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.

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.

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.

Clinical factors associated with left ventricular ejection fraction disparity in patients with left ventricular dysfunction undergoing multimodality imaging.

Drug and device therapy for heart failure is increasingly determined based on left ventricular ejection fraction. Significant disparity frequently exists between echocardiographic and nuclear scintigraphic techniques, even when testing is performed nearly simultaneously in clinically stable patients. In 119 patients with left ventricular dysfunction who underwent both echocardiography and stress testing with nuclear imaging within seven days (but with significant disparity in reported left ventricular ejection fraction), we identified four clinical variables which were associated with left ventricular ejection fraction difference. These clinical variables included atrial fibrillation, left ventricular hypertrophy, severe mitral regurgitation and paced rhythm.

Comparison of Outcomes Among Patients With Cardiogenic Shock Admitted on Weekends Versus Weekdays.

Cardiogenic shock (CS) is associated with high mortality and often requires involvement of a multidisciplinary provider team to deliver timely care. Care coordination is more difficult on weekends, which may lead to a delay in care. We sought to assess the effect of weekend admissions on outcomes in patients admitted with CS. Patients admitted with CS were identified from 2005 to 2014 in the National Inpatient Sample using ICD9 code 785.51. Baseline demographics, in-hospital procedures, and outcomes were obtained and compared by day of admission. A multivariable model was used to assess the impact of weekend admission on in-hospital mortality. A total of 875,054 CS admissions were identified (age 67.4 ± 15.1 years, 40.2% female, 72.1% Caucasian), with 23% of patients being admitted on weekends. Baseline co-morbidities were similar between groups. Weekend admissions were associated with higher in-hospital mortality (40.6% vs 37.5%) and cardiac arrest (20.3% vs 18.1%, p < 0.001 for both) consistently over the study period. Use of temporary and permanent mechanical support devices and heart transplantation were slightly less common for weekend admissions. In a multivariable model adjusting for relevant confounders, weekend admission was associated with a 10% increased mortality in patients with CS. In conclusion, patients with CS admitted on weekends had higher in-hospital mortality and were slightly less likely to receive mechanical support and advanced therapies compared with those admitted on weekdays. Future studies and health system initiatives should focus on rectifying these disparities with around-the-clock multidisciplinary coordinated care for CS.

Combined assessment of myocardial perfusion and diastolic function enhances risk stratification in patients with anterior wall myocardial infarction.

OBJECTIVE: Evaluate the utility of a combined risk stratification scheme including diastolic dysfunction and "no-reflow," to identify high-risk patients following acute myocardial infarction (AMI). BACKGROUND: Recent studies have demonstrated that the "no-reflow" phenomenon (defined by myocardial contrast echocardiography) and severe diastolic dysfunction (identified by Doppler echocardiography) identify patients at high risk for mortality following AMI. METHODS: We evaluated 111 patients with recent anterior acute myocardial infarction from July 2000 to June 2004. Diastolic function and myocardial perfusion was evaluated by echocardiography. Patients were placed into 1 of 3 groups based on diastolic function and myocardial perfusion: Group 1 (normal perfusion and normal diastolic function), Group 2 (abnormal perfusion or abnormal diastolic function), and Group 3 (abnormal perfusion and abnormal diastolic function). We compared the long term all-cause mortality within these groups. RESULTS: Patients in each group were similar with respect to myocardial infarction size as defined by biomarkers, extent and severity of coronary artery disease, and medical and interventional therapy. Mortality was much higher in Group 3 (26.9%) compared to Group 1 (0%) and Group 2 (15.2%) (p = 0.048). CONCLUSION: Combined assessment of diastolic function and myocardial perfusion enhances risk stratification post myocardial infarction.

Mortality rates and clinical predictors of reduced survival after cardioverter defibrillator implantation.

