Genotype and Phenotype of Transthyretin Cardiac Amyloidosis: THAOS (Transthyretin Amyloid Outcome Survey)

Background Transthyretin amyloidosis (ATTR) is a heterogeneous disorder with multiorgan involvement and a genetic or nongenetic basis. Objectives The goal of this study was to describe ATTR in the United States by using data from the THAOS (Transthyretin Amyloidosis Outcomes Survey) registry. Methods Demographic, clinical, and genetic features of patients enrolled in the THAOS registry in the United States (n = 390) were compared with data from patients from other regions of the world (ROW) (n = 2,140). The focus was on the phenotypic expression and survival in the majority of U.S. subjects with valine-to-isoleucine substitution at position 122 (Val122Ile) (n = 91) and wild-type ATTR (n = 189). Results U.S. subjects are older (70 vs. 46 years), more often male (85.4% vs. 50.6%), and more often of African descent (25.4% vs. 0.5%) than the ROW. A significantly higher percentage of U.S. patients with ATTR amyloid seen at cardiology sites had wild-type disease than the ROW (50.5% vs. 26.2%). In the United States, 34 different mutations (n = 201) have been reported, with the most common being Val122Ile (n = 91; 45.3%) and Thr60Ala (n = 41; 20.4%). Overall, 91 (85%) of 107 patients with Val122Ile were from the United States, where Val122Ile subjects were younger and more often female and black than patients with wild-type disease, and had similar cardiac phenotype but a greater burden of neurologic symptoms (pain, numbness, tingling, and walking disability) and worse quality of life. Advancing age and lower mean arterial pressure, but not the presence of a transthyretin mutation, were independently associated with higher mortality from a multivariate analysis of survival. Conclusions In the THAOS registry, ATTR in the United States is overwhelmingly a disorder of older adult male subjects with a cardiac-predominant phenotype. Val122Ile is the most common transthyretin mutation, and neurologic phenotypic expression differs between wild-type disease and Val122Ile, but survival from enrollment in THAOS does not. (Transthyretin-Associated Amyloidoses Outcome Survey [THAOS]; NCT00628745

Tissue Doppler Image-Derived Measurements During Isovolumic Contraction Predict Exercise Capacity in Patients With Reduced Left Ventricular Ejection Fraction

ObjectivesWe explored the incremental value of quantification of tissue Doppler (TD) velocity during the brief isovolumic contraction (IVC) phase of the cardiac cycle for the prediction of exercise performance in patients referred for cardiopulmonary exercise testing (CPET).BackgroundExperimental studies have shown that rapid left ventricular (LV) shape change during IVC is essential for optimal onset of LV ejection. However, the incremental value of measuring IVC velocities in clinical settings remains unclear.MethodsA total of 82 subjects (age 53 ± 14 years, 56 men) were studied with echocardiography and CPET. Reduced LV ejection fraction (EF) (EF <50%) was present in 38 (46%) subjects. Pulsed-wave annular TD velocities were averaged from the LV lateral and septal annulus during isovolumic contraction (IVCa), ejection, isovolumic relaxation, and early and late diastole (Aa) and compared with peak oxygen consumption (VO2) and percentage of the predicted peak VO2 (% predicted peak VO2) obtained from CPET.ResultsPatients with reduced EF had lower IVCa (6.3 vs. 4.5 cm/s, p = 0.04), ejection (7.7 vs. 5.5 cm/s, p < 0.001), and Aa velocities (7.9 vs. 6.6 cm/s, p = 0.04). Similarly, % predicted peak VO2 was lower in patients with reduced EF (52.9% vs. 73.1%, p < 0.001) and correlated with the variations in IVCa (r = 0.7, p = 0.001). Multivariate analysis of 2-dimensional and Doppler variables in the presence of reduced LV EF revealed only IVCa and Aa as independent predictors of % predicted peak VO2 (r2 = 0.612, p = 0.02 for IVCa and p = 0.009 for Aa). The overall performance of IVCa in the prediction of exercise capacity was good (area under the curve = 0.86, p < 0.001).ConclusionsAssessment of TD-derived IVC and atrial stretch velocities provide independent prediction of exercise capacity in patients with reduced LV EF. Assessment of LV pre-ejectional stretch and shortening mechanics at rest may be useful for determining the myocardial functional reserve of patients with reduced EF

Soluble ST2 does not change cardiovascular risk prediction compared to cardiac troponin T in kidney transplant candidates

