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This study was designed to determine the potential therapeutic effects of a new sodium-hydrogen exchanger (NHE-1) inhibitor in the rat coronary artery ligation model of chronic heart failure. After the induction of acute myocardial infarction, rats were entered into a randomly designed pilot dose study from 0.3 mg/kg, 1.0 mg/kg, and 3.0 mg/kg. Solid state micrometer hemodynamics, echocardiographic, and pressure-volume relationships were measured after 6 weeks of treatment. Treatment with this NHE-¬1 inhibitor at 3 mg/kg increased (P

Hemodynamic support with the Impella device is an important tool during high risk percutaneous coronary intervention. This device is usually inserted via the femoral artery. However, some patients have severe peripheral artery disease precluding the use of the femoral artery for this purpose. The axillary artery is a viable alternative in these cases. We reviewed the two access techniques for inserting the Impella via the axillary artery and also described 6 cases of successful implantation.

Background Chronic total occlusions (CTOs) represent the most complex and challenging coronary lesions for percutaneous coronary intervention (PCI). PCI for a CTO is a high-risk procedure and the long-term benefits of a successful percutaneous CTO recanalization over the medical management (as a result of failed PCI) are not clear, as the studies have shown conflicting results in the past. The goal of this analysis was to clarify this issue by performing a meta-analysis of the available literature. Methods Using major electronic databases, we searched for studies (randomized or observational) comparing death, major adverse cardiovascular events (MACE), myocardial infarction (MI), and target vessel revascularization (TVR) between patients who underwent PCI recanalization of CTOs versus those treated with medical management as a result of failed PCI attempts. Results We identified 23 observational studies comparing the desired clinical parameters between patients with successful CTO recanalization and those managed conservatively as a result of attempted but failed PCI. The total number of patients observed in all of the studies was 12,970 and the mean time of follow up was 3.7 ± 2.1 years. Our results indicated that successful recanalization of a CTO results in improved all-cause mortality (relative risk [RR] of 0.54, 95% confidence interval [CI] (0.45-0.65), P-value

Angiotensin II type 1 (AT1) receptor blockade attenuates myocardial fibrosis after myocardial infarction (MI). However, whether inhibition of fibrosis by AT1 receptor blockade influences myocardial stiffness and contractility is unknown. We measured left ventricular (LV) hemodynamics, papillary muscle function, and myocardial stiffness and fibrosis in rats randomized to losartan or placebo 1 day after MI and treated subsequently for 8 wk. Losartan decreased LV and right ventricular weights as well as mean aortic and LV systolic pressures in sham and MI rats. LV end-diastolic pressure increased after MI and was decreased with losartan. Maximal developed tension and peak rate of tension rise and decline were decreased in MI vs. sham rats. Interstitial fibrosis developed after MI and was prevented in losartan-treated MI rats. The development of abnormal myocardial stiffness after MI was prevented by losartan. After MI, AT1 receptor blockade prevents an abnormal increase in myocardial collagen content. This effect was associated with a normalization of passive myocardial stiffness.

Chronic total occlusions (CTOs) represent the most complex and challenging coronary lesions for percutaneous coronary intervention (PCI). PCI for a CTO is a high-risk procedure and the long-term benefits of a successful percutaneous CTO recanalization over the medical management (as a result of failed PCI) are not clear, as the studies have shown conflicting results in the past. The goal of this analysis was to clarify this issue by performing a meta-analysis of the available literature.Using major electronic databases, we searched for studies (randomized or observational) comparing death, major adverse cardiovascular events (MACE), myocardial infarction (MI), and target vessel revascularization (TVR) between patients who underwent PCI recanalization of CTOs versus those treated with medical management as a result of failed PCI attempts.We identified 23 observational studies comparing the desired clinical parameters between patients with successful CTO recanalization and those managed conservatively as a result of attempted but failed PCI. The total number of patients observed in all of the studies was 12,970 and the mean time of follow up was 3.7 ± 2.1 years. Our results indicated that successful recanalization of a CTO results in improved all-cause mortality (relative risk [RR] of 0.54, 95% confidence interval [CI] (0.45-0.65), P-value0.001), lower rates of MACE (RR of 0.70, 95% CI 0.60-0.83, P-value0.001) and reduced needs for subsequent bypass surgery (RR of 0.25, 95% CI (0.21-0.30), P-value0.001). The difference in long-term mortality remained statistically significant even after the adjustment for procedure related complications and in-hospital deaths.As compared to conservative management (as a result of failed intervention), successful PCI recanalization of a CTO appears to be associated with improved long-term clinical outcomes; however, randomized controlled trials (RCTs) are needed to further confirm these results.

