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Identifying Mixed Phenotype: Evaluating the Presence of Polyneuropathy in Patients with Hereditary Transthyretin-Mediated Amyloidosis with Cardiomyopathy
The 23rd Annual Scientific Meeting HFSA
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dysfunction, however this ratio was not associated with LV recovery. Multiple echocardiographic measures were associated with recovery, including initial LVEF, LV GLS and SLS. However, strain does not appear to provide added predictive value for recovery when accounting for initial LVEF. Additional work, combining imaging and clinical data, is needed to better predict donor LV recovery and thus expand the cardiac donor pool.
Table 1. Donor Heart Echocardiographic Measurements
023 Identifying Mixed Phenotype: Evaluating the Presence of Polyneuropathy in Patients with Hereditary Transthyretin-Mediated Amyloidosis with Cardiomyopathy Martha Grogan1, Philip N. Hawkins2, Arnt V. Kristen3, John L. Berk4, Ole B. Suhr5, Hollis Lin6, Madeline Merkel6, Anastasia McManus6, Christine Powell6, John Vest6, Verena Karsten6, Daniel P. Judge7; 1Mayo Clinic, Rochester, MN; 2National Amyloidosis Centre, London, United Kingdom; 3Heidelberg University Hospital, Heidelberg, Germany; 4Boston University, Boston, MA; 5Umea University, Umea, Sweden; 6 Alnylam Pharmaceuticals, Cambridge, MA; 7Medical University of South Carolina, Charleston, SC
022 Donor-Recipient Predicted Heart Mass Ratio as Predictor of Right VentricularPulmonary Arterial Coupling Post Heart Transplantation ^ Raffaela A. Nazario, Angela B.S. Santos, Laura C.T. Hastenteufel, Luciana Carrion, Nadine Clausell, Lıvia A. Goldraich; Hospital de Clinicas de Porto Alegre, Porto Alegre, Brazil Background: Right ventricular dysfunction is a frequent complication after heart transplantation. Right ventricular-pulmonary arterial (RV-PA) coupling interactions negatively impact right ventricular function and have prognostic implications in heart failure; yet, the temporal profile of RV-PA interactions in the context of heart transplantation has not been explored, particularly its relationship with donor-recipient size matching. Our aim was to assess RV-PA coupling at seven and 30 days after heart transplantation and to study its association with donor-recipient size matching. Methods: Clinical, echocardiographic and hemodynamic data from a retrospective cohort of consecutive adult heart transplant recipients and their respective donors were reviewed. Coupling between RV-PA was examined by the ratio between right ventricular fractional area change and pulmonary artery systolic pressure (RVFAC/ PASP) at seven and 30 days post-transplant. Donor-recipient size matching was assessed by donor-recipient predicted heart mass (PHM) ratio, and appropriate size graft was defined as PHM ratio 1. Predictors of RV-PA coupling were examined by multiple linear regression analysis. Results: Thirty-four patients transplanted between July/2015 and June/2018 were included (48 § 15 years, 50% male). Fifty percent had pre-transplant pulmonary hypertension (mean pulmonary artery pressure 25.71 § 7.12 mmHg). Median PHM ratio was 1.08 (p25-75: 0.94-1.29), and 40% grafts were considered undersized. Post-transplant RV-PA coupling was decreased and improved from seven to 30 days (RVFAC/PASP 0.98 § 0.24 vs. 1.26 § 0.27; p<0.001). There was a positive association between PHM ratio and RV-PA coupling at 30 days, independent of graft ischemic time and pre-existing pulmonary hypertension (B 0.51; 95% CI 0.13-0.90; p=0.01; R2=0.29). Recipients with appropriate size graft as per PHM ratio had the largest improvement in RV-PA coupling at 30 days (Figure). Conclusions: These findings suggest the impact of PHM on RV-PA coupling interactions and, subsequently, in right ventricular dysfunction post heart transplantation. This highlights the role of PHM ratio as a metric to improve donor selection.
