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Mid- to Late-Life Systemic Inflammation and Late-Life Cardiac Structure and Function: The Atherosclerosis Risk in Communities (ARIC) Study
The 23rd Annual Scientific Meeting HFSA 016 Tafamidis Reduced the Decline in Health-Related Quality of Life in the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT) Mazen Hanna1, Michelle Stewart2, Balarama Gundapaneni2, Terrell A. Patterson2, Jeffrey H. Schwartz3, Marla S. Sultan3, Mathew S. Maurer4; 1Cleveland Clinic, Cleveland, OH; 2Pfizer, Groton, CT; 3Pfizer, New York, NY; 4Columbia University College of Physicians and Surgeons, New York, NY Introduction: In the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT), tafamidis reduced all-cause mortality and cardiovascular-related hospitalizations in patients with transthyretin amyloid cardiomyopathy (ATTRCM). ATTR-CM is associated with a significant burden of disease and tafamidis reduced the decline in health-related quality of life (as assessed by the Kansas City Cardiomyopathy Questionnaire-Overall Summary [KCCQ-OS] score). Hypothesis: Analysis of the changes in KCCQ-OS domains in patients with ATTR-CM over 30 months, together with the impact of tafamidis on these changes, will provide new data on the progression of disease and the efficacy of tafamidis. Methods: In ATTR-ACT, 441 adult patients with ATTR-CM (variant or wild-type) were randomized (2:1:2) to tafamidis 80 mg, tafamidis 20 mg, or placebo for 30 months, with pooled tafamidis (80mg and 20mg) compared with placebo. Change from baseline in the four KCCQ-OS domain scores were pre-specified exploratory endpoints and analyzed using a mixed model, repeated measures ANCOVA. The KCCQ is a 23-item self-administered questionnaire in which scores range from 0 to 100, with higher scores reflecting better health status. Results: Tafamidis significantly reduced the decline in the KCCQ-OS and all four of its domains (P<0.0001 for all; see Figure): quality of life (LS mean difference [95% CI] compared with placebo, 14.4 [9.07, 19.74]); total symptoms (12.48 [8.13, 16.84]); social limitations (15.87 [10.34, 21.40]); and physical limitations (12.64 [8.54, 16.75]). Conclusions: Treatment with tafamidis effectively reduced the decline in all components of the KCCQ-OS, providing further insight into its efficacy in health-related quality of life in patients with ATTR-CM.
017 Mid- to Late-Life Systemic Inflammation and Late-Life Cardiac Structure and Function: The Atherosclerosis Risk in Communities (ARIC) Study Aaron J. Cohen1, Kanako Teramoto1, Jenine E. John1, Brian Claggett1, Scott D. Solomon1, Christie M. Ballantyne2, Elizabeth Selvin3, Amil M. Shah1; 1Brigham and Women’s Hospital, Boston, MA; 2Baylor College of Medicine, Houston, TX; 3Johns Hopkins Bloomberg School of Public Health, Baltimore, MD Introduction: Systemic inflammation has been implicated in the development of heart failure with preserved ejection fraction (HFpEF) through left ventricular (LV) systolic and diastolic dysfunction via impairments in nitric oxide generation, reduced cyclic GMP, and altered titan phosphorylation. However, few studies have examined the association of systemic inflammation with cardiac structure and function. Hypothesis: Greater systemic inflammation from mid- to late-life is associated with worse LV systolic and diastolic function in late-life. Methods: We conducted a prospective cohort analysis of 4,011 participants in the ARIC Study who underwent hs-CRP measurements at visits 2 (1990-92), 4 (1996-98), and 5 (2011-13). Echocardiography was conducted at Visit 5. We calculated the timeweighted mean hs-CRP concentration as the sum of the mean hs-CRP values at 3 consecutive visits multiplied by the time between visits. Participants were categorized as hs-CRP <2.0 (mg/L) (reference group) at all 3 visits (n=1,175), and the remaining 2,836 participants were categorized by tertile of time averaged hs-CRP. The association of log-transformed time averaged hs-CRP with echocardiographic measures was assessed using multivariable linear regression and restricted cubic
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splines to assess non-linear associations. Results: Mean age at Visit 2 was 54.6§ 5.0 and at Visit 5 was 75.3§5.1, 64% were female, and 21% were black. Covariates at visit 5 associated with higher hs-CRP were female sex, black race, presence of diabetes (DM), obesity, and CKD. Greater time averaged hs-CRP predicted higher LV mass index related to both greater LV dimension and wall thickness, worse longitudinal strain, and higher E/e’ ratio in models adjusted for demographics (Figure). After further adjustment for SBP, DM, smoking, BMI, heart rate, and eGFR, higher hs-CRP remained associated with worse longitudinal strain (p=0.009). Conclusions: Higher time averaged hs-CRP exposure from mid- to late-life predicts greater LV mass, and worse LV systolic and diastolic function in late life. These associations were attenuated after accounting for clinical comorbidities associated with systemic inflammation.
