Transthyretin cardiac amyloid: Broad heart failure phenotypic spectrum and implications for diagnosis.

AIMS: Transthyretin cardiac amyloidosis (ATTR-CA) is most often associated with heart failure with preserved ejection fraction (HFpEF). However, patients may present with impaired systolic function at the time of diagnosis, which has not been widely investigated. We sought to explore the prevalence of various heart failure (HF) phenotypes and their associated clinical characteristics at the time of ATTR-CA diagnosis. METHODS: We performed a single-centre retrospective cohort study of consecutive patients with ATTR-CA evaluated between February 2016 and December 2022. Data on patient demographics, comorbidities, imaging and laboratory findings were compared across HF phenotypes (age: 78.1 ± 8.6 years, with 91.1% male). A total of 21.6% (n = 46) presented with heart failure with reduced ejection fraction (HFrEF), 17.8% (n = 38) with heart failure with mildly reduced ejection fraction (HFmrEF) and 60.6% (n = 129) with HFpEF at the time of diagnosis with ATTR-CA. Those presenting with HFrEF or HFmrEF were more likely to be African American and had significantly worse New York Heart Association (NYHA) functional class, higher N-terminal pro-brain natriuretic peptide (NT-proBNP) and higher serum creatinine levels as compared with those with HFpEF. CONCLUSIONS: Although ATTR-CA is traditionally thought to be seen primarily among patients with HFpEF, our data suggest that ATTR-CA has a higher prevalence among patients with HFrEF, which underscores the importance of heightened clinical suspicion regardless of ejection fraction when considering ATTR-CA. Furthermore, although comorbidities are similar, patients with HFmrEF and HFrEF had a worse symptom burden.

Predictors of developing renal dysfunction following diagnosis of transthyretin cardiac amyloidosis.

BACKGROUND: In patients with transthyretin cardiac amyloidosis (ATTR-CA), renal dysfunction is a poor prognostic indicator. Limited data are available on variables that portend worsening renal function (wRF) among ATTR-CA patients. OBJECTIVES: This study assesses which characteristics place patients at higher risk for the development of wRF (defined as a drop of ≥10% in glomerular filtration rate [GFR]) within the first year following diagnosis of ATTR-CA. METHODS: We included patients with ATTR-CA (n = 134) evaluated between 2/2016 and 12/2022 and followed for up to 1 year at our amyloid clinic. Patients were stratified into two groups: a group with maintained renal function (mRF) and a group with wRF and compared using appropriate testing. Significant variables in the univariate analysis were included in the multivariable logistic regression model to determine characteristics associated with wRF. RESULTS: Within a follow-up period of 326 ± 118 days, the median GFR% change measured -6% [-18%, +8]. About 41.8% (n = 56) had wRF, while the remainder had mRF. In addition, in patients with no prior history of chronic kidney disease (CKD), 25.5% developed de novo CKD. On multivariable logistic regression, only New York Heart Association (NYHA) class ≥III (odds ratio [OR]: 3.9, 95% confidence interval [CI]: [1.6-9.3]), history of ischemic heart disease (IHD) (OR: 0.3, 95% CI: [0.1-0.7]), and not receiving SGLT-2i (OR: 0.1, 95% CI: [0.02-0.5]) were significant predictors of wRF. CONCLUSION: Our study demonstrated that the development of de novo renal dysfunction or wRF is common following the diagnosis of ATTR-CA. Additionally, we identified worse NYHA class and no prior history of IHD as significant predictors associated with developing wRF, while receiving SGLT-2i therapy appeared to be protective in this population.

Race, Genotype, and Prognosis in Black Patients With Transthyretin Cardiac Amyloidosis.