<div><p>Background</p><p>Solubility of Tumorigenicity 2 (sST2) is a novel biomarker that better stratifies risk of cardiovascular events (CVE) compared to cardiac troponin T(cTnT) in heart failure. We assessed the association of sST2 with the composite outcome of CVE and/or mortality compared to cTnT in kidney transplant candidates.</p><p>Methods</p><p>200 kidney transplant candidates between 2010 and 2013 were included. Elevated sST2 was defined as ≥30ng/ml, cTnT≥0.01 ng/ml.</p><p>Results</p><p>Median age 53 (interquartile range (IQR) 42–61) years, 59.7% male and 82.0% white. 33.5% had history of CVE, 42.5% left ventricular hypertrophy (LVH) and 15.6% positive cardiac stress test. Elevated sST2 correlated with male gender, history of prior-transplants, CVE, positive stress test, LVH, elevated cTnT, anemia, hyperphosphatemia, increased CRP and non-transplanted status. Male gender, history of CVE and LVH were independent determinants of sST2. During 28 months (IQR 25.3–30), 7.5% died, 13.0% developed CVE and 19.0% developed the composite outcome. Elevated sST2 was associated with the composite outcome (hazard ratio = 1.76, CI 1.06–2.73, p = 0.029) on univariate analysis but not after adjusting for age, diabetes and cTnT (p = 0.068). sST2 did not change the risk prediction model for composite outcome after including age, diabetes, prior history of CVE and elevated cTnT.</p><p>Conclusions</p><p>Increased sST2 level is significantly associated with variables associated with CVE in kidney transplant candidates. sST2 was associated with increased risk of the composite outcome of CVE and/or death but not independent of cTnT. Larger studies are needed to confirm these findings and determine whether sST2 has added value in CV risk stratification in this cohort of patients.</p></div

Sirolimus-Based Immunosuppression Is Associated with Decreased Incidence of Post-Transplant Lymphoproliferative Disorder after Heart Transplantation: A Double-Center Study

Mammalian target of rapamycin (mTOR) inhibitors have been shown to reduce proliferation of lymphoid cells; thus, their use for immunosuppression after heart transplantation (HT) may reduce post-transplant lymphoproliferative disorder (PTLD) risk. This study sought to investigate whether the sirolimus (SRL)-based immunosuppression regimen is associated with a decreased risk of PTLD compared with the calcineurin inhibitor (CNI)-based regimen in HT recipients. We retrospectively analyzed 590 patients who received HTs at two large institutions between 1 June 1988 and 31 December 2014. Cox proportional-hazard modeling was used to examine the association between type of primary immunosuppression and PTLD after adjustment for potential confounders, including Epstein–Barr virus (EBV) status, type of induction therapy, and rejection. Conversion from CNI to SRL as primary immunosuppression occurred in 249 patients (42.2%). During a median follow-up of 6.3 years, 30 patients developed PTLD (5.1%). In a univariate analysis, EBV mismatch was strongly associated with increased risk of PTLD (HR 10.0, 95% CI: 3.8–26.6; p p = 0.02). In a multivariable model and after adjusting for EBV mismatch, conversion to SRL remained protective against risk of PTLD compared with continued CNI use (HR 0.12, 95% CI: 0.03–0.55; p = 0.006). In conclusion, SRL-based immunosuppression is associated with lower incidence of PTLD after HT. These findings provide evidence of a benefit from conversion to SRL as maintenance therapy for mitigating the risk of PTLD, particularly among patients at high PTLD risk

Univariate and multivariate analysis of determinants of an elevated sST2 level.

<p>Univariate and multivariate analysis of determinants of an elevated sST2 level.</p

Soluble ST2 does not change cardiovascular risk prediction compared to cardiac troponin T in kidney transplant candidates

<div><p>Background</p><p>Solubility of Tumorigenicity 2 (sST2) is a novel biomarker that better stratifies risk of cardiovascular events (CVE) compared to cardiac troponin T(cTnT) in heart failure. We assessed the association of sST2 with the composite outcome of CVE and/or mortality compared to cTnT in kidney transplant candidates.</p><p>Methods</p><p>200 kidney transplant candidates between 2010 and 2013 were included. Elevated sST2 was defined as ≥30ng/ml, cTnT≥0.01 ng/ml.</p><p>Results</p><p>Median age 53 (interquartile range (IQR) 42–61) years, 59.7% male and 82.0% white. 33.5% had history of CVE, 42.5% left ventricular hypertrophy (LVH) and 15.6% positive cardiac stress test. Elevated sST2 correlated with male gender, history of prior-transplants, CVE, positive stress test, LVH, elevated cTnT, anemia, hyperphosphatemia, increased CRP and non-transplanted status. Male gender, history of CVE and LVH were independent determinants of sST2. During 28 months (IQR 25.3–30), 7.5% died, 13.0% developed CVE and 19.0% developed the composite outcome. Elevated sST2 was associated with the composite outcome (hazard ratio = 1.76, CI 1.06–2.73, p = 0.029) on univariate analysis but not after adjusting for age, diabetes and cTnT (p = 0.068). sST2 did not change the risk prediction model for composite outcome after including age, diabetes, prior history of CVE and elevated cTnT.</p><p>Conclusions</p><p>Increased sST2 level is significantly associated with variables associated with CVE in kidney transplant candidates. sST2 was associated with increased risk of the composite outcome of CVE and/or death but not independent of cTnT. Larger studies are needed to confirm these findings and determine whether sST2 has added value in CV risk stratification in this cohort of patients.</p></div

Distribution of patients with an elevated sST2 level across different causes of ESRD.

<p>sST2 level was higher in patients with ESRD secondary to hypertension, renovascular disease and chronic allograft failure compared to other causes.</p

Variables associated with the composite outcome of cardiovascular events and/or death.

<p>Variables associated with the composite outcome of cardiovascular events and/or death.</p

Baseline characteristics.

<p>Baseline characteristics.</p

Flowchart of patients screened and included in the study.

<p>Flowchart of patients screened and included in the study.</p