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Effects of B-Adrenergic Blockade on Left Ventricular Remodeling among Hispanic, African Americans and Caucasians with Chronic Heart Failure
S78 Journal of Cardiac Failure Vol. 15 No. 6S Suppl. 2009 256
258
Activated Vitamin D Compound Doxercalciferol Prevents the Development of Cardiac Hypertrophy in Dahl Salt Sensitive Rats Jun H. Choi1, Qingen Ke1, Soochan Bae1, Natalya Bodyak1, Christine Kajunski2, Steve Strugnell2, Cynthia Arbeeny2, Ravi Thadhani3, Peter M. Kang1; 1 Cardiovascular Diseases, Beth Israel Deaconess Medical Center, Boston, MA; 2 Genzyme Corporation, Cambridge, MA; 3Renal Unit, Massachusetts General Hospital, Boston, MA
Effects of B-Adrenergic Blockade on Left Ventricular Remodeling among Hispanic, African Americans and Caucasians with Chronic Heart Failure Christopher J. Varughese, Iosif Kelesidis, Patrick Hourani, Ronald Zolty; Department of Cardiology/Division of Congestive Heart Failure, Einstein - Montefiore Medical Center, Bronx, NY
Introduction: Vitamin D deficiency is associated with left ventricular hypertrophy (LVH) and cardiac dysfunction. We previously showed that paricalcitol, an activated vitamin D analog, attenuated the development of high salt-induced cardiac hypertrophy and cardiac dysfunction in Dahl salt sensitive (DSS) rats. However, whether antihypertrophic effects of activated vitamin D compounds are class specific or now has not been tested. Hypothesis: We hypothesized that administration of doxercalciferol (a vitamin D2 analog) will attenuate the development of cardiac hypertrophy and improve cardiac dysfunction in Dahl salt sensitive (DSS) rats following a high salt (HS) diet. Methods: Male DSS rats were fed a HS diet (6% NaCl) for 6 weeks beginning at 6 wk of age. Doxercalciferol was administered intraperitoneally at 150ng, 3 times a week (Mon, Wed, Fri) for six weeks. Animals were evaluated for organ weights, cardiac function, left ventricular gene expression, and plasma BNP levels after 6 weeks of HS diet. Results: We found that rats on HS þ doxercalciferol compared with HS þ vehicle demonstrated a significant decrease in heart weight/tibial length (HW/TL) ratio (-11% reduction, p!0.05) and lung weight/body weight (LW/BW) ratio (-29 % reduction, p!0.05). Echocardiogram analysis also revealed that doxercalciferol treatment lead to significant decrease in posterior wall thickness (-13% reduction, p!0.05), and improvement of fractional shortening compared with HS þ vehicle treated animals (þ17 % improvement, p!0.05). In addition, there was a significant decrease in plasma BNP level (-70% reduction, p!0.05) and ANF mRNA level (-72% decrease, p!0.05) with doxercalciferol treatment showing that the biochemical evidences for cardiac hypertrophy and cardiac dysfunction was also significantly attenuated with doxercalciferol treatment. There was no significant change in serum calcium levels between vehicle and doxercalciferol treated animals, confirming that the dose used did not resulted in hypercalcemia. Conclusions: Administration of doxercalciferol attenuated the development of HS diet induced cardiac hypertrophy and cardiac dysfunction in DSS rats.
