Thiazolidinedione Therapy Associated with Improved Clinical Outcomes in Heart Failure Patients with Diabetes

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Journal of Cardiac Failure Vol. 10 No. 4 Suppl. 2004

031

WITHDRAWN

033 Identification of Beta-Blocker Responsive Genes in Human Heart Failure with a Multi-Comparison Pharmacogenomic Analysis Sunil N. Matiwala,1 Kenneth B. Margulies1; 1Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, PA

032 Valsartan Produces More Regression of Left Ventricular Hypertrophy after Aortic Valve Replacement than Atenolol Does Ruri Chihara,1 Osami Kohmoto,1 Shigeyuki Nishimura,1 Kazuhito Imanaka,2 Shunei Kyo2; 1Cardiology, Saitama Mecidal School, Iruma-gun, Saitama, Japan; 2 Cardiovascular Surgery, Saitama Mecidal School, Iruma-gun, Saitama, Japan Background: We previously showed that strict blood pressure control had beneficial effects on reverse remodeling after aortic valve replacement (AVR) in patients with pure aortic stenosis. Recent large scale trial (LIFE) showed that angiotensin receptor blocker (ARB) in comparison with β blocker (atenolol) produced more regression of left ventricular hypertrophy (LVH) in patients with hypertension while blood pressure was similarly controlled. Patients undergoing AVR generally have more marked LVH than hypertensive patients. We expected that even small size study with this marked LVH population might reveal differential effects of ARB and β blocker on reverse remodeling. Methods: To investigate if valsartan may accelerate the regression of LVH compared with atenolol, we randomly assigned 28 cases of AVR for aortic stenosis and regurgitation into two groups (14 by14 cases) by automated internet randomization system (provided by Japan Clinical Research Assist Center) after obtaining informed consent: (1) atenolol(25-100mg)⫹diuretics and (2) valsartan(40160mg) ⫹ diuretics. Patients who have obious indications for ACE inhbitors or β blockers were excluded. Background parameters including age (64 ⫾ 10/65 ⫾ 8years old)), sex (female 3/4 cases), NYHA class were matched between two groups. Angiotensin convertng enzyme inhibitors and β blockers were washed out during preoperative period. We added long acting calcium channel blockers in some cases to obtain optimal blood pressure control. Two cases were lost due to in-hospital death. LV mass index (LVMI) was calculated using Devereux’s formula. Results: LVMI was significantly lower in valsartan group than in atenolol group both at 3 and 6 months after AVR (see figure). No cases were lost during follow up after discharge up to 6 months. There were no significant differences in systolic blood pressure (124 ⫾ 26 mmHg vs. 125 ⫾ 22mmHg), pressure gradients through prosthetic valve (28 ⫾ 5mmHg vs. 30 ⫾ 6mmHg), and left ventricular ejection fraction (0.51 ⫾ 0.09 vs. 0.52 ⫾ 0.08) between two groups at three months. Conclusion: Valsartan accelerated regression of LVH after AVR beyond blood pressure control.

Background: Studies with beta-blockers (BB) in heart failure have consistently shown improved myocardial function, but the molecular mechanisms of this improvement remains unclear. The purpose of this study was to identify changes in myocardial gene expression associated with BB use in humans. Methods: We performed microarray analysis on high-quality left ventricular specimens obtained at transplantation from 14 nonfailing hearts (NF), 112 failing hearts not on BB (HF-NBB), and 51 failing hearts on BB (HF-BB). Recognizing that not all beta-blocker associated changes represent normalization, we developed a new analytical strategy in which three separate comparisons are generated. Results: Conventional two-way analysis demonstrated that there were 3140 genes with dysregulation in HF-NBB compared with NF. Similarly, there were 531 genes with differential regulation between HFNBB and HF-BB. However, the multi-comparison analysis demonstrated that, only 70 genes exhibited a true recovery pattern. Of the genes exhibiting recovery pattern, none had a greater than two-fold-change in expression, and most have a less than 1.5fold difference in mean transcript abundance. We also employed a separate multicomparison analysis to explore which genes might exhibit an expression pattern suggestive of persistent pathologic dysregulation. This analysis demonstrates that genes showing a pattern of persistent dysregulation are almost 35 times more abundant than genes showing a recovery despite beta-blocker therapy. When we assessed the effect of heart failure etiology on BB-induced transcriptional changes, multicomparison analysis revealed about twice as many genes showing recovery in ischemic cardiomyopathy (ICM) group receiving BB compared to dilated cardiomyopathy (DCM). Our analysis also demonstrated that the proportion of genes showing a recovery or persistence pattern varies in a pathway-specific fashion. For example, several sarcomeric proteins and Ca2⫹ handling proteins appear to normalize with BB therapy, while genes associated with carbohydrate and lipid metabolism show a persistent dysregulation despite BB treatment. Conclusion: These studies provide new insights into the pharmacologic actions of beta blocker therapy and the biology of myocardial recovery. These studies may also help define where post-transcriptional changes may be most important. This approach may also help identify which pathways require adjuvant interventions to promote more comprehensive myocardial recovery with beta-blockers.