Previous studies suggest worse outcomes in patients with variant transthyretin cardiac amyloidosis (ATTR-CA) because of valine-to-isoleucine substitution at Position 122 (V122I) (ATTRv-CA) compared with patients with wild-type (WT) disease (ATTRwt-CA). Given V122I is almost exclusively found in Black patients, it is unclear if this is attributable to the biology of genotype or racial differences. Patients with ATTR-CA diagnosed between January 2001 and August 2021 were characterized into 3 categories: (1) White with ATTRwt-CA (White-WT); (2) Black with V122I ATTRv-CA (Black-V122I), and (3) Black with ATTRwt-CA (Black-WT). Event-free survival (composite of death, left ventricular assist device, or cardiac transplant) was evaluated using univariable and multivariable analyses over a median follow-up of 1.6 (0.7 to 2.90) years. Of 694 ATTR-CA patients, 502 (72%) were White-WT, 139 Black-V122I (20%), and 53 Black-WT (8%). Notably, 28% of Black patients with ATTR-CA had WT disease and not the V122I variant. Using multivariable modeling to adjust for several prognostic features, Black-V122I had higher risk of the composite adverse outcome compared with a grouped cohort of patients with WT disease (White-WT and Black-WT) (hazard ratio [HR] 1.82, confidence interval [CI] 1.30-2.56, p < 0.001). Furthermore, the Black cohort as a whole (Black-V122I and Black-WT) demonstrated greater risk of adverse outcomes compared with White-WT (HR 1.63, CI 1.19-2.24, p = 0.002). Black-V122I had greater risk of the primary end point compared with White-WT (HR 1.80, CI 1.27-2.56, p = 0.001). Black patients with ATTR-CA have worse event-free survival than White-WT despite risk adjustment. However, it remains unclear whether this is driven by differences in race or genotype given the smaller number of Black-WT patients. Approximately one-quarter of Black patients had WT, of which a greater proportion were female compared with White-WT.

Changes in Left Ventricular Ejection Fraction and Clinical Trajectories of Transthyretin Cardiac Amyloidosis with Systolic Dysfunction.

BACKGROUND: Transthyretin cardiac amyloidosis (ATTR-CM) is classically thought of as a progressive disease with preserved systolic function. The longitudinal clinical trajectories of ATTR-CM with impaired left ventricular ejection fraction (LVEF) remain unclear. METHODS: This is a single-center retrospective cohort study of consecutive patients with ATTR-CM who underwent two or more echocardiograms with baseline LVEF < 50%. Patients were stratified according to the presence of ≥5% change in LVEF. A Cox proportional hazard model examined hazard of a composite outcome of death, transplant, or LVAD insertion over the two years following diagnosis. RESULTS: In our study cohort of 179 patients, 62 patients (34.6%) experienced an increase in LVEF while 33 (18.4%) experienced a decrease in LVEF. After adjusting for covariates, patients with a decrease in EF experienced increased hazard of death (HR 2.15, 95% CI 1.05-4.40, p = 0.038) compared to those with stable or an increase in LVEF. Changes in LVEF corresponded with significant differences in NT proBNP trajectories, but initial biomarker levels or clinical staging were not predictive of LVEF trajectory. CONCLUSIONS: in ATTR-CM patients with impaired LVEF, over a third demonstrated improved LVEF over time, while those with a decrease in LVEF had worse long-term outcomes.

Value of psychosocial evaluation for left ventricular assist device candidates.