257 The Aldosterone Antagonist Spironolactone Improves Cardiac Function in Experimental Cancer Cachexia Jochen Springer, Sandra Palus, Stephan von Haehling, Stefan D. Anker; Applied Cachexia Research, CCR, Charite Medical School, Berlin, Germany Cachexia is a very common co-morbidity in cancer patients. It significantly reduces quality of life and survival. Aldosterone is part of the neurohormonal activation cascade and linked to fibrosis, inflammation and oxygen free radical generation. We hypothesised that the aldosterone antagonist spironolactone can positively impact on cancer cachexia. Juvenile rats (weight approx. 200g) were inoculated intra-peritoneally with 108 AH-130 hepatoma cells and treated with 2 (n56), 5 (n516), or 50 mg/ kg/d (n516) spironolactone or placebo (n549). Food intake and locomotor activity were assessed before inoculation and on day 11 (d11) of the 16-day protocol. Weight and body composition (NMR-scan) were assessed on day 0 and day 16 after sacrifice (without tumour). The severe cachexia seen in placebo-treated animals was partially prevented by 5 and 50 mg/kg/d spironolactone (see table) and similarly affected muscle and fat tissue mass. Spironolactone at 2 mg/kg/d was ineffective. Food intake and activity as measure of quality of life were improved by 5 and 50mg/kg/d spironolactone. Cardiac function was significantly improved only in the 50 mg/kg/d spironolactone group (table). Survival was improved by 5 mg/kg/d (HR: 0.26, 95%CI: 0.120.55, p50.0004) and 50 mg/kg/d spironolactone (HR: 0.31, 95%CI: 0.15-0.64, p50.0015) compared to placebo. Conclusion: In this animal model, aldosterone antagonism with spironolactone can improve important aspects of cancer cachexia. Compared to placebo, 5 and 50 mg/kg/d of spironolactone reduced muscle and fat tissue wasting and increased food intake, physical activity and survival. At 50 mg/kg/d, spironolactone also improved cardiac function.
Placebo Delta BW [g] Delta fat [g] Delta lean [g] Food intake, d11 [g/d] Physical activity, d11 [counts/d] LVEF, d11 [%] FS, d11 [%] SV, d11 [ml]
-50.2 -11.2 -37.1 4.1 29209 57.3 31.5 105.6
6 6 6 6 6 6 6 6
2.2 0.4 2.0 0.6 2270 2.7 1.9 8.4
Spiro 2 mg/kg/d -64.5 -13.8 -50.6 3.8 24128 45.8 27.8 62.4
6 6 6 6 6 6 6 6
4.1# 1.5 3.6# 1.0 5878 4.4 2.5 10.2
Spiro 5 mg/kg/d -28.9 -7.7 -21.5 9.0 38948 63.8 36.2 124.4
6 6 6 6 6 6 6 6
8.5** 1.9** 6.4** 1.1*** 3524* 3.8 3.0 18.6
Spiro 50 mg/kg/d -21.0 -6.7 -11.9 9.8 44817 70.5 41.2 178.9
6 6 6 6 6 6 6 6
11.0*** 2.1** 8.7*** 1.7*** 5286** 2.6** 2.3** 18.3***
BW 5 body weight; LVEF 5 left ventricular ejection fraction; FS 5 fractional shortening; SV 5 stroke volume; ND 5 not done; *p!0.05; **p!0.01; ***p!0.001; improved vs placebo #p!0.05; ## p!0.01 reduced vs placebo.
Background: Randomized trials have confirmed the beneficial role of b-blockade in improving cardiac function. However, clinical response to b-blocker (BB) therapy displays individual and ethnic variation. We examined the effects of BB on left ventricular remodeling among African Americans (AA), Hispanics and Whites with systolic heart failure. Methods: Sixty five AA, 77 Hispanics and 45 whites with EF # 40% from any etiology were selected from the heart failure clinic at the Weiler Hospital of the Albert Einstein College of Medicine. Change in left ventricular ejection fraction (LVEF), left ventricular end diastolic dimensions (LVEDD), and degree of mitral regurgitation (MR) in response to 1 year of BB was evaluated retrospectively. BB were titrated to a maximally tolerated dose and results were determined using 2D- echocardiography. Results: An improvement in LVEF was noted among all ethnicities (p!0.001). Significant predictors included diabetes (p50.01) and male sex (p50.04). Whites exhibited an improvement in LVEDD (-2.636 6 6.98, p50.016) while AA revealed no change and Hispanics displayed worsening LVEDD (-0.54 6 7.30 mm, p 5 0.59 and 1.64 6 4.76 mm, p 50.006, respectively). Dose of BB was a significant predictor of LVEDD (p50.019). Wilcoxon rank signed test revealed significant improvement in degree of MR among whites, while AA and Hispanics remained unchanged. Conclusions: All patients demonstrated improvement of LVEF; however, a large proportion, specifically AA and Hispanics, were non-responders. Degree of MR and LVEDD failed to show improvement among AA and Hispanics. Individual ethnic groups may have a difference in response to BB.