018 Acute and Chronic Subcutaneous Administration of ZD100, a Novel pGC-A/ cGMP Peptide Activator, Demonstrates Robust Antihypertensive Efficacy in Rodents Yang Chen, Seethalakshmi R. Iyer, Gerald E. Harders, Margaret M. Redfield, John C. Burnett; Mayo Clinic, Rochester, MN Introduction: Hypertension remains a prevalent challenge that induces high morbidity and mortality in the general population. It is also known to be an important risk factor for heart failure (HF) incidence. There remains an urgent need for the development of antihypertensive agents with novel mechanisms of action, particularly for resistant hypertension which markedly increases risk for HF. ZD100 (also called MANP) is a novel designer natriuretic peptide that potently activates particulate guanylyl cyclase A receptor (pGC-A) and its second messenger cGMP, is highly resistant to neprilysin degradation and mediates vasodilation with marked natriuresis and diuresis and inhibition of aldosterone, supporting its potential effectiveness for hypertension. The use of ZD100 for hypertension, however, is limited by its delivery method in which its activity to date was only tested with continuous intravenous infusion in short-term acute studies. Subcutaneous (SC) injection of peptide therapeutics has demonstrated impressive safety, greater convenience and lower medical cost. Importantly, the long term effects of ZD100 in experimental hypertension remain unknown. Hypothesis: We hypothesize that ZD100 SC administration yields favorable cardiovascular (CV) and renal actions in normal rats and chronically ZD100 reduces blood pressure (BP) in a hypertensive rat model. Methods: In normal Sprague Dawley rats, acute SC ZD100 (low: 1.94 mg/kg, high: 3.88 mg/kg, n=5) or vehicle (0.9% saline, n=5) were administered and BP, urine output, urinary sodium excretion, and plasma cGMP, ZD100, and aldosterone were measured. In sodium-deficient-diet induced hypertensive Sprague Dawley rats, daily SC injection for 7 days of ZD100 (3.88mg/kg, n=10) or vehicle (n=9) were performed and CV, renal and neurohumoral parameters were obtained at day 7. Data are presented as absolute changes from baseline values and expressed as Mean§SEM. *p<0.05 significant vs vehicle group, by 1-way or 2-way ANOVA or unpaired t-test analysis. Results: Acute SC ZD100 induced potent and dosedependent BP lowering effects over 360 min compared to vehicle in normal rats (high: -29.0§8.2*, low: -14.8§5.5, veh: -6.3§3.6 mmHg). In parallel, robust diuresis, natriuresis and GMP activation were seen with ZD100. Specifically, diuresis and natriuresis increased 3-5 fold by ZD100 compared to vehicle. We then determined its chronic CV and renal actions in a hypertensive model in rats. ZD100 SC daily for 7 days elevated plasma ZD100 levels and exhibited BP lowering effects compared to vehicle (ZD100: -6.1§4.9*, veh: +10.5§5.7 mmHg), with increased plasma levels of cGMP (ZD100: 112§18*, veh: 33§5 pmol/mL) and a trend for diuretic and natriuretic enhancement and aldosterone suppression. Conclusion: Our study thus supports the effectiveness of chronic SC use of ZD100, a novel and best-in-class pGC-A/cGMP peptide activator in experimental hypertension and supporting its clinical development in hypertension.
019 First in Human Experience with Direct Sodium Removal Using a Zero Sodium Peritoneal Solution V. Rao, J. Turner, D. Mahoney, M. Griffin, J. Asher, J. Ivey-Miranda, N. Gomez, F. Finkelstein, J. Testani; Yale University, New Haven, CT Introduction: There is interest in developing alternative therapies to loop diuretics for decongestion heart failure (HF). One approach is peritoneal dialysis (PD). However, PD requires large intraperitoneal volumes and delivers limited sodium removal due to the high concentration of sodium in standard PD solutions. Previously, we
017 Mid- to Late-Life Systemic Inflammation and Late-Life Cardiac Structure and Function: The Atherosclerosis Risk in Communities (ARIC) Study Aaron J. Cohen1, Kanako Teramoto1, Jenine E. John1, Brian Claggett1, Scott D. Solomon1, Christie M. Ballantyne2, Elizabeth Selvin3, Amil M. Shah1; 1Brigham and Women’s Hospital, Boston, MA; 2Baylor College of Medicine, Houston, TX; 3Johns Hopkins Bloomberg School of Public Health, Baltimore, MD Introduction: Systemic inflammation has been implicated in the development of heart failure with preserved ejection fraction (HFpEF) through left ventricular (LV) systolic and diastolic dysfunction via impairments in nitric oxide generation, reduced cyclic GMP, and altered titan phosphorylation. However, few studies have examined the association of systemic inflammation with cardiac structure and function. Hypothesis: Greater systemic inflammation from mid- to late-life is associated with worse LV systolic and diastolic function in late-life. Methods: We conducted a prospective cohort analysis of 4,011 participants in the ARIC Study who underwent hs-CRP measurements at visits 2 (1990-92), 4 (1996-98), and 5 (2011-13). Echocardiography was conducted at Visit 5. We calculated the timeweighted mean hs-CRP concentration as the sum of the mean hs-CRP values at 3 consecutive visits multiplied by the time between visits. Participants were categorized as hs-CRP <2.0 (mg/L) (reference group) at all 3 visits (n=1,175), and the remaining 2,836 participants were categorized by tertile of time averaged hs-CRP. The association of log-transformed time averaged hs-CRP with echocardiographic measures was assessed using multivariable linear regression and restricted cubic
S7
splines to assess non-linear associations. Results: Mean age at Visit 2 was 54.6§ 5.0 and at Visit 5 was 75.3§5.1, 64% were female, and 21% were black. Covariates at visit 5 associated with higher hs-CRP were female sex, black race, presence of diabetes (DM), obesity, and CKD. Greater time averaged hs-CRP predicted higher LV mass index related to both greater LV dimension and wall thickness, worse longitudinal strain, and higher E/e’ ratio in models adjusted for demographics (Figure). After further adjustment for SBP, DM, smoking, BMI, heart rate, and eGFR, higher hs-CRP remained associated with worse longitudinal strain (p=0.009). Conclusions: Higher time averaged hs-CRP exposure from mid- to late-life predicts greater LV mass, and worse LV systolic and diastolic function in late life. These associations were attenuated after accounting for clinical comorbidities associated with systemic inflammation.
