time points. RESULTS: There was no difference in sensing among the follow-up time points (p = 0.9). Thresholds at 3 months were significantly higher compared to the day of implant (p = 0.005) and the day after implant (p = 0.03). Impedances at implant were significantly higher compared to day 1 (p < 0.001), 3 months (p < 0.003), and 12 months (p < 0.001) post-implant. The mean percentage of RA pacing was 85 ± 6% the day after implant, 74 ± 6% at 3 months, and 80 ± 6% at 1 year (p = 0.17). CONCLUSION: In cardiac transplant patients, pacing impedances decrease and thresholds trend up in short-term follow-up, but subsequent sensing, threshold, and impedance remain stable at 1 year. This is comparable to the pattern observed among noncardiac transplant PPM recipients. The atrial pacing percentage was stable over 1 year, suggesting continued relative sinus node dysfunction.

RNA Interference Mediated Interleukin-1ß Silencing in Inflamed Chondrocytes Decreases Target and Downstream Catabolic Responses.

Posttraumatic activation of the catabolic cascade plays a major role in degradation of cartilage. Interleukin-1ß (IL-1ß), a primary instigator in the catabolic axis, is upregulated in chondrocytes following injury. IL-1ß activates key degradative enzymes, including MMPs and aggrecanases, and other proinflammatory mediators such as PGE2 which contribute to ECM breakdown. Posttranscriptional silencing of IL-1ß by RNA interference (RNAi) may drive a reduction in IL-1ß. We hypothesized that transduction of chondrocytes using rAAV2 expressing a short hairpin RNAi motif targeting IL-1ß (shIL-1ß) would significantly decrease IL-1ß expression and, in turn, decrease expression of other catabolic enzymes. Chondrocyte cultures were transduced with rAAV2-tdT-shIL-1ß in serum-free media. The fluorescent protein, tdTomato, was used to determine transduction efficiency via flow cytometry and fluorescent microscopy. Cells were stimulated with lipopolysaccharide (LPS) 48 hours following transduction. After 24-hour stimulation, supernatants were collected for cytokine analysis, and cells lysed for gene expression analysis. IL-1ß knockdown led to significantly decreased expression of IL-1ß, TNF-α, and ADAMTS5. PGE2 synthesis was also significantly downregulated. Overall, effective silencing of IL-1ß using rAAV2 vector expressing a short hairpin IL-1ß knockdown sequence was shown. Additionally, significant downstream effects were evident, including decreased expression of TNF-α and ADAMTS5. Targeted silencing of catabolic cytokines may provide a promising treatment avenue for osteoarthritic (OA) joints.

Surrogate markers of rejection.

PURPOSE OF REVIEW: There is continued interest in defining viable noninvasive alternatives to endomyocardial biopsy (EMB) for monitoring recipients of orthotopic heart transplantation for episodes of rejection. This review summarizes the evidence of clinical utility for both available and emerging surrogate markers of rejection. RECENT FINDINGS: A variety of imaging modalities and peripheral biomarkers has been evaluated for this purpose and to date have had inadequate accuracy to replace EMB. Gene expression profile analysis is the most promising complementary technology to emerge, but there is insufficient clinical trial evidence at this time to allow gene expression profile as a substitution for EMB in all but a select group of patients. SUMMARY: The gold standard at this time for routine surveillance of orthotopic heart transplantation rejection remains EMB. However, on the basis of recent clinical trial results, gene expression profile analysis appears to be a useful adjunctive tool in monitoring for rejection and may permit a significant reduction in the frequency of EMB in low-risk patients.

Aortic stiffness independently predicts exercise capacity in hypertrophic cardiomyopathy: a multimodality imaging study.