Poloxamer-188 (P-188) is a biological membrane sealant that prevents the unregulated entry of Ca into cardiomyocytes and has been shown to have the ability to act as a membrane-repair agent in isolated cardiac myocytes. The purpose of this study was to determine if treatment with P-188 would improve left ventricular (LV) function in a rat chronic heart failure (CHF) model.We ligated the left coronary artery of adult male Sprague-Dawley rats to induce a myocardial infarction (MI). The rats were allowed to recover for 8 weeks until stable CHF was present and treated with a range of P-188 doses [1.5 mg/kg (N = 6), 4.6 mg/kg (N = 11), 15.3 mg/kg (N = 11), and 460 mg/kg (N = 6)] delivered via 30 minutes of intravenous infusion. The rats were randomized to study groups: control, 2 hours, 24 hours, 48 hours, 1 week, and 2 weeks posttreatment (N = 8 in each group).Two weeks after high dose (460 mg/kg) administration, P-188 improved (P0.05) left ventricular ejection fraction from 34% to 51%, which persisted over 38 hours and decreased (P0.05) LV end systolic diameter from 0.9 ± 0.07 to 0.6 ± 0.08 cm, in the rats with CHF. There was no statistical change in hemodynamics. Additionally, P-188 reduced (P0.05) circulating troponin levels 2 weeks after treatment.Treatment with P-188 improves the LV function and partially reverses maladaptive LV remodeling in rats with moderate CHF after MI. These data introduce the idea of using a biological membrane sealant as a new approach to treating CHF after MI.

Granulocyte macrophage colony-stimulating factor (GM-CSF) promotes infarct expansion and inappropriate collagen synthesis in a myocardial infarction (MI). This study was designed to determine if treatment with anti-GM-CSF will inhibit macrophage migration, preserve function, and limit left ventricular (LV) remodeling in the rat coronary artery ligation model. Treatment with a monoclonal antibody to GM-CSF (5 mg/kg) was initiated 24 hours before coronary artery ligation and continued every 3 days for 3 weeks. Left coronary arteries of rats were ligated, animals were recovered, and cardiac function was evaluated 3 weeks postligation. Tissue samples were processed for histochemistry. Anti-GM-CSF treatment increased LV ejection fraction (37 ± 3% vs 47 ± 5%) and decreased LV end systolic diameter (0.75 ± 0.12 vs 0.59 ± 0.05 cm) with no changes in LV systolic pressure (109 ± 4 vs 104 ± 5 mm Hg), LV end diastolic pressure (22 ± 4 vs 21 ± 2 mm Hg), LV end diastolic diameter (0.96 ± 0.04 vs 0.92 ± 0.05 cm), or the time constant of LV relaxation tau (25.4 ± +2.4 vs 22.7 ± 1.4 milliseconds) (P < 0.05). Significantly lower numbers of tissue macrophages and significant reductions in infarct size were found in the myocardium of antibody-treated animals (81 ± 21.24 vs 195 ± 31.7 positive cells per 0.105 mm, compared with controls. These findings suggest that inhibition of macrophage migration may be beneficial in the treatment of heart failure after MI.