259 Left Ventricular Ejection Fraction Decline after Response to Beta Blocker Therapy in Patients with Non-Ischemic Cardiomyopathy Patrick Hourani, Iosif Kelesidis, Christopher Varughese, Ronald Zolty; Internal Medicine/Cardiology, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY Background: Beta blockade (BB) is an established therapy in Heart failure (HF), a major public health problem due to its poor outcomes. However, some patients whose left ventricular ejection fraction (LVEF) initially increases on BB experience a subsequent LVEF decline. This study aimed to evaluate the proportion of patients with non-ischemic cardiomyopathy (NICM) whose LVEF declines after initially increasing on BB therapy. Methods: 56 patients with NICM and LVEF # 40% whose LVEF rose $ 5% after one year of BB were selected from the HF Clinic at AECOM. Post-response LVEF decline $ 5% to a final LVEF # 35% was evaluated. To determine LVEF, the modified Simpson’s Rule using 2D echocardiography was used. Results: Shown in the graph are NICM patients with and without post-response LVEF decline. 35.7% of patients were treated with metoprolol and 64.3% with carvedilol. 16.1% of patients had a post-response LVEF decline. The mean nadir LVEF of patients with post-response LVEF decline was 24.4 6 3.0 at a mean interval of 3.9 6 2.4 years after initial LVEF. Ethnicity and gender did not have a confounding influence on the proportion of patients who experienced a post-response LVEF decline (p50.429 and p50.361 respectively.) Conclusion: A significant proportion (16.1%) of NICM patients whose LVEF increased over one year of BB experienced a subsequent LVEF decline. There were no significant differences in the proportion of patients with post-response LVEF decline between ethnicities and between genders.
258
Activated Vitamin D Compound Doxercalciferol Prevents the Development of Cardiac Hypertrophy in Dahl Salt Sensitive Rats Jun H. Choi1, Qingen Ke1, Soochan Bae1, Natalya Bodyak1, Christine Kajunski2, Steve Strugnell2, Cynthia Arbeeny2, Ravi Thadhani3, Peter M. Kang1; 1 Cardiovascular Diseases, Beth Israel Deaconess Medical Center, Boston, MA; 2 Genzyme Corporation, Cambridge, MA; 3Renal Unit, Massachusetts General Hospital, Boston, MA
Effects of B-Adrenergic Blockade on Left Ventricular Remodeling among Hispanic, African Americans and Caucasians with Chronic Heart Failure Christopher J. Varughese, Iosif Kelesidis, Patrick Hourani, Ronald Zolty; Department of Cardiology/Division of Congestive Heart Failure, Einstein - Montefiore Medical Center, Bronx, NY
Introduction: Vitamin D deficiency is associated with left ventricular hypertrophy (LVH) and cardiac dysfunction. We previously showed that paricalcitol, an activated vitamin D analog, attenuated the development of high salt-induced cardiac hypertrophy and cardiac dysfunction in Dahl salt sensitive (DSS) rats. However, whether antihypertrophic effects of activated vitamin D compounds are class specific or now has not been tested. Hypothesis: We hypothesized that administration of doxercalciferol (a vitamin D2 analog) will attenuate the development of cardiac hypertrophy and improve cardiac dysfunction in Dahl salt sensitive (DSS) rats following a high salt (HS) diet. Methods: Male DSS rats were fed a HS diet (6% NaCl) for 6 weeks beginning at 6 wk of age. Doxercalciferol was administered intraperitoneally at 150ng, 3 times a week (Mon, Wed, Fri) for six weeks. Animals were evaluated for organ weights, cardiac function, left ventricular gene expression, and plasma BNP levels after 6 weeks of HS diet. Results: We found that rats on HS þ doxercalciferol compared with HS þ vehicle demonstrated a significant decrease in heart weight/tibial length (HW/TL) ratio (-11% reduction, p!0.05) and lung weight/body weight (LW/BW) ratio (-29 % reduction, p!0.05). Echocardiogram analysis also revealed that doxercalciferol treatment lead to significant decrease in posterior wall thickness (-13% reduction, p!0.05), and improvement of fractional shortening compared with HS þ vehicle treated animals (þ17 % improvement, p!0.05). In addition, there was a significant decrease in plasma BNP level (-70% reduction, p!0.05) and ANF mRNA level (-72% decrease, p!0.05) with doxercalciferol treatment showing that the biochemical evidences for cardiac hypertrophy and cardiac dysfunction was also significantly attenuated with doxercalciferol treatment. There was no significant change in serum calcium levels between vehicle and doxercalciferol treated animals, confirming that the dose used did not resulted in hypercalcemia. Conclusions: Administration of doxercalciferol attenuated the development of HS diet induced cardiac hypertrophy and cardiac dysfunction in DSS rats.
257 The Aldosterone Antagonist Spironolactone Improves Cardiac Function in Experimental Cancer Cachexia Jochen Springer, Sandra Palus, Stephan von Haehling, Stefan D. Anker; Applied Cachexia Research, CCR, Charite Medical School, Berlin, Germany Cachexia is a very common co-morbidity in cancer patients. It significantly reduces quality of life and survival. Aldosterone is part of the neurohormonal activation cascade and linked to fibrosis, inflammation and oxygen free radical generation. We hypothesised that the aldosterone antagonist spironolactone can positively impact on cancer cachexia. Juvenile rats (weight approx. 200g) were inoculated intra-peritoneally with 108 AH-130 hepatoma cells and treated with 2 (n56), 5 (n516), or 50 mg/ kg/d (n516) spironolactone or placebo (n549). Food intake and locomotor activity were assessed before inoculation and on day 11 (d11) of the 16-day protocol. Weight and body composition (NMR-scan) were assessed on day 0 and day 16 after sacrifice (without tumour). The severe cachexia seen in placebo-treated animals was partially prevented by 5 and 50 mg/kg/d spironolactone (see table) and similarly affected muscle and fat tissue mass. Spironolactone at 2 mg/kg/d was ineffective. Food intake and activity as measure of quality of life were improved by 5 and 50mg/kg/d spironolactone. Cardiac function was significantly improved only in the 50 mg/kg/d spironolactone group (table). Survival was improved by 5 mg/kg/d (HR: 0.26, 95%CI: 0.120.55, p50.0004) and 50 mg/kg/d spironolactone (HR: 0.31, 95%CI: 0.15-0.64, p50.0015) compared to placebo. Conclusion: In this animal model, aldosterone antagonism with spironolactone can improve important aspects of cancer cachexia. Compared to placebo, 5 and 50 mg/kg/d of spironolactone reduced muscle and fat tissue wasting and increased food intake, physical activity and survival. At 50 mg/kg/d, spironolactone also improved cardiac function.
Placebo Delta BW [g] Delta fat [g] Delta lean [g] Food intake, d11 [g/d] Physical activity, d11 [counts/d] LVEF, d11 [%] FS, d11 [%] SV, d11 [ml]
-50.2 -11.2 -37.1 4.1 29209 57.3 31.5 105.6
6 6 6 6 6 6 6 6
2.2 0.4 2.0 0.6 2270 2.7 1.9 8.4
Spiro 2 mg/kg/d -64.5 -13.8 -50.6 3.8 24128 45.8 27.8 62.4
6 6 6 6 6 6 6 6
4.1# 1.5 3.6# 1.0 5878 4.4 2.5 10.2
Spiro 5 mg/kg/d -28.9 -7.7 -21.5 9.0 38948 63.8 36.2 124.4
6 6 6 6 6 6 6 6
8.5** 1.9** 6.4** 1.1*** 3524* 3.8 3.0 18.6
Spiro 50 mg/kg/d -21.0 -6.7 -11.9 9.8 44817 70.5 41.2 178.9
6 6 6 6 6 6 6 6
11.0*** 2.1** 8.7*** 1.7*** 5286** 2.6** 2.3** 18.3***
BW 5 body weight; LVEF 5 left ventricular ejection fraction; FS 5 fractional shortening; SV 5 stroke volume; ND 5 not done; *p!0.05; **p!0.01; ***p!0.001; improved vs placebo #p!0.05; ## p!0.01 reduced vs placebo.