We aimed to identify mortality rates and clinical predictors of reduced survival in a large cohort of patients after implantation of an implantable cardioverter-defibrillator (ICD). Although existing data from clinical trials report annual mortality after ICD implantation from 2% to 9%, there are few data available on mortality rates or predictors of reduced survival in this patient population in clinical practice. In this single-center, retrospective analysis of 286 patients who underwent ICD implantation between June 1, 2000 and December 30, 2003, candidate predictors of mortality were assessed and subjected to multivariable analysis. Outcomes were documented using the Social Security Death Master File and hospital medical records. Overall annualized mortality was 11.3% after ICD implantation. Mortality rates in patients with left ventricular ejection fraction (LVEF) <25% were 27.2% at 1 year and 50.5% at 3 years. Digoxin (hazard ratio 1.86, 95% confidence interval [CI] 1.21 to 2.86, p = 0.0046) and loop diuretics (hazard ratio 1.59, 95% CI 1.06 to 2.38, p = 0.024) were associated with reduced survival. Angiotensin-converting enzyme inhibitor or aldosterone receptor blocker use was associated with reduced mortality (hazard ratio 0.50, 95% CI 0.31 to 0.80, p = 0.0038). In conclusion, mortality after ICD implantation is higher than demonstrated in primary or secondary prevention ICD trials; LVEF remains a potent predictor of mortality after ICD implantation, particularly in patients with an LVEF <25%; loop diuretic and digoxin use is associated with an approximate twofold increase in mortality in this population; and angiotensin-converting enzyme inhibitor or aldosterone receptor blocker use is associated with improved survival after ICD implantation.

Transesophageal echocardiographic diagnosis of left atrial appendage occluder device infection.

The safety and efficacy of a left atrial appendage closure device is currently under evaluation in a large-scale multi-center clinical trial. We report an initial case of left atrial appendage occluder device infection with Staphylococcus aureus; transesophageal echocardiography played a pivotal role in diagnosis and treatment.

Clinical and echocardiographic markers of mortality risk in patients with atrial fibrillation.

Atrial fibrillation (AF) is independently associated with increases in cardiovascular and all-cause mortality. Although cardiovascular co-morbidities predict stroke risk in AF, their relation with mortality has not been well described. To identify clinical and echocardiographic markers of mortality in patients with AF, 524 patients with AF underwent transesophageal echocardiography from August 2000 to March 2005. Clinical risk factors for systemic thromboembolism were determined for each patient. A CHADS2 (congestive heart failure, hypertension, age>75 years, diabetes, and previous stroke or transient ischemic attack) score ranging from 0 to 6 was calculated for each patient. Transesophageal echocardiographic reports were reviewed for the presence of left atrial spontaneous echocardiographic contrast, left atrial thrombus, the left ventricular ejection fraction, aortic arch atheroma, and the presence and severity of mitral regurgitation. Mortality data were obtained from the Social Security Death Master File. Univariate and multivariate models were structured to assess which variables predicted mortality. In a multivariate model, a history of heart failure, age>75 years, the absence of systemic anticoagulation with warfarin, the presence of left atrial spontaneous echocardiographic contrast, and greater than moderate mitral regurgitation were independent predictors of mortality. Increasing CHADS2 score was also an independent predictor of mortality. A CHADS2 score of 5 or 6 was associated with a >50-fold increase in mortality compared with patients with CHADS2 scores of 0. In conclusion, a history of heart failure, age>or=75 years, the absence of chronic oral anticoagulation, a CHADS2 score>0, and greater than moderate mitral regurgitation are independent predictors of mortality in patients with AF.

Contrast administration reduces interobserver variability in determination of left ventricular ejection fraction in patients with left ventricular dysfunction and good baseline endocardial border delineation.

Echocardiographic contrast agents improve endocardial border delineation in patients with technically difficult baseline studies. With medical and device therapy for heart failure increasingly based on left ventricular (LV) ejection fraction (EF) partition values, the accurate and reproducible assessment of LV function is necessary. It was hypothesized that routine contrast enhancement would significantly reduce interobserver variability in the determination of LVEFs in a cohort of patients with LV dysfunction and good baseline endocardial delineation. All patients underwent baseline noncontrast studies followed by contrast-enhanced imaging using Definity. Two experienced echocardiographers, blinded to the clinical data, determined LVEFs using 4 different techniques: noncontrast estimated (NCE), noncontrast calculated (NCC), contrast estimated (CE), and contrast calculated (CC). Using a mixed-model procedure that allows for fixed and random events, the variance due to error and that due to the patient was obtained (interclass correlation). The proportion of variation due to the reader was calculated as 1--interclass correlation. Mean standardized percentage differences ([reader 1 EF--reader 2 EF]/mean EF) were also calculated for each method. The proportion of variation due to the reader was smallest in the CC group and largest in the NCC group (NCE = 0.21, NCC = 0.33, CE = 0.25, CC = 0.11). The results were similar when only patients with NCE EFs >or=20% and or=20% and or=20% and

Usefulness of myocardial contrast echocardiography in predicting late mortality in patients with anterior wall acute myocardial infarction.

