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Mechanical Asynchrony in Experimental Hypertensive Heart Disease
The 11th Annual Scientific Meeting of assessing diastolic stiffness (as quantified by b or EDV10-30) shows good correlation and agreement with the MB method. Methods: P, V were invasively measured and the RCSB followed by MB methods performed in 26 young normal or elderly hypertensive dogs before and during phenylephrine (to vary afterload) or acute volume expansion. In the RCSB method, diastolic P was corrected by subtracting the P due to relaxation, monoexponentially extrapolated from isovolumic relaxation. Correlation was assessed by linear regression. Agreement was expressed as the mean 6 SD of the paired difference between MB and RCSB values for b or EDV10-30, expressed as percentages of their mean values; p is for paired t-test. Results: Over widely varying afterloads (LV systolic P 95 to 236 mmHg), EDV10-30 derived from RCSB and MB methods showed excellent correlation (r 5 0.98, p ! 0.0001) and agreement (0.6 6 5%, p 5 0.6). Correlation (r 5 0.62, p 5 0.002) and agreement (4.2 6 45%, p 5 0.7) between b from SB and MB was poorer. Use of a limited number of P and V points for the RCSB method (at minimum LV P, pre-atrial contraction, and ED) resulted in less agreement between the methods in assessing EDV10-30 (4.4 6 9%, p 5 0.0003) or b (21 6 40%, p 5 0.025). Neither b (12.5 6 55%, p 5 0.5) nor EDV10-30 (10 6 10%, p ! 0.0001) derived from RCSB agreed with MB after marked volume expansion in presence of pericardium. Conclusion: Clinical studies seeking to compare diastolic stiffness between groups can use the clinically more feasible RCSB to substitute for the complex MB technique under a wide range of afterload. Accuracy will be influenced by the number of P and V points used and by presence of acute volume overload. Comparison of stiffness between groups will be enhanced by methods which account for the covariance between a and b.
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exogenous U-II and a peptidic U-II receptor antagonist (GSK248451 A, 1 mM). Rapid cooling contractures (RCCs) were employed to define SR Ca2þ load. Results: Exogenous U-II induced dose-dependent increases in developed tension (DT) in NF trabeculae and decreases in DT in F trabeculae. Conversely, UT-A induced a mild decrease in DT in NF trabeculae and a pronounced increase in DT in F trabeculae. UTA also increased the rates of force generation and relaxation in F trabeculae, but had little effect in NF trabeculae. RCC amplitude increased following UT-A in both NF and F trabeculae, suggesting similar increases in SR Ca2þ load and possible differences in myofilament responses. Administration of U-II during ongoing UT-A had little effect on DT and RCC amplitude, confirming effective U-II receptor blockade. Conclusion: Positive inotropic responses to UT-A in isolated cardiac muscle trabeculae from F human hearts suggest that endogenous U-II is exerting a negative inotropic action via an autocrine and/or paracrine mechanism in these hearts. Such findings support a pathophysiological role for endogenous U-II and a potential therapeutic role for UT-A in the failing human heart.
044 Mechanical Asynchrony in Experimental Hypertensive Heart Disease Josef Korinek1, Brian P. Shapiro1, Carolyn S.P. Lam1, Donna M. Meyer1, Margaret M. Redfield1; 1Cardiovascular Diseases, Mayo Clinic, Rochester, MN Introduction: Elderly patients (pts) with hypertensive heart disease (HHD) develop heart failure with preserved ejection fraction (HFpEF). Recently, left ventricular (LV) mechanical asynchrony (MA) has been reported in HFpEF. The factors which mediate development of MA and its role in progression from HHD to HFpEF remain unclear. Objective: Determine if aging or HHD is associated with MA and whether MA is related to alterations in LV structure or function. Methods: Elderly (n 5 22; 8-12 years) dogs were studied before (Old) and 8 weeks after (Old-HTN) renal wrapping to produce chronic HHD with (n 5 11) or without (n 5 11) concomitant DOCA administration to vary degree of LV fibrosis. Young normal dogs (YN; n 5 11) were controls. Conscious 2D echo was performed at mid-LV short axis to measure radial strain by speckle tracking. MA was calculated as standard deviation of the time to peak radial strain in 6 segments normalized to RR interval (%). LV mass/body wt (LVMI), end systolic wall stress (ses, when invasive blood pressure data available) and collagen (hydroxyproline assay in harvested LV tissue of 20 elderly dogs and 6 YN) were measured. Results: QRS duration was similar in all groups. Compared to Old, Old-HTN dogs had higher ses, LV mass, and modest reduction in EF. MA was increased in Old-HTN dogs compared to Old or YN. MA correlated with collagen (r 5 0.59, p ! 0.005), LVMI (r 5 0.28,p ! 0,05), ses (r 5 0.40, p ! 0.05) and inversely with EF (r 5 0.39, p ! 0.005). Conclusions: Elderly dogs with HHD display MA. The association of MA with LV fibrosis and hypertrophy suggests that MA may develop with progressive LV remodeling, contribute to progression to HFpEF and represent a target for therapy. However, like EF, MA was related to increases in wall stress and thus may merely represent another ‘‘load dependent’’ index of LV dysfunction. Young Elderly Elderly dogs-controls dog - baseline dogs - 8 weeks hypertension MA (%) EF (%) LV Mass index (g/kg) MWS (kdynes/cm2) Collagen (mg/mg)
2.8 6 1.0 62 6 6 4.7 6 1.0 N/A 2.0 6 0.5
3.7 6 1.7 56 6 7* 5.5 6 1.0* 26.4 6 3.2 N/A
5.5 50 6.9 33.4 2.9
6 6 6 6 6
2.5y 10*y 1.8*y 4.9y 0.6*
*P ! 0.05 vs. young, y P ! 0.05 vs. Elderly at baseline.