Background: Randomized trials have confirmed the beneficial role of b-blockade in improving cardiac function. However, clinical response to b-blocker (BB) therapy displays individual and ethnic variation. We examined the effects of BB on left ventricular remodeling among African Americans (AA), Hispanics and Whites with systolic heart failure. Methods: Sixty five AA, 77 Hispanics and 45 whites with EF # 40% from any etiology were selected from the heart failure clinic at the Weiler Hospital of the Albert Einstein College of Medicine. Change in left ventricular ejection fraction (LVEF), left ventricular end diastolic dimensions (LVEDD), and degree of mitral regurgitation (MR) in response to 1 year of BB was evaluated retrospectively. BB were titrated to a maximally tolerated dose and results were determined using 2D- echocardiography. Results: An improvement in LVEF was noted among all ethnicities (p!0.001). Significant predictors included diabetes (p50.01) and male sex (p50.04). Whites exhibited an improvement in LVEDD (-2.636 6 6.98, p50.016) while AA revealed no change and Hispanics displayed worsening LVEDD (-0.54 6 7.30 mm, p 5 0.59 and 1.64 6 4.76 mm, p 50.006, respectively). Dose of BB was a significant predictor of LVEDD (p50.019). Wilcoxon rank signed test revealed significant improvement in degree of MR among whites, while AA and Hispanics remained unchanged. Conclusions: All patients demonstrated improvement of LVEF; however, a large proportion, specifically AA and Hispanics, were non-responders. Degree of MR and LVEDD failed to show improvement among AA and Hispanics. Individual ethnic groups may have a difference in response to BB.
259 Left Ventricular Ejection Fraction Decline after Response to Beta Blocker Therapy in Patients with Non-Ischemic Cardiomyopathy Patrick Hourani, Iosif Kelesidis, Christopher Varughese, Ronald Zolty; Internal Medicine/Cardiology, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY Background: Beta blockade (BB) is an established therapy in Heart failure (HF), a major public health problem due to its poor outcomes. However, some patients whose left ventricular ejection fraction (LVEF) initially increases on BB experience a subsequent LVEF decline. This study aimed to evaluate the proportion of patients with non-ischemic cardiomyopathy (NICM) whose LVEF declines after initially increasing on BB therapy. Methods: 56 patients with NICM and LVEF # 40% whose LVEF rose $ 5% after one year of BB were selected from the HF Clinic at AECOM. Post-response LVEF decline $ 5% to a final LVEF # 35% was evaluated. To determine LVEF, the modified Simpson’s Rule using 2D echocardiography was used. Results: Shown in the graph are NICM patients with and without post-response LVEF decline. 35.7% of patients were treated with metoprolol and 64.3% with carvedilol. 16.1% of patients had a post-response LVEF decline. The mean nadir LVEF of patients with post-response LVEF decline was 24.4 6 3.0 at a mean interval of 3.9 6 2.4 years after initial LVEF. Ethnicity and gender did not have a confounding influence on the proportion of patients who experienced a post-response LVEF decline (p50.429 and p50.361 respectively.) Conclusion: A significant proportion (16.1%) of NICM patients whose LVEF increased over one year of BB experienced a subsequent LVEF decline. There were no significant differences in the proportion of patients with post-response LVEF decline between ethnicities and between genders.