Hereditary transthyretin-mediated (hATTR) amyloidosis is an inherited, progressively debilitating, fatal disease caused by amyloid accumulation in tissues and organs. Historically, patients were grouped by their predominant phenotype: cardiomyopathy or polyneuropathy. However, recent studies have shown that the majority of patients develop a mixed phenotype of polyneuropathy and cardiomyopathy. This analysis describes the prevalence of polyneuropathy signs and symptoms among patients with hATTR amyloidosis with confirmed cardiomyopathy. Patients enrolled in the Phase 3 ENDEAVOUR study had hATTR amyloidosis with cardiomyopathy (n=206) with a documented TTR mutation, amyloid deposition by biopsy or technetium (99mTc) scintigraphy, echocardiographic evi-
Table 1. Baseline Demographics, Disease Characteristics, and Select Medical History in Patients with hATTR Amyloidosis
S10 Journal of Cardiac Failure Vol. 25 No. 8S August 2019 dence of cardiac amyloid involvement, and medical history or clinical evidence of heart failure. Baseline disease characteristics and medical history were analyzed in the overall group and by genotype to identify the presence of polyneuropathy signs and symptoms. The 3 most common genotypes in the Phase 3 study included Val122Ile (n=118), Thr60Ala (n=35), and Val30Met (n=9). Baseline demographics, disease characteristics, and medical history terms are presented in Table 1. Majority of patients had symptomatic heart failure at baseline (61% NYHA Class II and 31% Class III) and medical history of heart failure (85%). By Polyneuropathy Disability (PND) Score at enrollment, symptoms of polyneuropathy were present in the majority of patients; 53% of patients had sensory abnormalities (PND I) or sensorimotor impairment affecting ambulation (PND II). Based on medical history, 54% of patients had a diagnosis that coded to the nervous system disorders based on peripheral neuropathy standard MedDRA query (49% of Val122Ile patients, 66% Thr60Ala patients, and 78% Val30Met patients). hATTR amyloidosis is a debilitating disease with variable genotypephenotype relationship. In patients with hATTR amyloidosis with cardiomyopathy, signs and symptoms of polyneuropathy were common. The mixed presentation of hATTR amyloidosis highlights the importance of multisystem disease assessment in this patient population.
024 Inability to Achieve Adequate Left Ventricular Unloading Predicts Hospitalization or Death after Invasive Optimization in LVAD Patients Andrew Rosenbaum, Alfredo Clavell, John Stulak, Atta Behfar; Mayo Clinic, Rochester, MN Background: A left heart catheterization optimization protocol was recently developed at our institution and several physiologic indices, including LV end diastolic pressure (LVEDP) and trans-aortic gradient (TAG), previously only available in computational or animal models, were evaluated in patients supported on LVAD therapy. We sought to evaluate the prognostic significance of these markers. Hypothesis: Inability to achieve adequate ventricular unloading will result in worse heart failure hospitalization-free survival. Methods: All patients undergoing combined left and right heart catheterization protocol at our institution between 2015 and 2018 were evaluated. Patients whose left ventricles were inaccessible or who underwent non-standard protocols were excluded. Comprehensive clinical data were obtained. Primary endpoints included a composite outcome of hospitalization or death and overall survival. Results: Thirty one patients were analyzed from the cohort. Optimization resulted in normalization of hemodynamic parameters on average (RA 11 mmHg, PA 25 mmHg, PCWP 13 mmHg, LVEDP 12 mmHg, cardiac index 2.53 L/min/m2), which was significantly improved from baseline for all variables [p 0.05]). On univariate modeling, only LVEDP was associated with the primary endpoint (HR 1.2 per 1 mmHg increase, CI[1.1-1.3], p<0.01). After inclusion of LVAD speed, transaortic gradient,and cardiac index in a multivariate model, the association between LVEDP and the composite endpoint remained significant (HR 1.4 per 1 mmHg, CI [1.21.4], p<0.001). Conclusions: Left ventricular offloading as measured by left ventricular end-diastolic pressure was a significant marker of poor outcomes over time. Further research should focus on pathophysiology corresponding to poor unloading.