034 Thiazolidinedione Therapy Associated with Improved Clinical Outcomes in Heart Failure Patients with Diabetes Mary C. Langford,1 Pamela P. Barnett,1 Sharon R. Josephson,1 Judith I. Spicer,1 Catherine C. Fallick,1 John S. Golden1; 1Heart Failure Treatment Program, MidAtlantic Permanente Medical Group, Fairfax, VA Background: The role of thiazolidinediones (TZDs) in the treatment of diabetic patients (pts) with Heart Failure (HF) is controversial. Though their favorable endovascular effects may contribute to delayed HF progression, their use has been associated with fluid retention and clinical decompensation. Concern regarding fluid retention, particularly when used in combination with Insulin (I), has led to several guideline recommendations against the use of TZDs in HF. To date, there have been no trials assessing the impact of TZD therapy on HF outcomes. We analyzed our experience with TZDs to better define the role of these agents in HF. Methods: We retrospectively analyzed 97 consecutive diabetic pts referred to our Heart Failure Treatment Program with systolic dysfunction (LVEF ⱕ 35%) and NYHA class II-IV HF. 37% were treated with TZDs and 15% with TZD⫹I. The TZD⫹ and TZD⫺ groups were wellmatched with regard to baseline LVEF (TZD⫹ 23.7%, TZD⫺ 25.9%, p ⫽ NS), glycosylated hemoglobin (TZD⫹ 7.1, TZD⫺ 6.9, p ⫽ NS), and NYHA class (TZD⫹ 2.56, TZD⫺ 2.79, p ⫽ NS). Baseline renal function was slightly worse in the TZD⫺ group (1.15 vs 1.33 mg/dl, p ⫽ 0.03). All pts were treated with ACE-inhibitors or ARBs and 97% with beta blockers. We assessed clinical outcomes at one year. Results: All 97 pts were alive at one year. Clinical outcomes were analyzed by TZD use both alone and in combination with I:

The 8th Annual Scientific Meeting

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HFSA

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036 Clinical Outcomes by Thiazolidinedione Use TZD⫹

TZD⫺

⫺0.21 0.19 0.03 0.67

⫺0.12 0.71 0.16 2.72

∆NYHA class All-cause hospitalizations (per patient) HF hospitalizations (per patient) Total hospital days

p ⫽ NS p ⫽ 0.01 p ⫽ 0.04 p ⫽ 0.02

Clinical Outcomes by Combined TZD and I Use TZD,I⫹

TZD,I⫺

⫺0.13 0.20 0.20 0.07

⫺0.16 0.59 0.43 2.30

∆NYHA Class All-cause hospitalizations (per patient) HF hospitalizations (per patient) Total Hospital Days (per patient)

p ⫽ NS p ⫽ 0.11 p ⫽ NS p ⫽ 0.0005

There was a trend toward increased diuretic requirements in the TZD,I⫹ group (69.3mg vs 45.5 mg furosemide/day, p ⫽ 0.08). This was not seen in pts treated with TZDs alone. Conclusions: We saw no adverse effect of TZDs on outcomes. In fact, TZD use was associated with reductions in both hospitalizations and hospital days. The hospital day reduction was independent of I use. These findings challenge recommendations against TZD use in HF. Clinial trials will determine the degree to which these findings can be extrapolated to broader HF populations.