We investigated whether myocardial contrast echocardiography (MCE) performed soon after acute myocardial infarction (AMI) improves risk stratification for late mortality. MCE after AMI identifies microvascular "no-reflow" and predicts early outcomes; however, the predictive value of MCE for late mortality is unknown. One hundred sixty-seven patients with anterior AMI and left ventricular dysfunction underwent MCE 2 days after admission, and a perfusion score index (PSI) was calculated. Long-term follow-up (mean 39 months) was available for all patients. Patients with normal and abnormal perfusion had similar baseline characteristics. Myocardial contrast echocardiographic PSI was a predictor of mortality as a continuous variable (odds ratio 3.2 for each 1.0 increase in PSI, 95% confidence interval 1.1 to 9.7, p = 0.04). In a logistic regression model, age (odds ratio 2.6 per decade, 95% confidence interval 1.6 to 4.4, p = 0.0002) and PSI (odds ratio 4.5 for each 1.0 increase in PSI, 95% confidence interval 1.3 to 15.4, p = 0.02) were the only significant predictors of mortality. In a subanalysis comparing patients >70 years old with abnormal PSI with all other patients, Kaplan-Meier estimates showed a marked difference in survival over a mean follow-up of 39 months (24% vs 4% mortality, p = 0.0002). In conclusion, MCE refines risk stratification soon after anterior AMI in patients with left ventricular dysfunction. Patients at very high and very low risk of mortality can be identified, and myocardial contrast echocardiographic data are incrementally useful compared with existing clinical and angiographic variables.

Usefulness of left ventricular diastolic dysfunction as a predictor of one-year rehospitalization in survivors of acute myocardial infarction.

Presence of severe left ventricular (LV) diastolic function has been shown to independently predict risk of heart failure or death after acute myocardial infarction (AMI). We aimed to determine whether common echocardiographic parameters and (LV) diastolic function evaluated during AMI hospitalization can predict the risk of rehospitalization, up to 1 year after AMI. One hundred ninety consecutive patients with AMI, who were prospectively enrolled in a longitudinal post-AMI registry, had survived for 1 year, and had a clinically indicated echocardiogram during the index admission, were included in the study. The independent effect of diastolic dysfunction on 1-year all-cause rehospitalization was assessed using multivariable proportional hazards regression. Average age was 62.5 years, 93% were Caucasian, 66% were men, and mean LV ejection fraction was 46%. At 1 year, 78 patients (41%) had been rehospitalized >or=1 time. In multivariable analysis, presence of severe LV diastolic dysfunction was the only echocardiographic variable that predicted increased risk of rehospitalization 1 year after AMI (hazard ration 3.31, 95% confidence interval 1.26 to 8.69). Seventy-eight percent of patients with severe LV diastolic dysfunction (restrictive diastolic physiology) compared with 30% with normal diastolic function (p = 0.0052) and 37% with nonrestrictive physiology during the index admission were rehospitalized. In conclusion, severe LV diastolic dysfunction is the only echocardiographic predictor of rehospitalization in survivors of AMI and routine assessment of diastolic function during AMI hospitalization can provide additional prognostic risk stratification at dismissal.

Acute mortality in hospitalized patients undergoing echocardiography with and without an ultrasound contrast agent: results in 18,671 consecutive studies.