025 Increasing Burden of Heart Failure in Black Adults in the US: 1999-2016 Leah Rethy, Thanh-Huyen T. Vu, Kiarri Kershaw, Rupal Mehta, Nilay S. Shah, Mercedes Carnethon, Clyde W. Yancy, Donald M. Lloyd-Jones, Sadiya S. Khan; Northwestern University, Chicago, IL Background: Given increasing rates of heart failure (HF) risk factors (e.g. obesity, diabetes) that disproportionally affect black adults, we sought to describe contemporary trends in HF prevalence and examine differences between blacks and whites. Hypothesis: Racial disparities in HF exist and are widening. Methods: Non-pregnant adults aged 35 years who identified as non-Hispanic black or white from the National Health and Nutrition Examination Survey (NHANES) between 1999 and 2016 were included. Age-adjusted HF prevalence was calculated by two-year cycles and weighted linear regression was used to examine trends over time. Odds ratios (OR) and 95% confidence intervals (CI) of HF in blacks vs. whites were calculated by pooling cycles into six-year periods with adjustment for age, sex, cardiovascular risk factors (CV RF), renal function, and proxies of socioeconomic status (SES: education level and health insurance status). Given a significant interaction between race and age group, analyses were stratified by age groups: 35-64 and 65+ years. Results: Of 20,290 participants with mean age 55.3§0.2 years, 52% were women and 12% black. Age-adjusted prevalence of HF per 100,000 increased linearly among blacks from 3921 (2663, 5178) in 1999-2000 to 6568 (4557, 8580) in 2015-2016 (ptrend<0.05). Overall prevalence of HF per 100,000 was stable among whites between 1999 (3770 [3090, 4451]) and 2016 (3090 [2572, 3706], p-trend>0.05). Age and sexadjusted odds of HF in blacks compared to whites (TABLE) was higher between 2005-10 (period 2) and 2011-16 (period 3). After adjustment for RF and SES, odds of HF remained higher in blacks in periods 2 and 3 by 1.51 (1.11, 2.04) and 1.55 (1.16, 2.06), respectively. This appeared to be primarily driven by differences in HF prevalence between younger blacks and whites (age 35-64 years). Conclusions: The prevalence of HF in blacks is increasing and the odds of HF was significantly higher in blacks compared to whites. While the increased odds of HF was attenuated after adjusting for RF and SES, disparities persisted and have widened over time. Research and resources aimed at identifying social determinants of HF, alongside aggressive management of risk factors, are needed to prevent HF and reduce disparities.
Table. Adjusted Odds Ratios (95% Confidence Interval) of Heart Failure in Blacks Compared to Whites
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dysfunction, however this ratio was not associated with LV recovery. Multiple echocardiographic measures were associated with recovery, including initial LVEF, LV GLS and SLS. However, strain does not appear to provide added predictive value for recovery when accounting for initial LVEF. Additional work, combining imaging and clinical data, is needed to better predict donor LV recovery and thus expand the cardiac donor pool.
Table 1. Donor Heart Echocardiographic Measurements
023 Identifying Mixed Phenotype: Evaluating the Presence of Polyneuropathy in Patients with Hereditary Transthyretin-Mediated Amyloidosis with Cardiomyopathy Martha Grogan1, Philip N. Hawkins2, Arnt V. Kristen3, John L. Berk4, Ole B. Suhr5, Hollis Lin6, Madeline Merkel6, Anastasia McManus6, Christine Powell6, John Vest6, Verena Karsten6, Daniel P. Judge7; 1Mayo Clinic, Rochester, MN; 2National Amyloidosis Centre, London, United Kingdom; 3Heidelberg University Hospital, Heidelberg, Germany; 4Boston University, Boston, MA; 5Umea University, Umea, Sweden; 6 Alnylam Pharmaceuticals, Cambridge, MA; 7Medical University of South Carolina, Charleston, SC