OBJECTIVE: Left ventricular assist devices require a psychosocial assessment to determine candidacy despite limited data correlating with outcome. Our objective is to determine whether the Stanford Integrated Psychosocial Assessment for Transplant, a tool validated for transplant and widely used by left ventricular assist device programs, predicts left ventricular assist device program hospital readmissions and death. METHODS: We performed a retrospective analysis of adults at the Cleveland Clinic with Stanford Integrated Psychosocial Assessment for Transplant scores before primary left ventricular assist device program implantation from April 1, 2013, to December 31, 2018. The primary outcome was unplanned hospital readmissions censored at death, transplantation, and transfer of care. The secondary outcome was death. RESULTS: There were 263 patients in the left ventricular assist device program with a median (Q1, Q3) Stanford Integrated Psychosocial Assessment for Transplant score of 16 (8, 28). During a median follow-up 1.2 years, 56 died, 65 underwent transplantation, and 21 had transferred care. There were 640 unplanned hospital readmissions among 250 patients with at least 1 outpatient visit at our center. In a multivariable analysis, Stanford Integrated Psychosocial Assessment for Transplant components but not total Stanford Integrated Psychosocial Assessment for Transplant score was associated with readmissions. Psychopathology (Stanford Integrated Psychosocial Assessment for Transplant C-IX) was associated with hemocompatibility (coefficient 0.21 ± standard error 0.11, P = .040) and cardiac (0.15 ± 0.065, P = .02) readmissions. Patient readiness was associated with noncardiac (Stanford Integrated Psychosocial Assessment for Transplant A-III, 0.24 ± 0.099, P = .016) and cardiac (Stanford Integrated Psychosocial Assessment for Transplant A-low total, 0.037 ± 0.014, P = .007) readmissions. Poor living environment (Stanford Integrated Psychosocial Assessment for Transplant B-VIII) was associated with device-related readmissions (0.83 ± 0.34, P = .014). Death was associated with organic psychopathology or neurocognitive impairment (Stanford Integrated Psychosocial Assessment for Transplant C-X, 0.59 ± 0.21, P = .006). CONCLUSIONS: Total Stanford Integrated Psychosocial Assessment for Transplant score was not associated with left ventricular assist device program readmission or mortality. However, we identified certain Stanford Integrated Psychosocial Assessment for Transplant components that were associated with outcome and could be used to create a left ventricular assist device program specific psychosocial tool.

Prediction of Survival After Implantation of a Fully Magnetically Levitated Left Ventricular Assist Device.

BACKGROUND: Clinical trials inform on average efficacy, but individualized risk assessments for outcome prediction are important in guiding treatment implementation. OBJECTIVES: The authors developed and validated a patient-specific risk score to predict survival at 1 and 2 years after HeartMate 3 (HM3) left ventricular assist device (LVAD) implantation. METHODS: The MOMENTUM 3 (Multicenter Study of MagLev Technology in Patients Undergoing Mechanical Circulatory Support Therapy with HeartMate 3) trial includes 2,200 HM3 LVAD patients in the pivotal trial and Continued Access Protocol study (2014-2018). The authors randomly assigned all patients to a derivation cohort (n = 1,540) or validation cohort (n = 660). Univariate mortality predictors were screened for potential model inclusion, stepwise selection was used to build the multivariable Cox proportional hazards regression model, and performance (discrimination and calibration) was evaluated. RESULTS: Age, prior cardiac surgery (coronary artery bypass grafting [CABG] or valve procedure), lower serum sodium, higher blood urea nitrogen (BUN), small left ventricular size, and right atrial pressure-to-pulmonary capillary wedge pressure (RAP/PCWP) ratio >0.6 were significant risk factors for mortality. Receiver-operating characteristic (ROC) analysis in the validation cohort demonstrated an area under the curve (AUC) of 0.76 (95% CI: 0.70-0.81) at 1 year and 0.71 (95% CI: 0.66-0.77) at 2 years. Calibration between predicted and observed survival of the risk quintiles was high, with Pearson correlation coefficients of 0.986 and 0.994 at 1 and 2 years, respectively. Patients were successfully stratified into tertiles with higher-than-average, average, and lower-than-average survival, and observed mortality risk increased by 2-fold from one tertile to the next. CONCLUSIONS: A practical, easy-to-use HM3 Survival Risk Score with 6 components was developed to accurately predict 1- and 2-year survival after HM3 LVAD implantation. The survival risk score can be used to provide individual survival estimates to facilitate shared decision making when considering HM3 LVAD therapy. (MOMENTUM 3 Trial Portfolio; NCT02224755, NCT02892955).