018 Acute and Chronic Subcutaneous Administration of ZD100, a Novel pGC-A/ cGMP Peptide Activator, Demonstrates Robust Antihypertensive Efficacy in Rodents Yang Chen, Seethalakshmi R. Iyer, Gerald E. Harders, Margaret M. Redfield, John C. Burnett; Mayo Clinic, Rochester, MN Introduction: Hypertension remains a prevalent challenge that induces high morbidity and mortality in the general population. It is also known to be an important risk factor for heart failure (HF) incidence. There remains an urgent need for the development of antihypertensive agents with novel mechanisms of action, particularly for resistant hypertension which markedly increases risk for HF. ZD100 (also called MANP) is a novel designer natriuretic peptide that potently activates particulate guanylyl cyclase A receptor (pGC-A) and its second messenger cGMP, is highly resistant to neprilysin degradation and mediates vasodilation with marked natriuresis and diuresis and inhibition of aldosterone, supporting its potential effectiveness for hypertension. The use of ZD100 for hypertension, however, is limited by its delivery method in which its activity to date was only tested with continuous intravenous infusion in short-term acute studies. Subcutaneous (SC) injection of peptide therapeutics has demonstrated impressive safety, greater convenience and lower medical cost. Importantly, the long term effects of ZD100 in experimental hypertension remain unknown. Hypothesis: We hypothesize that ZD100 SC administration yields favorable cardiovascular (CV) and renal actions in normal rats and chronically ZD100 reduces blood pressure (BP) in a hypertensive rat model. Methods: In normal Sprague Dawley rats, acute SC ZD100 (low: 1.94 mg/kg, high: 3.88 mg/kg, n=5) or vehicle (0.9% saline, n=5) were administered and BP, urine output, urinary sodium excretion, and plasma cGMP, ZD100, and aldosterone were measured. In sodium-deficient-diet induced hypertensive Sprague Dawley rats, daily SC injection for 7 days of ZD100 (3.88mg/kg, n=10) or vehicle (n=9) were performed and CV, renal and neurohumoral parameters were obtained at day 7. Data are presented as absolute changes from baseline values and expressed as Mean§SEM. *p<0.05 significant vs vehicle group, by 1-way or 2-way ANOVA or unpaired t-test analysis. Results: Acute SC ZD100 induced potent and dosedependent BP lowering effects over 360 min compared to vehicle in normal rats (high: -29.0§8.2*, low: -14.8§5.5, veh: -6.3§3.6 mmHg). In parallel, robust diuresis, natriuresis and GMP activation were seen with ZD100. Specifically, diuresis and natriuresis increased 3-5 fold by ZD100 compared to vehicle. We then determined its chronic CV and renal actions in a hypertensive model in rats. ZD100 SC daily for 7 days elevated plasma ZD100 levels and exhibited BP lowering effects compared to vehicle (ZD100: -6.1§4.9*, veh: +10.5§5.7 mmHg), with increased plasma levels of cGMP (ZD100: 112§18*, veh: 33§5 pmol/mL) and a trend for diuretic and natriuretic enhancement and aldosterone suppression. Conclusion: Our study thus supports the effectiveness of chronic SC use of ZD100, a novel and best-in-class pGC-A/cGMP peptide activator in experimental hypertension and supporting its clinical development in hypertension.
019 First in Human Experience with Direct Sodium Removal Using a Zero Sodium Peritoneal Solution V. Rao, J. Turner, D. Mahoney, M. Griffin, J. Asher, J. Ivey-Miranda, N. Gomez, F. Finkelstein, J. Testani; Yale University, New Haven, CT Introduction: There is interest in developing alternative therapies to loop diuretics for decongestion heart failure (HF). One approach is peritoneal dialysis (PD). However, PD requires large intraperitoneal volumes and delivers limited sodium removal due to the high concentration of sodium in standard PD solutions. Previously, we