Altering the renin-angiotensin aldosterone system improve mortality in heart failure (HF) in part through an improvement in nitric oxide (NO)-mediated endothelial function. This study examined if spironolactone affects endothelial nitric oxide synthase (eNOS) and NO-mediated vasorelaxation in HF.Rats with HF after coronary artery ligation were treated with spironolactone for 4 weeks. Rats with HF had a decrease (P.05) in left ventricular (LV) systolic pressure (130 +/- 7 versus 118 +/- 6 mm Hg) and LV pressure with respect to time (9,122 +/- 876 versus 4,500 +/- 1971 mm Hg/second) with an increase in LV end-diastolic pressure (4 +/- 2 versus 23 +/- 8 mm Hg). Spironolactone did not affect hemodynamics but it improved (P.05) endothelial-dependent vasorelaxation at more than 10(-8) M acetylcholine that was abolished with N(G)-monomethyl-L-arginine. The eNOS levels were decreased (P.05) in the LV and the aorta; spironolactone restored LV and aortic eNOs levels to normal.Spironolactone prevents the decrease in eNOS in the LV and aorta and improves NO-dependent vasorelaxation, suggesting that one potential mechanism of spironolactone is an improvement in vasoreactivity mediated though an increase in NO.

The ultimate percutaneous coronary interventional complication is death. Acute hemodynamic collapse and resultant cardiac arrest is a dramatic pathway, though not always an irreversible pathway to this dreaded complication.

This study was designed to determine if the thyroid hormone analog 3,5 diiodothyropropionic acid (DITPA), now in clinical trials for heart failure, alters endothelial function after myocardial infarction (MI). Three weeks after MI, adult Sprague-Dawley rats were randomly assigned to DITPA (375 microg/100 g subcutaneous) or no treatment of 3 weeks. In MI rats, left ventricular (LV) end-diastolic pressure and LV dP/dt decreased (P < 0.05). DITPA did not change MAP (87 +/- 10 versus 90 +/- 7 mm Hg) or LV end-diastolic pressure (23 +/- 3 versus 19 +/- 9 mm Hg) but did lower (P < 0.05) LV dP/dt (4,633 +/- 797 versus 3,650 +/- 1,236 mm Hg/s). In aortic segments from MI rats, DITPA enhanced the acetylcholine dependent vasorelaxation (59 +/- 11% at 10(-4) M, P < 0.05) and isoproterenol induced vasorelaxation (57 +/- 13% at 10(-4) M, P < 0.05). The increases in vasorelaxation were blocked with l-NAME and restored with L-arginine. Treatment with DITPA increased (P < 0.05) eNOS protein content in aortic tissue from sham rats (3.8 +/- 2.8 to 44.5 +/- 7.1 integrated intensity units (II)/microg) and in MI rats (5.3 +/- 3.4 to 28.3 +/- 8.9 II/microg). In endothelial cells, 24 hours' treatment with DITPA (10 microM) increased (P < 0.01) eNOS protein expression from 22.1 +/- 4.8 to 52.7 +/- 16.8 II/microg protein and DITPA (20 microM) increased eNOS to 49.1+/- 15.2 II/microg protein. The thyroid analog DITPA enhances endothelial nitric oxide and beta-adrenergic-mediated vasorelaxation by increasing nitric oxide in the vasculature.

To determine whether angiotensin receptor blockade decreases vascular tone in heart failure by improving endothelial-dependent vasorelaxation and increasing nitric oxide (NO) bioavailability, we treated infarcted adult male Sprague-Dawley rats with candesartan for 7 days or 8 weeks (10 mg/kg/day in drinking water). Candesartan, at both time points, lowered left ventricular (LV) systolic pressure (P < 0.05) (122 +/- 22 versus 74 +/- 16 and 73 +/- 10 mm Hg) and LV dP/dt (5914 +/- 1294 versus 2857 +/- 1672 versus 3175 +/- 769 mm Hg/s), but lowered LV end-diastolic pressure only at 8 weeks (16.9 +/- 9.7 versus 11.2 +/- 5.7 versus 6.9 +/- 5.3 mm Hg). The vasorelaxation response to acetylcholine (ACh) in thoracic aortic segments was decreased with infarction (P < 0.05), remained unchanged with 1 week of candesartan, but increased 84 and 86% at 10-4 and 10-5 M ACh (P < 0.05) at 8 weeks. The enhanced candesartan-induced vasorelaxation at 8 weeks was abolished with NG-nitro-l-arginine methyl ester (200 microM). In bovine pulmonary endothelial cells, 20 microM candesartan increased endothelial nitric-oxide synthase (eNOS) protein levels (P < 0.05) (28.9 +/- 2.6 versus 16.1 +/- 3.7 intensity units/microg of protein); the increased eNOS was abolished by a specific angiotensin subtype 2 (AT2) receptor antagonist, PD 123319. These data suggest that AT1 receptor blockade enhances vasorelaxation in heart failure by increasing NO bioavailability, in part via an AT2 receptor-mediated up-regulation of eNOS protein.