Opportunities for Earlier Diagnosis and Treatment of Cardiac Amyloidosis.

Despite the rapid expansion of noninvasive (nonbiopsy) diagnosis, contemporary patients with cardiac amyloidosis too often present with advanced features of disease, such as diminished quality of life, elevated natriuretic peptides, and advanced heart failure. Therapeutics for transthyretin cardiomyopathy (ATTR-CM) are most effective when administered before significant symptoms of cardiac dysfunction manifest, making early identification of affected individuals of paramount importance. Community engagement and ensuring that a broad range of clinicians have working knowledge of how to screen for ATTR-CM in everyday practice will be an important step in moving disease identification further upstream. However, reliance on the appropriate and timely diagnosis by individual clinicians may continue to underperform. This review highlights how targeted screening of special populations may facilitate earlier diagnosis. Systems of care that operationalize screening of high-risk subpopulations and prospective validation of novel approaches to ATTR-CM identification are needed.

The Association of Cardiac Biomarkers, the Intensity of Tc99 Pyrophosphate Uptake, and Survival in Patients Evaluated for Transthyretin Cardiac Amyloidosis in the Early Therapeutics Era.

BACKGROUND: Transthyretin amyloid cardiomyopathy (ATTR-CM) is an increasingly recognized cause of heart failure. Given the expansion of noninvasive diagnosis with 99mTc-pyrophosphate (99mTc-PYP) scanning, and clinical use of the transthyretin stabilizer, tafamidis, we sought to examine the interplay of planar imaging heart-to-contralateral lung (H/CL) ratio, cardiac biomarkers, and survival probability in a contemporary cohort of patients referred for noninvasive evaluation of ATTR-CM. METHODS: This single-center retrospective cohort study included 351 consecutive patients who underwent a standardized imaging protocol with 99mTc-PYP scanning for the evaluation of ATTR-CM from January 1, 2018, to January 1, 2020. After the exclusion of light chain amyloidosis, patients were characterized as scan consistent with ATTR (+ATTR-CM) or scan not consistent with ATTR (-ATTR-CM) using current guidelines. Linear regression was used to examine the relationship between biomarkers and H/CL and univariate Cox proportional hazards models were used to assess the probability of transplant-free survival. RESULTS: We included 318 patients in the analysis (n = 86 patients +ATTR-CM; n = 232 patients -ATTR-CM). The median follow-up time was 20.1 months. During the study period, 67% of +ATTR-CM patients received tafamidis (median treatment duration, 17 months). The median H/CL ratio was 1.58 (interquartile range, 1.40-1.75). An H/CL ratio of more than 1.6 or less than 1.6 did not seem to have an impact on survival probability in +ATTR-CM patients (P = .30; hazard ratio, 0.65; 95% confidence interval, 0.31-1.41). Cardiac biomarkers were poorly correlated with H/CL (troponin T, R2 = 0.024; N-terminal pro-B-type natriuretic peptide, R2 =0.023). The Gillmore staging system predicted survival probability in +ATTR-CM as well as in the entire cohort referred for scanning. There was a trend toward longer survival among those who were -ATTR-CM compared with +ATTR-CM (P = .051; hazard ratio, 0.64; 95% confidence interval, 0.40-1.00). CONCLUSIONS: At a large referral center, the intensity of 99mTc-PYP uptake (H/CL ratio) has neither correlation with cardiac biomarker concentrations nor prognostic usefulness in an analysis of intermediate term outcomes in the early therapeutics era. The H/CL ratio has diagnostic value, but offers little prognostic value in patients with ATTR-CM. Established staging schema were predictive of survival in this contemporary cohort, re-emphasizing the importance of cardiac biomarkers and renal function in assessing disease severity and prognosis.

Arrhythmias in Cardiac Sarcoidosis Bench to Bedside: A Case-Based Review.

