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.

Predictive Modeling to Assess Pretest Probability of Transthyretin Gene Variants Based on Demographic Information.

BACKGROUND: Transthyretin amyloid cardiomyopathy (ATTR-CM) is a morbid condition, though recent advances in diagnosis and therapy stand to change its natural history. Patients' TTR genotype may guide family screening as more treatments and preventive strategies become available. An efficient, intuitive means of determining pretest genetic risk may better inform patients/clinicians when pursuing genetic testing. METHODS: This is a cohort study of 767 consecutive patients diagnosed with ATTR-CM who underwent genetic testing. Classification and regression trees (CART) analysis created a decision tree assessing likelihood of carrying a pathologic TTR gene variant. Age, sex, and race were used as independent variables. Logistic regression was also performed to model probability of pathologic TTR genotype. The primary outcome was the decision tree's accuracy in 2 separate institutions' ATTR-CM registry. RESULTS: In our study cohort, 208 patients (27.1%) had ATTRv. Race has served most efficiently as the root node followed by age and sex in a CART algorithm, and showed 88.2% accuracy (75.3% sensitivity, 93.9% specificity) in the validation cohort. The odds of having a TTR gene variant were greater in Black patients compared with non-Black patients (OR, 34.6 [95% CI, 20.5-58.3]; P<0.001). Non-Black patients with ATTR-CM aged 69 years and older had <4% risk of having a predisposing mutation. CONCLUSIONS: This CART algorithm incorporating age, sex, and race was able to determine which patients with ATTR-CM have pathogenic TTR mutations with high specificity. Non-Black patients diagnosed at age 69 years or older with ATTR-CM have a low likelihood to have ATTRv.

Hemodynamic Profiling and Prognosis in Cardiac Amyloidosis.

BACKGROUND: Little information is available on the prognostic relevance of cardiac hemodynamic cutoffs in cardiac amyloidosis (CA) and its subtypes. METHODS: Consecutive patients diagnose with light chain-CA or transthyretin CA undergoing right heart catheterization were analyzed. Prognostic relevance of classic hemodynamic cutoffs of cardiac index (CI <2.2 L/min per m2), pulmonary capillary wedge pressure (>18 mm Hg), right atrial pressure (>8 mm Hg), and mean pulmonary artery pressure (≥25 mm Hg or pulmonary hypertension) with the combined end point of cardiac transplant/left ventricular assist device and death and heart failure admissions separately was assessed. RESULTS: A total of 469 CA patients underwent right heart catheterization (light chain CA=42% and transthyretin CA=52%) of whom 69%, 64%, and 79% had elevated right atrial pressure, pulmonary capillary wedge pressure, and pulmonary hypertension, respectively. The classic hemodynamic cutoffs for right atrial pressure (hazard ratio, 1.26 [0.98-1.62]) and mean pulmonary artery pressure (hazard ratio, 1.28 [0.96-1.71]) did not identify patients at higher risk for adverse outcome; however, cutoffs of 14 mm Hg for right atrial pressure (hazard ratio, 1.59 [1.26-2.00]) and 35 mm Hg for mean pulmonary artery pressure (hazard ratio, 1.30 [1.01-1.66]) performed better to detect worse outcome (P<0.05 for both). Reduced CI occurred in 55% of patients and was the strongest variable associated with the risk for cardiac transplant/left ventricular assist device and death, heart failure admissions, and reduced functional capacity. Reduced CI independently predicted risk on top of the Mayo-score in light chain CA and National Amyloid Center score in transthyretin CA (P<0.05 for both). Patients with light chain CA had higher pulmonary capillary wedge pressure and lower stroke volume index but maintained CI through a higher heart rate. CONCLUSIONS: Hemodynamic variables are grossly abnormal in CA, but elevated filling pressures are prognostic at significantly higher threshold values than classic cutoff values. CI is the hemodynamic variable most strongly associated with outcome and functionality in CA.

Prevalence of Orthopedic Manifestations in Patients With Cardiac Amyloidosis With a Focus on Shoulder Pathologies.