Background: While direct cell injections have been the main focus of cell-based therapies for chronic heart failure (CHF) newer approaches utilizing tissue engineered scaffolds have evolved. Previous work from our laboratory has evaluated a viable 3-dimensional fibroblast construct (3DFC) for the treatment of acute myocardial infarction and CHF. While the initial findings are impressive, the 3DFC does little to reverse maladaptive remodeling. Ideal treatment for reversing remodeling would involve revascularization of the ischemic tissue and repopulation of the anterior wall with cardiomyocytes. Hypothesis: Neonatal cardiomyocytes can be seeded onto a 3-dimensional fibroblast construct and co-cultured to generate a multicellular, biologically active cardiomyocyte scaffold for treatment of CHF. Methods: Cardiomyocytes are isolated from neonatal rats 1-2 days old and seeded onto 3DFC scaffolds (Theregen, Inc) using methods developed in our laboratory at concentrations ranging from 0.6x106 to 2.7x106 cells/cm2. The neonatal cardiomyocyte-3DFC were cultured between 110 days at 37oC with 5% CO2 in 10% FBS in DMEM-LG. Media was changed 24 hrs after initial plating then every 48 hrs. Results: Higher density cardiomyocyte seedings (1.8x106 to 2.7x106 cells/cm2) of the 3DFC show synchronized and spontaneous contractions of the entire scaffold after 48 hrs in culture. Contractions increased in robustness from 48 hrs to 5 days. At 5 days, scaffolds seeded with 2.7x106 cells/cm2 contract in a consistent rhythmic and directional fashion. Contractions were recorded at 71+3 beats BPM with a mean displacement of 2.9+0.1 mm and contraction velocity of 3.4+0.5 mm/sec (N=10). Conclusion: These findings show isolated cardiomyocytes can be seeded and co-cultured onto a biodegradable 3-dimensional construct in a manner allowing cellular survival, communication and electrical coupling. These claims are supported by the observation that the newly seeded neonatal cardiomyocyte-3DFC scaffolds beat spontaneously and in a synchronized, directional fashion with no electrical stimulation. This newly formed neonatal cardiomyocyte 3DFC scaffold is a new and unique cell delivery system to potentially treat infarcted hearts.

Background Evidence suggests that aortic stenosis (AS) may be related to atherosclerosis and dyslipidemia. This is supported by data demonstrating echocardiographic attenuation of AS progression by HMG-CoA reductase inhibitors (statins). Unfortunately, not many data are available concerning the role of statin therapy in the clinical progression of AS. We attempted to clarify if dyslipidemia and statin therapy has any role in the clinical outcomes of patients with AS. Methods A review of 272 patients with moderate AS was performed. Data analyzed included current lipid profiles and use of statins. The primary end points examined included the major adverse cardiac events (MACE) such as angina, syncope, heart failure, strokes, and hospitalizations; In addition secondary end points such as all-cause mortality and aortic valve replacement (AVR) were also evaluated. Logistic regression analysis (LRA) was used to adjust for potential confounding factors including coronary artery disease (CAD), diabetes, renal insufficiency, hypertension, and current smoking. Results 272 patients, with a mean age of 74.8 and a mean AVA of 1.2 cm2 were included. 141 patients (51.8%) were on a statin. LRA revealed an adjusted odds ratio of 3.16 (p 100 mg/dL. There was no association between statin use and reduction in MACE (p = .82), aortic valve replacement (p = .94) as well as all-cause mortality (p = .46). Elevated LDL (p = .016), low HDL (p = .018), and high non-HDL cholesterol (p = .05) were all independent predictors of all-cause mortality and MACE. Conclusions In patients with AS there was no significant correlation between statin use and a reduction in event rates. Nevertheless, major markers of dyslipidemia were significantly associated with all-cause mortality and MACE in patients with AS. This suggests that in patients with AS, the clinical outcomes appear to be determined by the mechanical obstruction. The role of statin therapy may be limited to preventing development of AS in patients with aortic sclerosis.

