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Mixed Lineage Kinase 3 Regulates Blood Pressure through Kinase Independent Effects in the Vasculature
The 23rd Annual Scientific Meeting HFSA 033 Effect Modification by Clinical Decongestion on the Association Between Worsening Renal Function and Mortality in Patients with Acute Decompensated Heart Failure Takayuki Yamada1, Claudio Bravo2, Maria A. Rodriguez2, Paulina Partridge3, Jeffrey Testani4, Steven Coca5; 1Mount Sinai Beth Israel, New York, NY; 2Montefiore Medical Center, Bronx, NY; 3University of Miami, Coral Gables, FL; 4Yale School of Medicine, New Haven, CT; 5Mount Sinai Hospital, New York, NY Introduction: Worsening renal function (WRF) is common among patients with acute decompensated heart failure (ADHF) and is associated with increased risk of mortality. Recent data suggest, however, that decongestion may serve as an effect modifier on the association between WRF and mortality. Hypothesis: We hypothesized that in patients with ADHF, achievement of concomitant decongestion would abolish the signal for harm associated with WRF. Methods: We searched in PubMed, EMBASE and the Cochrane Library from inception to March 2019 for studies that assessed signs of decongestion via clinical and laboratory parameters in patients with WRF during ADHF admission and performed stratified analyses for mortality by the presence or absence of decongestion and WRF. Results: Among 8 studies that included 4,864 patients with ADHF, 1,435 (29.5%) had WRF, with 50.5% of those with WRF experiencing decongestion. Unstratified, patients with WRF vs. no WRF had a higher risk for mortality (pooled odds ratio [OR] 1.63, 95% CI 1.41 to 1.88; I2 = 0%) (Figure 1 upper forest plot). However, when patients with WRF were stratified by the decongestion status, there was evidence for interaction. Compared to patients without WRF, patients with WRF that had features consistent with decongestion, had similar risk of mortality (pooled OR 1.09, 95% CI 0.90 to 1.34; I2 = 0%) (Figure 1 lower forest plot). Finally, the pooled mortality was lower for patients with WRF that achieved decongestion (26.6%) than for patients without WRF that did not achieve decongestion (51.8%) (Figure 1 lower panel). Conclusions: Decongestion is a powerful effect modifier that nullifies harmful associations of WRF with mortality, and patients that experience decongestion with WRF fare better than those that do not achieve decongestion with stable kidney function. Future studies should not assess WRF in isolation as an endpoint without concomitant assessment of the clinical status that accompanied WRF.
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Rahul Gupta, Joseph Harburger, Gregg M. Lanier; Westchester Medical Center, Valhalla, NY Background: The impact of angiotensin converting enzyme inhibitors (ACEI) on functional capacity and quality of life in elderly patients with heart failure and preserved ejection fraction (HFpEF) is not well understood. This systematic review sought to evaluate the efficacy of ACEI in elderly patients with HFpEF. Methods: We performed electronic searches on PubMed, The Cochrane Library, EMBASE, EBSCO, Web of Science, and CINAHL databases from inception through December 15, 2018 to identify randomized controlled trials that evaluated the efficacy of ACEI in elderly patients with HFpEF. The primary outcomes of our study were improvement in quality of life (QoL; as assessed by Minnesota Living with Heart Failure questionnaire) and 6-minute walk test. The results were expressed as a standard mean difference (SMD) for the continuous variables with 95% confidence intervals (CIs). A Mantel-Haenszel random effects model was used to summarize data across treatment arms. Heterogeneity between the studies was assessed using the chi square test and was considered significant for p values < 0.10 orI2> 50%. Results: Four randomized trials with 1,090 patients (mean age 73.5 years) were included, in which 545 patients received ACEI. Weighted mean duration of follow-up was 10.4 months. There were no significant improvements observed in QoL measures (SMD: 0.26; 95% CI: -0.04 to 0.57, p=0.09) or 6-minute walk test performance (SMD: -0.08; 95% CI: -0.39 to 0.22, p=0.60) with ACEI use. Conclusion: The use of ACEI in elderly patients with HFpEF was not associated with improvements in exercise tolerance or quality of life. There was non-significant trend to improvement of quality of life in patients who received placebo. Future studies are necessary to better define the role of ACEI in this patient subset.
Figure 1a. Forest plots of the association between WRF and mortality in patients with ADHF overall (upper) and WRF with decongestion vs. patients without WRF (lower).