OBJECTIVES: We sought to define acute mortality in hospitalized patients undergoing clinically indicated echocardiography with and without use of an ultrasound contrast agent. BACKGROUND: The U.S. Food and Drug Administration recently issued a boxed warning and new contraindications for the perflutren-containing ultrasound contrast agents following post-marketing reports of 4 patient deaths that were temporally related to Definity (Bristol-Myers Squibb Medical Imaging, Billerica, Massachusetts) administration. To appreciate the incremental risk of any medical procedure, the ambient risk of untoward outcome in the population in question must first be defined. There are no published data on short-term major adverse cardiac events in hospitalized patients undergoing echocardiography, either with or without administration of an ultrasound contrast agent. METHODS: A retrospective analysis of hospitalized patients undergoing clinically indicated echocardiography between January 2005 and October 2007, within Saint Luke's Health System, Kansas City, Missouri, was performed. Studies were separated into 2 groups, those performed without contrast enhancement (n = 12,475) and those performed with Definity (n = 6,196). Vital status within 24 h of the echocardiographic study was available for all patients using a combination of the Social Security Death Master File and Saint Luke's Health System medical records. Incidence of death within 24 h was compared by chi-square test between Definity and unenhanced procedures. RESULTS: Of the 18,671 patient events, 72 patients died within 24 h. Of those that underwent unenhanced echocardiography, 46 died within 24 h (0.37%). Of patients receiving Definity during the echocardiogram, 26 died within 24 h (0.42%). There was no statistical difference between these 2 groups (p = 0.60). No patient died within 1 h of the echocardiographic study. In a random sampling from the unenhanced (n = 201) and Definity groups (n = 202), patients who underwent Definity-enhanced echocardiography exhibited higher clinical acuity, and more significant comorbidities. CONCLUSIONS: Approximately 0.4% of hospitalized patients die within 24 h of echocardiography. There is no increased mortality risk associated with Definity-enhanced examinations, despite evidence for higher clinical acuity and more comorbid conditions in patients undergoing contrast studies.

Clinical predictors of left atrial thrombus and spontaneous echocardiographic contrast in patients with atrial fibrillation.

OBJECTIVES: We sought to determine the relationship between clinical risk factors for systemic thromboembolism in patients with atrial fibrillation and the prevalence of left atrial (LA) spontaneous echocontrast (SEC) and LA thrombus (LAT). BACKGROUND: Atrial fibrillation is associated with an increased risk of systemic thromboembolism. LA SEC and LAT also predict thromboembolic events. The relationship between clinical risk factors for systemic thromboembolism and prevalence of LA SEC and LAT is unknown. METHODS: In all, 524 patients with atrial fibrillation underwent transesophageal echocardiography between August 2000 and March 2005. Clinical risk factors for systemic thromboembolism were determined for each patient. A CHADS(2) score ranging from 0 to 6 was calculated for each patient as: congestive heart failure = 1 point; hypertension = 1 point; age 75 years or older = 1 point; diabetes mellitus = 1 point; and history of stroke including transient ischemic attack or systemic embolism = 2 points. Transesophageal echocardiography reports were reviewed for the presence of LA SEC and LAT. Univariate and multivariable models were structured to assess which clinical risk factors predicted the presence of LA SEC or LAT. RESULTS: In a multivariable model, age 75 years or older, previous thromboembolic event, and left ventricular ejection fraction (LVEF) less than 40% predicted LA SEC, whereas LVEF less than 40% was the only predictor of LAT. LA SEC was present in 24% of patients with a CHADS(2) score of 0, but was present in 58% with a CHADS(2) score of 5 or 6 (P < .0001). LAT was present in 3% percent of patients with a CHADS(2) score of 0, but in 17% of patients with a CHADS(2) score of 5 or 6 (P = .0026). CONCLUSION: Age 75 years or older, previous thromboembolic event, and LVEF less than 40% predict presence of LA SEC. LVEF less than 40% is the only multivariate predictor of LAT. The prevalence of LA SEC and LAT increases with increasing CHADS(2) score.

Transesophageal echocardiographic diagnosis of Aspergillus fumigatus aortitis after percutaneous coronary intervention.

Aspergillus aortitis is an uncommon infection with high mortality and has been reported in patients after cardiopulmonary bypass. We report the first case of Aspergillus aortitis in an immunocompetent man immediately after percutaneous coronary intervention to an aortocoronary bypass graft. In this case, transesophageal echocardiography played a pivotal role in diagnosis.