045 Urotensin-II Receptor Antagonism Improves Contractility in Failing Human Myocardium Michael P. Quaile1, Kenneth B. Margulies2; 1Physiology, Temple University School of Medicine, Philadelphia, PA; 2Heart Failure & Transplantation, University of Pennsylvania School of Medicine, Philadelphia, PA Introduction: Urotensin-II (U-II), an endogenous vasoconstrictor peptide, is upregulated in failing hearts and some studies suggest that UII modulates cardiac contractility. Therefore, our goal was to examine whether endogenous U-II modulates cardiac function independent of alterations in blood flow. Methods: We examined the direct effects of exogenous U-II and U-II receptor antagonism (UT-A) on in-vitro contractile performance in isolated failing (F) and non failing (NF) human myocardium. Isometric force was measured in F (n 5 14) and NF (n 5 9) right ventricular trabeculae (0.5 Hz, 1.75 mM Ca2þ, 80% Lmax-Lo) before and after bath application of
046 Excess Ca2D Influx through the L-Type Ca2D Channel Exacerbates IschemiaInduced Cardiac Damage Hongyu Zhang1, Xiongwen Chen1, Erhe Gao2, David Harris2, Hiroyuki Nakayama4, Xiaoying Zhang3, Naser Jaleel1, Andrea Eckhart2, Walter Koch2, Jeffery Molkentin4, Steven Houser1; 1Physiology, Temple University School of Medicine, Philadelphia, PA; 2Medicine, Thomas Jefferson University, Philadelphia, PA; 3Fox Chase Cancer Center, Philadelphia, PA; 4Pediatrics, Cincinnati’s Children’s Hospital, Cincinnati, OH Pathological hemodynamic stress requires an increase in Ca2þ influx through the LTCC to produce increased cardiac contractility, e.g., in the survival zones after an ischemic insult. While increased myocyte [Ca2þ] can increase contractility, excess [Ca2þ] is known to induce myocyte death, especially during ischemia/reperfusion (I/R). Whether increased Ca2þ influx through LTCC promotes or prevents myocyte death after an ischemic event is the topic here. Methods: We established transgenic (TG) mouse lines with inducible (Tet-off) overexpression of the b2a subunit of the LTCC (b2a). b2a gene is expressed only in double transgenic mice (DTG) and caused increased Ca2þ influx. Single transgenic (b2a or tTA gene) or wildtype littermates served as controls (CTR). Animals with myocardial infarction (MI) surgery were sacrificed 6 weeks later. Ischemia/reperfusion (I/R) was done by ligating the LAD for 30 minutes followed by reperfusion for 3 hours and then animals were sacrificed. In MI
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exogenous U-II and a peptidic U-II receptor antagonist (GSK248451 A, 1 mM). Rapid cooling contractures (RCCs) were employed to define SR Ca2þ load. Results: Exogenous U-II induced dose-dependent increases in developed tension (DT) in NF trabeculae and decreases in DT in F trabeculae. Conversely, UT-A induced a mild decrease in DT in NF trabeculae and a pronounced increase in DT in F trabeculae. UTA also increased the rates of force generation and relaxation in F trabeculae, but had little effect in NF trabeculae. RCC amplitude increased following UT-A in both NF and F trabeculae, suggesting similar increases in SR Ca2þ load and possible differences in myofilament responses. Administration of U-II during ongoing UT-A had little effect on DT and RCC amplitude, confirming effective U-II receptor blockade. Conclusion: Positive inotropic responses to UT-A in isolated cardiac muscle trabeculae from F human hearts suggest that endogenous U-II is exerting a negative inotropic action via an autocrine and/or paracrine mechanism in these hearts. Such findings support a pathophysiological role for endogenous U-II and a potential therapeutic role for UT-A in the failing human heart.