BACKGROUND: Exercise capacity in patients with hypertrophic cardiomyopathy (HCM) varies despite similar diastolic dysfunction, left ventricular outflow tract (LVOT) obstruction and mitral regurgitation (MR). Pulse wave velocity (PWV), determined by cardiac magnetic resonance (CMR), measures aortic stiffness and is abnormal in patients with HCM in comparison with controls. OBJECTIVE: To determine potential clinical and imaging predictors of peak oxygen consumption (pVO(2)) in patients with HCM. METHODS: Fifty newly referred patients with HCM (62% men, 44+/-13 years, 90% receiving optimal drugs, 18% hypertensive) underwent Doppler echocardiography (transthoracic echocardiography (TTE)), cardiopulmonary exercise testing and CMR for symptom evaluation. TTE variables (diastology, post exercise MR and LVOT gradient (mmHg)), pVO(2) (ml/kg/min) and CMR variables (PWV (aortic path length between mid- and descending aorta/time delay between arrival of the foot of the pulse wave between two points, m/s), and LV volumetric indices) were measured. RESULTS: After exercise LVOT gradient, MR, deceleration time and pVO(2) were 104+/-52, 1+/-1, 240+/-79 ms, and 25+/-6, respectively. Mean basal septal thickness (cm), PWV, EF, ESV index (ml/m(2)), EDV index (ml/m(2)) and LV mass index (g/m(2)) were 1.9+/-0.5, 9.3+/-7, 64%+/-7, 32+/-9, 87+/-17 and 112+36, respectively. Multiple regression analyses showed that only age (beta=-0.38, p=0.004) and PWV (beta=-0.33, p=0.01) predicted pVO(2). CONCLUSION: In patients with HCM, age and PWV are predictors of pVO(2), independent of LV thickness, LVOT gradient and diastolic indices. Aortic stiffness potentially has a role in evaluation of symptoms of patients with HCM.

Relation of ventricular-vascular coupling to exercise capacity in ischemic cardiomyopathy: a cardiac multi-modality imaging study.

The purpose of this study was to examine the relationship between noninvasive measurements of ventricular-vascular coupling (VVC) with exercise tolerance, and compared the value of VVC versus other traditional determinants of exercise capacity in this population. 43 patients with ischemic CMP (age 59 +/- 9 years, mean EF 24 +/- 8%) underwent cardiopulmonary exercise testing, echocardiography and cardiac magnetic resonance (CMR). VVC was defined non-invasively by the ratio of ventricular systolic elastance (Ees) to the arterial elastance (Ea), where Ees = end-systolic pressure/end-systolic volume index and Ea = end-systolic pressure/stroke volume index. VVC significantly correlated with baseline heart rate (HR), peak exercise systolic blood pressure, maximum oxygen consumption (MVO(2)) and peak O(2) pulse (MVO(2)/HR). A higher VVC was associated with higher LVEF and RVEF but showed inverse relation to mitral E wave velocity. Univariate predictors of MVO(2) are baseline HR, chronotropic reserve, VVC and aortic distensibility; whilst mitral E wave velocity, LVEF, VVC, Ees significantly correlated with peak O(2) pulse. By stepwise multivariate analysis, VVC remained the only independent predictor of peak O(2) pulse. Ventricular-vascular coupling at rest may be a clinically important parameter in predicting exercise capacity in patients with advanced heart failure, and may become an additional target for therapeutic interventions.

Comparison of functional status, electrocardiographic, and echocardiographic parameters to mortality in endomyocardial-biopsy proven cardiac amyloidosis.

Cardiac amyloidosis (CA) is generally associated with a poor prognosis and significantly increased mortality. We sought to identify predictors of longer-term survival in patients with endomyocardial biopsy (EMB)-documented CA. Forty-five consecutive patients with EMB-documented CA were studied from January 1998 to December 2003. Age, gender, New York Heart Association class, medications, presence of light-chain amyloid, and electrocardiographic voltage were recorded. Baseline left ventricular (LV) ejection fraction, deceleration time, diastolic function, LV mass, ventricular septal thickness, and myocardial performance index ([isovolumic contraction time + isovolumic relaxation time]/ejection time) were recorded. Mean age was 66 +/- 10 years with 34 men (76%). New York Heart Association class >II was noted in 26 patients (58%) and low voltage on electrocardiogram (S wave [lead V(1)] + R wave [lead V(5)] < or =15) in 12 (27%). Mean LV ejection fraction, ventricular septal thickness, and LV mass were 46 +/- 13%, 1.7 +/- 0.42 cm, and 303 +/- 114 g, respectively. Deceleration time < or =150 ms was found in 19 (42%) and myocardial performance index >0.6 in 15 (33%). At a median follow-up of 1.7 years, there were 25 deaths (56%). On univariate Kaplan-Meier analysis, New York Heart Association class >II, deceleration time <150 ms, and beta-blocker use were associated with increased mortality (log-rank statistic p values <0.001, <0.05, and 0.01, respectively). On Cox proportional hazard survival analysis, only New York Heart Association class was significantly associated with increased mortality (hazard ratio 3.92, 1.92 to 7.95, p = 0.0002). In conclusion, in patients with EMB-documented CA, longer-term survival is more strongly associated with New York Heart Association functional class compared with electrocardiographic and echocardiographic variables.