037 Mixed Lineage Kinase 3 Regulates Blood Pressure through Kinase Independent Effects in the Vasculature Timothy D. Calamaras1, Robert A.U. Baumgartner1, Mark Aronovitz1, Joseph McCarthy1, Kelly Tam1, Syung Kyum Kim1, Gregory Martin1, Daniel A. Richards1, Paulina Baca2, Iris Z. Jaffe1, Robert M. Blanton1; 1Tufts Medical Center, Boston, MA; 2 Tufts University Sackler School of Biomedical Sciences, Boston, MA
Figure 1b. Mortality stratified by WRF status and achieved congestion status at discharge
035 Effect of Angiotensin Converting Enzyme Inhibitors on Functional Capacity in Elderly Patients with Heart Failure and Preserved Ejection Fraction: A Systematic Review and Meta-Analysis
Background: Many anti-remodeling signaling molecules also modulate blood pressure. Thus, therapeutic modulation of these potential therapeutic targets has been limited by hypotension. Mixed lineage kinase 3 (MLK3) opposes pathologic cardiac remodeling, but its role in blood pressure (BP) has not been studied. MLK3 activates JNK signaling through kinase dependent effects, and opposes RhoA activation through kinase-independent mechanisms, but the relevance of these mechanisms to BP is unknown. We investigated the effect of genetic deletion of MLK3 on BP. Methods and Results: Using ambulatory telemetric monitoring in 3 month old male mice, MLK3 -/- mice had significant hypertension compared to wild type (WT) littermates (WT systolic BP 121 § 2 mmHg, MLK3-/- 162 § 5 mmHg; n=3; p<0.05). The MLK3 kinase inhibitor URMC-099 (10 mg/kg IP) did not affect BP in WT mice. By contrast, inhibition of downstream RhoA dependent Kinase (ROCK) with Y-27632 (15 mg/kg) fully normalized BP in MLK3 -/- mice (SBP WT baseline 126 § 2 mmHg; WT ROCK inhibitor 94 § 2 mmHg; MLK-/- baseline 163 §6 mmHg; MLK3 -/- ROCK
S14 Journal of Cardiac Failure Vol. 25 No. 8S August 2019 inhibitor 94 § 12 mmHg; n=5 WT, 9 MLK3-/-). Aortic pulse wave velocity was elevated in MLK-/- mice (2.7 § 0.1 mm/ms WT vs 3.6 § 0.2 mm/ms MLK3-/-; p<0.05) indicating increased aortic stiffness. Pressure myography in mesenteric resistance arterioles of MLK3 -/- mice revealed reduced distensibility compared to WT. Both pressure myography and direct histological measurement in resistance arterioles demonstrated reduced passive luminal diameter but preserved wall cross sectional area in MLK3-/- arterioles, indicating eutrophic remodeling. Compared with dispersed aortic smooth muscle cells from WT littermates, MLK3 -/cells had increased actin stress fiber accumulation. Conclusions: These data demonstrate that MLK3 deletion leads to hypertension with increased arterial stiffness, reduced distensibility and eutrophic remodeling of resistance vessels, but retained BP responsiveness to downstream ROCK inhibition. Together with previous work, these findings support that MLK3 modulates cardiac remodeling through a kinase dependent mechanism while modulating blood pressure through kinase-independent effects. Because hypotension limits many heart failure therapies, delineating vascular versus cardiac mechanisms of MLK3 signaling has the potential to suggest novel approaches to heart failure treatment.
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Rahul Gupta, Joseph Harburger, Gregg M. Lanier; Westchester Medical Center, Valhalla, NY Background: The impact of angiotensin converting enzyme inhibitors (ACEI) on functional capacity and quality of life in elderly patients with heart failure and preserved ejection fraction (HFpEF) is not well understood. This systematic review sought to evaluate the efficacy of ACEI in elderly patients with HFpEF. Methods: We performed electronic searches on PubMed, The Cochrane Library, EMBASE, EBSCO, Web of Science, and CINAHL databases from inception through December 15, 2018 to identify randomized controlled trials that evaluated the efficacy of ACEI in elderly patients with HFpEF. The primary outcomes of our study were improvement in quality of life (QoL; as assessed by Minnesota Living with Heart Failure questionnaire) and 6-minute walk test. The results were expressed as a standard mean difference (SMD) for the continuous variables with 95% confidence intervals (CIs). A Mantel-Haenszel random effects model was used to summarize data across treatment arms. Heterogeneity between the studies was assessed using the chi square test and was considered significant for p values < 0.10 orI2> 50%. Results: Four randomized trials with 1,090 patients (mean age 73.5 years) were included, in which 545 patients received ACEI. Weighted mean duration of follow-up was 10.4 months. There were no significant improvements observed in QoL measures (SMD: 0.26; 95% CI: -0.04 to 0.57, p=0.09) or 6-minute walk test performance (SMD: -0.08; 95% CI: -0.39 to 0.22, p=0.60) with ACEI use. Conclusion: The use of ACEI in elderly patients with HFpEF was not associated with improvements in exercise tolerance or quality of life. There was non-significant trend to improvement of quality of life in patients who received placebo. Future studies are necessary to better define the role of ACEI in this patient subset.