044 Mechanical Asynchrony in Experimental Hypertensive Heart Disease Josef Korinek1, Brian P. Shapiro1, Carolyn S.P. Lam1, Donna M. Meyer1, Margaret M. Redfield1; 1Cardiovascular Diseases, Mayo Clinic, Rochester, MN Introduction: Elderly patients (pts) with hypertensive heart disease (HHD) develop heart failure with preserved ejection fraction (HFpEF). Recently, left ventricular (LV) mechanical asynchrony (MA) has been reported in HFpEF. The factors which mediate development of MA and its role in progression from HHD to HFpEF remain unclear. Objective: Determine if aging or HHD is associated with MA and whether MA is related to alterations in LV structure or function. Methods: Elderly (n 5 22; 8-12 years) dogs were studied before (Old) and 8 weeks after (Old-HTN) renal wrapping to produce chronic HHD with (n 5 11) or without (n 5 11) concomitant DOCA administration to vary degree of LV fibrosis. Young normal dogs (YN; n 5 11) were controls. Conscious 2D echo was performed at mid-LV short axis to measure radial strain by speckle tracking. MA was calculated as standard deviation of the time to peak radial strain in 6 segments normalized to RR interval (%). LV mass/body wt (LVMI), end systolic wall stress (ses, when invasive blood pressure data available) and collagen (hydroxyproline assay in harvested LV tissue of 20 elderly dogs and 6 YN) were measured. Results: QRS duration was similar in all groups. Compared to Old, Old-HTN dogs had higher ses, LV mass, and modest reduction in EF. MA was increased in Old-HTN dogs compared to Old or YN. MA correlated with collagen (r 5 0.59, p ! 0.005), LVMI (r 5 0.28,p ! 0,05), ses (r 5 0.40, p ! 0.05) and inversely with EF (r 5 0.39, p ! 0.005). Conclusions: Elderly dogs with HHD display MA. The association of MA with LV fibrosis and hypertrophy suggests that MA may develop with progressive LV remodeling, contribute to progression to HFpEF and represent a target for therapy. However, like EF, MA was related to increases in wall stress and thus may merely represent another ‘‘load dependent’’ index of LV dysfunction. Young Elderly Elderly dogs-controls dog - baseline dogs - 8 weeks hypertension MA (%) EF (%) LV Mass index (g/kg) MWS (kdynes/cm2) Collagen (mg/mg)
2.8 6 1.0 62 6 6 4.7 6 1.0 N/A 2.0 6 0.5
3.7 6 1.7 56 6 7* 5.5 6 1.0* 26.4 6 3.2 N/A
5.5 50 6.9 33.4 2.9
6 6 6 6 6
2.5y 10*y 1.8*y 4.9y 0.6*
*P ! 0.05 vs. young, y P ! 0.05 vs. Elderly at baseline.
045 Urotensin-II Receptor Antagonism Improves Contractility in Failing Human Myocardium Michael P. Quaile1, Kenneth B. Margulies2; 1Physiology, Temple University School of Medicine, Philadelphia, PA; 2Heart Failure & Transplantation, University of Pennsylvania School of Medicine, Philadelphia, PA Introduction: Urotensin-II (U-II), an endogenous vasoconstrictor peptide, is upregulated in failing hearts and some studies suggest that UII modulates cardiac contractility. Therefore, our goal was to examine whether endogenous U-II modulates cardiac function independent of alterations in blood flow. Methods: We examined the direct effects of exogenous U-II and U-II receptor antagonism (UT-A) on in-vitro contractile performance in isolated failing (F) and non failing (NF) human myocardium. Isometric force was measured in F (n 5 14) and NF (n 5 9) right ventricular trabeculae (0.5 Hz, 1.75 mM Ca2þ, 80% Lmax-Lo) before and after bath application of
046 Excess Ca2D Influx through the L-Type Ca2D Channel Exacerbates IschemiaInduced Cardiac Damage Hongyu Zhang1, Xiongwen Chen1, Erhe Gao2, David Harris2, Hiroyuki Nakayama4, Xiaoying Zhang3, Naser Jaleel1, Andrea Eckhart2, Walter Koch2, Jeffery Molkentin4, Steven Houser1; 1Physiology, Temple University School of Medicine, Philadelphia, PA; 2Medicine, Thomas Jefferson University, Philadelphia, PA; 3Fox Chase Cancer Center, Philadelphia, PA; 4Pediatrics, Cincinnati’s Children’s Hospital, Cincinnati, OH Pathological hemodynamic stress requires an increase in Ca2þ influx through the LTCC to produce increased cardiac contractility, e.g., in the survival zones after an ischemic insult. While increased myocyte [Ca2þ] can increase contractility, excess [Ca2þ] is known to induce myocyte death, especially during ischemia/reperfusion (I/R). Whether increased Ca2þ influx through LTCC promotes or prevents myocyte death after an ischemic event is the topic here. Methods: We established transgenic (TG) mouse lines with inducible (Tet-off) overexpression of the b2a subunit of the LTCC (b2a). b2a gene is expressed only in double transgenic mice (DTG) and caused increased Ca2þ influx. Single transgenic (b2a or tTA gene) or wildtype littermates served as controls (CTR). Animals with myocardial infarction (MI) surgery were sacrificed 6 weeks later. Ischemia/reperfusion (I/R) was done by ligating the LAD for 30 minutes followed by reperfusion for 3 hours and then animals were sacrificed. In MI