Cardiac sarcoidosis is a component of an often multiorgan granulomatous disease of still uncertain cause. It is being recognized with increasing frequency, mainly as the result of heightened awareness and new diagnostic tests, specifically cardiac magnetic resonance imaging and 18F-fluorodeoxyglucose positron emission tomography scans. The purpose of this case-based review is to highlight the potentially life-saving importance of making the early diagnosis of cardiac sarcoidosis using these new tools and to provide a framework for the optimal care of patients with this disease. We will review disease mechanisms as currently understood, associated arrhythmias including conduction abnormalities, and atrial and ventricular tachyarrhythmias, guideline-directed diagnostic criteria, screening of patients with extracardiac sarcoidosis, and the use of pacemakers and defibrillators in this setting. Treatment options, including those related to heart failure, and those which may help clarify disease mechanisms are included.

Evaluation of a hospital-wide vancomycin-dosing nomogram in patients with continuous-flow left ventricular assist devices.

INTRODUCTION: Hemodynamic derangements due to heart failure are associated with alterations in pharmacokinetics. Although use of mechanical circulatory support mitigates such derangements, little evidence is available regarding pharmacokinetics in patients with LVADs. A previous pharmacokinetic analysis of vancomycin among patients with LVADs observed a reduced volume of distribution and clearance compared with estimates based on population kinetics. METHODS: A total of 28 adult patients with LVADs hospitalized between January 2014 and May 2018 who received vancomycin through a pharmacist dosing consult were included. Internal medicine patients without heart failure receiving vancomycin were enrolled in a 2:1 fashion to make a control group. Exclusion criteria were unstable renal function, ESRD, acute decompensation, cardiac surgery within the preceding 5 days, or weight >110 kg. RESULTS: No difference was observed in the proportion achieving goal trough (64% of LVAD patients vs 71% control patients, p = 0.50). However, mean trough was significantly higher among LVAD patients (23.4 mg/L vs 17.7 mg/L, p = 0.017). Furthermore, there was a significant difference in the distribution of trough levels (p = 0.025) with LVAD patients being more likely to attain levels >25 mg/L (32% vs 14%) and less likely to have troughs <10 mg/L (4% vs 14%). A numerically greater number of LVAD patients experienced nephrotoxicity but this did not reach statistical significance (32% vs 18%, p = 0.14). CONCLUSION: The use of vancomycin in LVAD patients may result in higher trough levels when compared to internal medicine patients. Increased monitoring or conservative dosing may be warranted to improve safety and efficacy.

Temporal Trends of Cardiac Outcomes and Impact on Survival in Patients With Cancer.

To evaluate the temporal relations of cardiovascular disease in oncology patients referred to cardio-oncology and describe the impact of cardiovascular disease and cardiovascular risk factors on outcomes. All adult oncology patients referred to the cardio-oncology service at the Cleveland Clinic from January 2011 to June 2018 were included in the study. Comprehensive clinical information were collected. The impact on survival of temporal trends of cardiovascular disease in oncology patients were assessed with a Cox proportional hazards model and time-varying covariate adjustment for confounders. In total, 6,754 patients were included in the study (median age, 57 years; [interquartile range, 47 to 65 years]; 3,898 women [58%]; oncology history [60% - breast cancer, lymphoma, and leukemia]). Mortality and diagnosis of clinical cardiac disease peaked around the time of chemotherapy. 2,293 patients (34%) were diagnosed with a new cardiovascular risk factor after chemotherapy, over half of which were identified in the first year after cancer diagnosis. Patients with preexisting and post-chemotherapy cardiovascular disease had significantly worse outcomes than patients that did not develop any cardiovascular disease (p < 0.0001). The highest 1-year hazard ratios (HR) of post-chemotherapy cardiovascular disease were significantly associated with male (HR 1.81; 95% confidence interval 1.55 to 2.11; p < 0.001] and diabetes [HR 1.51; 95% confidence interval 1.26 to 1.81; p < 0.001]. In conclusion, patients referred to cardio-oncology, first diagnosis of cardiac events peaked around the time of chemotherapy. Those with preexisting or post-chemotherapy cardiovascular disease had worse survival. In addition to a high rate of cardiovascular risk factors at baseline, risk factor profile worsened over course of follow-up.