022 Donor-Recipient Predicted Heart Mass Ratio as Predictor of Right VentricularPulmonary Arterial Coupling Post Heart Transplantation ^ Raffaela A. Nazario, Angela B.S. Santos, Laura C.T. Hastenteufel, Luciana Carrion, Nadine Clausell, Lıvia A. Goldraich; Hospital de Clinicas de Porto Alegre, Porto Alegre, Brazil Background: Right ventricular dysfunction is a frequent complication after heart transplantation. Right ventricular-pulmonary arterial (RV-PA) coupling interactions negatively impact right ventricular function and have prognostic implications in heart failure; yet, the temporal profile of RV-PA interactions in the context of heart transplantation has not been explored, particularly its relationship with donor-recipient size matching. Our aim was to assess RV-PA coupling at seven and 30 days after heart transplantation and to study its association with donor-recipient size matching. Methods: Clinical, echocardiographic and hemodynamic data from a retrospective cohort of consecutive adult heart transplant recipients and their respective donors were reviewed. Coupling between RV-PA was examined by the ratio between right ventricular fractional area change and pulmonary artery systolic pressure (RVFAC/ PASP) at seven and 30 days post-transplant. Donor-recipient size matching was assessed by donor-recipient predicted heart mass (PHM) ratio, and appropriate size graft was defined as PHM ratio 1. Predictors of RV-PA coupling were examined by multiple linear regression analysis. Results: Thirty-four patients transplanted between July/2015 and June/2018 were included (48 § 15 years, 50% male). Fifty percent had pre-transplant pulmonary hypertension (mean pulmonary artery pressure 25.71 § 7.12 mmHg). Median PHM ratio was 1.08 (p25-75: 0.94-1.29), and 40% grafts were considered undersized. Post-transplant RV-PA coupling was decreased and improved from seven to 30 days (RVFAC/PASP 0.98 § 0.24 vs. 1.26 § 0.27; p<0.001). There was a positive association between PHM ratio and RV-PA coupling at 30 days, independent of graft ischemic time and pre-existing pulmonary hypertension (B 0.51; 95% CI 0.13-0.90; p=0.01; R2=0.29). Recipients with appropriate size graft as per PHM ratio had the largest improvement in RV-PA coupling at 30 days (Figure). Conclusions: These findings suggest the impact of PHM on RV-PA coupling interactions and, subsequently, in right ventricular dysfunction post heart transplantation. This highlights the role of PHM ratio as a metric to improve donor selection.
Hereditary transthyretin-mediated (hATTR) amyloidosis is an inherited, progressively debilitating, fatal disease caused by amyloid accumulation in tissues and organs. Historically, patients were grouped by their predominant phenotype: cardiomyopathy or polyneuropathy. However, recent studies have shown that the majority of patients develop a mixed phenotype of polyneuropathy and cardiomyopathy. This analysis describes the prevalence of polyneuropathy signs and symptoms among patients with hATTR amyloidosis with confirmed cardiomyopathy. Patients enrolled in the Phase 3 ENDEAVOUR study had hATTR amyloidosis with cardiomyopathy (n=206) with a documented TTR mutation, amyloid deposition by biopsy or technetium (99mTc) scintigraphy, echocardiographic evi-
Table 1. Baseline Demographics, Disease Characteristics, and Select Medical History in Patients with hATTR Amyloidosis
S10 Journal of Cardiac Failure Vol. 25 No. 8S August 2019 dence of cardiac amyloid involvement, and medical history or clinical evidence of heart failure. Baseline disease characteristics and medical history were analyzed in the overall group and by genotype to identify the presence of polyneuropathy signs and symptoms. The 3 most common genotypes in the Phase 3 study included Val122Ile (n=118), Thr60Ala (n=35), and Val30Met (n=9). Baseline demographics, disease characteristics, and medical history terms are presented in Table 1. Majority of patients had symptomatic heart failure at baseline (61% NYHA Class II and 31% Class III) and medical history of heart failure (85%). By Polyneuropathy Disability (PND) Score at enrollment, symptoms of polyneuropathy were present in the majority of patients; 53% of patients had sensory abnormalities (PND I) or sensorimotor impairment affecting ambulation (PND II). Based on medical history, 54% of patients had a diagnosis that coded to the nervous system disorders based on peripheral neuropathy standard MedDRA query (49% of Val122Ile patients, 66% Thr60Ala patients, and 78% Val30Met patients). hATTR amyloidosis is a debilitating disease with variable genotypephenotype relationship. In patients with hATTR amyloidosis with cardiomyopathy, signs and symptoms of polyneuropathy were common. The mixed presentation of hATTR amyloidosis highlights the importance of multisystem disease assessment in this patient population.