Novel Vasopressin V1A and V2 Antagonist (Conivaptan) Increases Serum Sodium Concentration and Effective Water Clearance in Patients with Hyponatremia Joseph G. Verbalis,1 Joseph G. Bisaha,2 Neila Smith2; 1Division of Endocrinology and Metabolism, Georgetown University Medical Center, Washington, DC; 2Yamanouchi Pharma America, Inc., Paramus, NJ Background: Inappropriate secretion of arginine vasopressin (AVP) causes water retention, resulting in hyponatremia and edema. This is associated with increased morbidity and mortality, especially in CHF. Conivaptan (CNV) is a novel vasopressin receptor antagonist that produces aquaresis by blocking AVP V2 receptors, and also blocks the AVP V1a receptors that mediate vasoconstriction. CNV is being evaluated for the treatment of hyponatremia in SIADH and CHF. Methods: A randomized, doubleblind, multicenter, placebo-controlled, parallel-group study assessed efficacy and tolerability of intravenous CNV in patients with euvolemic or hypervolemic hyponatremia. Men and women ⱖ 18 years with serum sodium concentration ([Na⫹]) 115 to ⬍130 mEq/L randomized to CNV received a 20 mg bolus, followed by continuous infusion of 40 or 80 mg/d for 4 d. The primary efficacy measure was change in serum [Na⫹] from baseline over treatment duration (AUC). Secondary efficacy measures included change in serum [Na⫹] from baseline at day 4, time from first dose to achieve a 4 mEq/L increase in serum [Na⫹], number of patients achieving ⱖ 6 mEq/L change in [Na⫹] or normal serum [Na⫹], and effective water clearance (EWC), a measure of electrolyte-free water excretion. Results: Baseline serum [Na⫹] was equivalent in all groups. Both doses of CNV markedly improved serum [Na⫹] and all secondary parameters (Table) compared to placebo. CNV was well tolerated over a 4-d treatment period. Conclusion: CNV significantly increased serum [Na⫹] in all patients with hyponatremia within 24 h. Ongoing trials are investigating the use of CNV to improve symptoms of acute decompensated chronic heart failure by increasing EWC via aquaresis. Conivaptan significantly improved serum sodium levels and water clearance in patients with hyponatremia

035 Acute Intravenous Infusion of CVT-4325 Improves Left Ventricular Function in Dogs with Chronic Heart Failure Makato Imai,1 Sharad Rastogi,1 Naveen Sharma,2 Margaret P. Chandler,2 Brent Blackburn,3 William C. Stanley,2 Hani N. Sabbah1; 1Medicine, Henry Ford Health System, Detroit, MI; 2Physiology and Biophysics, Case Western Reserve University, Cleveland, OH; 3CV Therapeutics, Inc., Palo Alto, CA CVT-4325 has been shown to inhibit free fatty acid (FFA) oxidation and stimulate glucose oxidation in isolated normoxic perfused rat hearts. In the present study, we tested the hemodynamic and metabolic effects of acute intravenous CVT-4325 in dogs with chronic heart failure (HF) (LV ejection fraction ⱕ35%) produced by multiple sequential intracoronary microembolizations. Eight dogs with HF were studied. Each dog underwent two blinded studies performed one week apart using two compounds. One compound was CVT-4325 and the other was CVT-2540 which is structurally similar to CVT-4325 but is devoid of any fatty acid inhibition or glucose oxidation stimulation properties. In all dogs, CVT-4325 was given as an intravenous bolus of 0.5 mg/kg followed by a 40 min continuous infusion of 0.8 mg/kg/hr. CVT-2540 was also given as an intravenous bolus of 0.5 mg/kg followed by a 40 min continuous infusion of 0.36 mg/kg/hr to achieve a plasma concentration similar to that of CVT-4325. LV ejection fraction (EF), end-systolic volume (ESV), stroke volume, total LV coronary blood flow (CBF), myocardial oxygen consumption (MVO2) and FFA uptake were measured at baseline and 40 minutes after initiation of intravenous therapy. The results are shown in the table. Compared to baseline, CVT-2540 had no effect on heart rate, LV systolic pressure, EF, ESV and SV, CBF, MVO2 or FFA uptake. Administration of CVT-4325 also had no effect on heart rate or LV systolic pressure but, in contrast to CVT-2540 it significantly increased EF and SV and significantly decreased ESV. CVT-4325 also significantly decreased CBF, MVO2 and FFA uptake. Conclusions: In dogs with chronic HF, acute intravenous infusion of CVT-4325 improved LV systolic function while decreasing CBF, MVO2 and reducing FFA uptake. The improvement in LV systolic function in the presence of reduced oxygen consumption and lower FFA uptake suggest that CVT-4325 elicits its benefits through a metabolic substrate shift mediated by partial inhibition of FFA oxidation.