Successful management of COVID-19 and associated coagulopathy in a patient with durable left ventricular assist device.

Patients with durable left ventricular assist devices pose special problems for management in the setting of COVID-19 infection. We describe the successful management of a 44-year-old man with severe COVID-19 infection and HeartMate 3 left ventricular assist device. His course was complicated by cytokine storm and COVID-19-associated coagulopathy. We describe our institutional protocol for managing COVID-19 infection in patients on mechanical circulatory support, focusing on the need for a thoughtful, multidisciplinary approach.

Digoxin Use in Cardiac Amyloidosis.

Despite limited options for rate control of atrial fibrillation and for low-output heart failure seen in cardiac amyloidosis (CA), digoxin use is discouraged due to a reported increased risk of sensitivity and toxicity. We present our experience with digoxin use in patients with CA and report the event rate of suspected digoxin-related arrhythmias and toxicity. This is a retrospective study of patients with CA seen at our institution between November 1995 and October 2018. Patients were screened for a history of ≥7 days of continuous digoxin use and stratified based on amyloid precursor protein-transthyretin (ATTR) and immunoglobulin light chain (AL). Medical records were used to identify suspected digoxin-related arrhythmias and toxicity events. Digoxin was used in 69 patients (42 ATTR, 27 AL) for a median duration of 6 months (IQR, 1 to 16). Indication for use was rate control in 64% of patients and symptomatic heart failure management in 36%. Suspected digoxin-related arrhythmias and toxicity events occurred in 12% of patients. No deaths were attributed to digoxin use or toxicity, but 11 patients died while on digoxin-most due to progressive heart failure in the setting of CA. In conclusion, digoxin may be a therapeutic option for rate and symptom control for some patients with AL-CA and ATTR-CA. Rigorous patient selection is recommended, and patients should be closely monitored during digoxin administration.

Bariatric Surgery in End-Stage Heart Failure: Feasibility in Successful Attainment of a Target Body Mass Index.

INTRODUCTION: Orthotopic heart transplantation (OHT) is contraindicated in morbidly obese patients with end-stage heart failure (HF), for whom cardiac allograft is the only means for long-term survival. Bariatric surgery may allow them to achieve target body mass index (BMI) for OHT METHODS: From 4/2014 to 12/2018, 26 morbidly obese HF patients who did not meet BMI eligibility criteria for OHT underwent laparoscopic bariatric surgery. Outcomes of interest were median difference in BMI, number of patients achieving target BMI for OHT, and 30-day mortality. RESULTS: Median age was 49 (IQR 14) years, and 13 (50%) were women. HF was mainly systolic (15 patients, 58%). The median LVEF was 27% (IQR 37%). At the time of bariatric surgery, 12 (46%) patients had mechanical circulatory support: 2 (8%) concomitant left ventricular assist device (LVAD) placements, 8 (31%) LVAD already-in-place, and 2 (8%) intra-aortic balloon pumps. There was no 30-day mortality, but one mortality on postoperative day 48. Over a median follow-up of 6 months (range 0-36 months, IQR 17), there was a significant reduction in BMI (p<0.0001). The median postoperative BMI was 36.7 (IQR 8.7), compared to preoperative median BMI of 42.7 (IQR 9.4). Target BMI of < 35 was achieved in 11 (42%) patients. Three patients (12%) have undergone OHT. CONCLUSION: Bariatric surgery in end-stage HF is feasible and results in a high number of patients achieving target BMI, increasing their probability of undergoing OHT. The presence of a LVAD should not preclude these patients from undergoing a bariatric intervention.