024 Inability to Achieve Adequate Left Ventricular Unloading Predicts Hospitalization or Death after Invasive Optimization in LVAD Patients Andrew Rosenbaum, Alfredo Clavell, John Stulak, Atta Behfar; Mayo Clinic, Rochester, MN Background: A left heart catheterization optimization protocol was recently developed at our institution and several physiologic indices, including LV end diastolic pressure (LVEDP) and trans-aortic gradient (TAG), previously only available in computational or animal models, were evaluated in patients supported on LVAD therapy. We sought to evaluate the prognostic significance of these markers. Hypothesis: Inability to achieve adequate ventricular unloading will result in worse heart failure hospitalization-free survival. Methods: All patients undergoing combined left and right heart catheterization protocol at our institution between 2015 and 2018 were evaluated. Patients whose left ventricles were inaccessible or who underwent non-standard protocols were excluded. Comprehensive clinical data were obtained. Primary endpoints included a composite outcome of hospitalization or death and overall survival. Results: Thirty one patients were analyzed from the cohort. Optimization resulted in normalization of hemodynamic parameters on average (RA 11 mmHg, PA 25 mmHg, PCWP 13 mmHg, LVEDP 12 mmHg, cardiac index 2.53 L/min/m2), which was significantly improved from baseline for all variables [p 0.05]). On univariate modeling, only LVEDP was associated with the primary endpoint (HR 1.2 per 1 mmHg increase, CI[1.1-1.3], p<0.01). After inclusion of LVAD speed, transaortic gradient,and cardiac index in a multivariate model, the association between LVEDP and the composite endpoint remained significant (HR 1.4 per 1 mmHg, CI [1.21.4], p<0.001). Conclusions: Left ventricular offloading as measured by left ventricular end-diastolic pressure was a significant marker of poor outcomes over time. Further research should focus on pathophysiology corresponding to poor unloading.
025 Increasing Burden of Heart Failure in Black Adults in the US: 1999-2016 Leah Rethy, Thanh-Huyen T. Vu, Kiarri Kershaw, Rupal Mehta, Nilay S. Shah, Mercedes Carnethon, Clyde W. Yancy, Donald M. Lloyd-Jones, Sadiya S. Khan; Northwestern University, Chicago, IL Background: Given increasing rates of heart failure (HF) risk factors (e.g. obesity, diabetes) that disproportionally affect black adults, we sought to describe contemporary trends in HF prevalence and examine differences between blacks and whites. Hypothesis: Racial disparities in HF exist and are widening. Methods: Non-pregnant adults aged 35 years who identified as non-Hispanic black or white from the National Health and Nutrition Examination Survey (NHANES) between 1999 and 2016 were included. Age-adjusted HF prevalence was calculated by two-year cycles and weighted linear regression was used to examine trends over time. Odds ratios (OR) and 95% confidence intervals (CI) of HF in blacks vs. whites were calculated by pooling cycles into six-year periods with adjustment for age, sex, cardiovascular risk factors (CV RF), renal function, and proxies of socioeconomic status (SES: education level and health insurance status). Given a significant interaction between race and age group, analyses were stratified by age groups: 35-64 and 65+ years. Results: Of 20,290 participants with mean age 55.3§0.2 years, 52% were women and 12% black. Age-adjusted prevalence of HF per 100,000 increased linearly among blacks from 3921 (2663, 5178) in 1999-2000 to 6568 (4557, 8580) in 2015-2016 (ptrend<0.05). Overall prevalence of HF per 100,000 was stable among whites between 1999 (3770 [3090, 4451]) and 2016 (3090 [2572, 3706], p-trend>0.05). Age and sexadjusted odds of HF in blacks compared to whites (TABLE) was higher between 2005-10 (period 2) and 2011-16 (period 3). After adjustment for RF and SES, odds of HF remained higher in blacks in periods 2 and 3 by 1.51 (1.11, 2.04) and 1.55 (1.16, 2.06), respectively. This appeared to be primarily driven by differences in HF prevalence between younger blacks and whites (age 35-64 years). Conclusions: The prevalence of HF in blacks is increasing and the odds of HF was significantly higher in blacks compared to whites. While the increased odds of HF was attenuated after adjusting for RF and SES, disparities persisted and have widened over time. Research and resources aimed at identifying social determinants of HF, alongside aggressive management of risk factors, are needed to prevent HF and reduce disparities.
Table. Adjusted Odds Ratios (95% Confidence Interval) of Heart Failure in Blacks Compared to Whites