Figure 1a. Forest plots of the association between WRF and mortality in patients with ADHF overall (upper) and WRF with decongestion vs. patients without WRF (lower).
037 Mixed Lineage Kinase 3 Regulates Blood Pressure through Kinase Independent Effects in the Vasculature Timothy D. Calamaras1, Robert A.U. Baumgartner1, Mark Aronovitz1, Joseph McCarthy1, Kelly Tam1, Syung Kyum Kim1, Gregory Martin1, Daniel A. Richards1, Paulina Baca2, Iris Z. Jaffe1, Robert M. Blanton1; 1Tufts Medical Center, Boston, MA; 2 Tufts University Sackler School of Biomedical Sciences, Boston, MA
Figure 1b. Mortality stratified by WRF status and achieved congestion status at discharge
035 Effect of Angiotensin Converting Enzyme Inhibitors on Functional Capacity in Elderly Patients with Heart Failure and Preserved Ejection Fraction: A Systematic Review and Meta-Analysis
Background: Many anti-remodeling signaling molecules also modulate blood pressure. Thus, therapeutic modulation of these potential therapeutic targets has been limited by hypotension. Mixed lineage kinase 3 (MLK3) opposes pathologic cardiac remodeling, but its role in blood pressure (BP) has not been studied. MLK3 activates JNK signaling through kinase dependent effects, and opposes RhoA activation through kinase-independent mechanisms, but the relevance of these mechanisms to BP is unknown. We investigated the effect of genetic deletion of MLK3 on BP. Methods and Results: Using ambulatory telemetric monitoring in 3 month old male mice, MLK3 -/- mice had significant hypertension compared to wild type (WT) littermates (WT systolic BP 121 § 2 mmHg, MLK3-/- 162 § 5 mmHg; n=3; p<0.05). The MLK3 kinase inhibitor URMC-099 (10 mg/kg IP) did not affect BP in WT mice. By contrast, inhibition of downstream RhoA dependent Kinase (ROCK) with Y-27632 (15 mg/kg) fully normalized BP in MLK3 -/- mice (SBP WT baseline 126 § 2 mmHg; WT ROCK inhibitor 94 § 2 mmHg; MLK-/- baseline 163 §6 mmHg; MLK3 -/- ROCK
S14 Journal of Cardiac Failure Vol. 25 No. 8S August 2019 inhibitor 94 § 12 mmHg; n=5 WT, 9 MLK3-/-). Aortic pulse wave velocity was elevated in MLK-/- mice (2.7 § 0.1 mm/ms WT vs 3.6 § 0.2 mm/ms MLK3-/-; p<0.05) indicating increased aortic stiffness. Pressure myography in mesenteric resistance arterioles of MLK3 -/- mice revealed reduced distensibility compared to WT. Both pressure myography and direct histological measurement in resistance arterioles demonstrated reduced passive luminal diameter but preserved wall cross sectional area in MLK3-/- arterioles, indicating eutrophic remodeling. Compared with dispersed aortic smooth muscle cells from WT littermates, MLK3 -/cells had increased actin stress fiber accumulation. Conclusions: These data demonstrate that MLK3 deletion leads to hypertension with increased arterial stiffness, reduced distensibility and eutrophic remodeling of resistance vessels, but retained BP responsiveness to downstream ROCK inhibition. Together with previous work, these findings support that MLK3 modulates cardiac remodeling through a kinase dependent mechanism while modulating blood pressure through kinase-independent effects. Because hypotension limits many heart failure therapies, delineating vascular versus cardiac mechanisms of MLK3 signaling has the potential to suggest novel approaches to heart failure treatment.