Transthyretin cardiac amyloidosis (ATTR-CA) is a restrictive cardiomyopathy that has been associated with multiple orthopedic pathologies years before it manifests in the heart. There have been no studies on the prevalence of a wide range of shoulder pathologies in patients with cardiac amyloidosis (CA). Due to the preferential deposition of transthyretin in the soft tissues and joints, we predicted a greater prevalence of shoulder pathologies and other orthopedic manifestations in patients with ATTR-CA. This single-center, retrospective, case-control study, analyzed 1,310 patients with CA, 830 with ATTR-CA, and 480 with light-chain CA (AL-CA) from a dedicated CA REDcap database. Odds ratios comparing patients with CA to the age-matched published estimate of over 300 million patients in the general population were determined for shoulder, hip, and knee arthroplasty. Years between a patient's first shoulder pathology (i.e., shoulder arthroplasty) and the year of their diagnosis with CA were determined using data from patients with a known date of surgery. Overall, patients with ATTR-CA compared with patients with AL-CA presented more frequently with shoulder pathologies (p <0.001) and at least 1 orthopedic manifestation (p <0.001). The odds of patients with ATTR-CA and AL-CA aged 60 years or older who underwent shoulder arthroplasty was 6.05 times greater (95% confidence interval 4.26 to 8.60) and 1.63 times greater (95% confidence interval 0.67 to 3.94), respectively, compared with age-matched controls. Shoulder pathologies and concomitant orthopedic pathologies are common in patients with ATTR-CA and may help identify patients with CA earlier in their disease progression for earlier intervention and treatment.

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.

Electrical Dyssynchrony in Cardiac Amyloidosis: Prevalence, Predictors, Clinical Correlates, and Outcomes.

BACKGROUND: Conduction-system involvement in cardiac amyloidosis (CA) is common. The prevalence, clinical correlates and impact on outcome related to ventricular electrical dyssynchrony in CA remain insufficiently elucidated. METHODS: Data from a prospectively maintained registry of patients with CA diagnosed in the Cleveland Clinic's amyloidosis clinic was used to determine the frequency of electrical dyssynchrony (defined as a QRS > 130 msec). The relation with the clinical profile and clinical outcome was assessed. To determine the impact of hypertrophy on QRS prolongation, a QRS-matched cohort without CA was used for comparison of cardiac magnetic resonance imaging. RESULTS: A total of 1140 patients with CA (39% AL, 61% TTR) were evaluated, of whom 230 (20%) had electrical dyssynchrony. The type of conduction block was predominantly a right bundle branch block (BBB, 48%) followed by left BBB (35%) and intraventricular conduction delay (17%). Presence of transthyretin amyloidosis (ATTR-CA), older age, male gender, white race, and coronary artery disease were independently (P< 0.05 for all) associated with electrical dyssynchrony, and patients were more commonly prescribed a mineralocorticoid receptor antagonist. In ATTR-CA, specifically, every increase in ATTR-CA disease stage was associated with a 1.55-fold (1.23--1.95; P< 0.001) increased odds for electrical dyssynchrony. In a subset of patients with CA who underwent cardiac magnetic resonance imaging (n = 41), left ventricular mass index was unrelated to the QRS duration (r = 0.187; P = 0.283) in CA, in contrast to a non-CA QRS-matched cohort (r = 0.397; P< 0.001). Patients with electrical dyssynchrony were more symptomatic at initial presentation, as illustrated by a higher New York Heart Association class (P= 0.041). During a median follow-up of 462 days (IQR:138--996 days), a higher proportion of patients with electrical dyssynchrony died from all-cause death (P= 0.037) or developed a permanent pacing indication (3% vs 10.4%; P< 0.001) during follow-up. CONCLUSION: Electrical dyssynchrony is common in CA, especially in ATTR-CA, and is associated with worse functional status and clinical outcome. Given the high rate of permanent pacing indications at follow-up, additional studies are necessary to determine the best monitoring and pacing strategies in CA.