Baseline serum [Na⫹], mEq/L (± SD) LS mean change in serum sodium AUC to day 4, mEq/Lh (⫾ SE) LS mean change in serum [Na⫹] at day 4, mEq/L (± SE) Median Time from first dose to 4 mEq/L increase in serum [Na⫹], h Number (%) of patients achieving ⱖ6 mEq/L increase in serum [Na⫹] or normal [Na⫹] (ⱖ135 mEq/L) Mean change from baseline in EWC on day 1, ml (± SD)

Placebo (n ⫽ 29)

CNV 40 mg/d (n ⫽ 29)

CNV 80 mg/d (n ⫽ 26)

124.3 (4.9)

123.3 (4.7)

124.8 (3.4)

12.9 (61.2)

490.9 (56.8)*

716.6 (60.5)*

2.0 (0.8)

6.8 (0.8)*

9.0 (0.8)*

23.7*

23.4*

6 (20.7)

20 (69)**

23 (88.5)*

⫺332.3 (434.1)

1984.0 (1559.4)***

1759.4 (1748.3)***

NE

*P ⬍ .001, **P ⬍ .01, ***P ⬍ .05 vs placebo; NE ⫽ not estimable

Table CVT-2540 Baseline EF (%) ESV (%) SV (ml) CBF (ml/min) MVO2 (umols/min) FFA uptake (umols/min)

40 min

037

CVT-4345 Baseline

40 min

30 ⫾ 2 42 ⫾ 2 18 ⫾ 1 48 ⫾ 7 170 ⫾ 27

30 ⫾ 2 42 ⫾ 3 18 ⫾ 1 52 ⫾ 8 174 ⫾ 17

33 ⫾ 2 42 ⫾ 2 18 ⫾ 1 56 ⫾ 3 240 ⫾ 25

37 38 21 46 172

3.89 ⫾ 1.57

4.88 ⫾ 1.57

4.51 ⫾ 1.04

1.65 ⫾ 0.34*

*⫽ p ⬍ 0.05 vs. Baseline

⫾ 1* ⫾ 3* ⫾ 1* ⫾ 4* ⫾ 7*

Effects of Sildenafil on Cardiac Sympathetic Activity in Patients with Chronic Heart Failure Abdul Al-Hesayen,1 John D. Parker1; 1Dept. Of Medicine, Division of Cardiology, Mount Sinai and University Health Network Hospitals, Toronto, ON, Canada Purpose: Sildenafil has been reported to increase sympathetic outflow in normal volunteers. To date, experience with sildenafil in patients with congestive heart failure (CHF) is limited and the impact of phosphodiesterase V inhibition on sympathetic activity in this population has not been evaluated. Methods: Eight patients with CHF secondary to dilated cardiomyopathy were studied. They were instrumented with pulmonary artery, femoral artery, and coronary sinus thermodilution catheters. Cardiac sympathetic activity was measured by the cardiac norepinephrine spillover (CANESP) technique. Hemodynamics and CANESP were determined at baseline and in response to a steady state infusion of sildenafil. Results: The mean age was 59 ⫾ 6 yr and their EF was 24 ⫾ 4%. Sildenafil was given as bolus of 2.6 ⫾ 0.1mg followed by an infusion of 0.8 ⫾ 0.1mg over 20 minutes. Sildenafil caused a significant reduction in right atrial (6 ⫾ 1 vs. 3 ⫾ 1 mmHg, P ⬍ 0.006), mean pulmonary artery (29 ⫾ 4 vs. 20 ⫾ 3 mmHg, P ⬍ 0.002), and mean arterial pressures (75 ⫾ 2 vs. 69 ⫾ 1 mmHg, P ⬍ 0.008). Heart rate and cardiac output did not change. Despite the fall in arterial pressure the infusion of sildenafil was associated with a significant reduction in CANESP (305 ⫾ 36 vs. 235 ⫾ 37 pmol/min, P ⬍ 0.02). Conclusion: Sildenafil infusion was associated with a significant reduction in cardiac sympathetic activity. These