Background Tissue engineering is a novel method to restore myocardial function in ischemic heart disease. One technique is to apply a biologically active graft onto the infarcted region (IR) of the left ventricle (LV). The effects of a fibroblast patch (3DFC) placement on the IR of the LV on systolic/diastolic function in a coronary artery ligation (CAL) model of heart failure were evaluated. Methods CAL to induce myocardial infarction (MI) is performed on Sprague-Dawley rats. The 3DFC patch is placed on the IR. Echos were done at 3 weeks. Hemodynamics was measured. LV regional systolic displacement (SD), LV ejection fraction (LVEF), LV fractional shortening (FS), and LV pressure/diameter relaxation curves were obtained. Results 3DFC patch placement improved (p Summary Implantation of a fibroblast mesh on the IR of the LV improved LV systolic function. The patch also prevented LV dilation and normalized LV diastolic function post MI. Our data illustrate the future potential of using a biologically active graft in the treatment of ischemic heart failure.

Background Myocardial perfusion imaging (MPI) is a powerful tool to detect myocardial ischemia. Nevertheless, it has not been well validated in women and obese patients due to image attenuation. We evaluated the role of attenuation correction software used in conjunction with MPI among obese women at risk for coronary heart disease (CHD). Methods MPI study data from 45 women who subsequently underwent coronary angiography were collected and analyzed. Three independent nuclear radiologists/cardiologist were asked to interpret these studies and calculate the sum stress score (SSS) and sum rest score (SRS) using nonattenuation corrected (NAC), attenuation corrected (AC), and a combine score (NAC + AC) methodologies. They were blinded to the results of the angiogram. Results The body mass index of these patients was 30.6 ± 6.6 kg/m2; the mean age was 63.3 ± 11.2. There was no difference between NAC SSS and AC SSS (6.5 ± 0.5 vs 6.7 ± 0.6; p = NS). When a combined score was calculated, there was a significant decrease in SSS between NAC SSS and combined SSS (6.5 ± 0.5 vs 4.1 ± 0.4, respectively; p 70% stenosis). Among these patients the NAC SSS was higher than the AC and combined SSS (6.7 ± 0.8 vs 4.9 ± 0.9 and 4.3 ± 0.7, respectively; p Conclusions A combined score appears to significantly lower the SSS among obese women undergoing MPI. This may lead to an increased specificity of MPI in ruling out myocardial ischemia. However, among patients with true disease, the lower combined score may also decrease the sensitivity of MPI in this setting.

Background Left ventricular (LV) remodeling after myocardial infarction (MI) leads to heart failure (HF). While alterations in LV wall strain are seen in the infarcted regions (IR), it is unclear if this also affects the non-infarcted regions (NIR) of the LV. Additionally, while LV tissue eNOS and constituitive microtubulin (CM) are altered in chronic HF, it is unknown what happens to these biomarkers acutely. We evaluated changes in LV wall strain; myocardial eNOS and CM acutely post MI. Methods LV wall motion of Sprague Dawley rats (N = 10) was analyzed by echocardiography at several time points after MI. Hemodynamic measurements were obtained via a Millar catheter. Alterations in myocardial contraction (δ strain) are measured via M-mode echocardiography. CM and eNOS were determined via immunoblot techniques. Results Systolic blood pressure decreased (P ≤ 0.05) acutely post MI (127.1 ± 6.1 vs 101.7± 10.1 mmHg). LV end diastolic pressure increased (P≤0.05) acutely after MI (5.8 ± 0.5 vs. 19.9 ± 2.0 mmHg). These changes were accompanied by a decrease (P≤ 0.05) in LV dP/dt after MI (7106 ± 520 vs. 4671± 350, mmHg/sec). δ strain was decreased in the anterior IR immediately (0.15 ± 0.04 vs 0.1 ± 0.02 mm, P ≤ 0.01); similarly δ strain was also decreased in the posterior NIR starting at 1 minute (0.17 ± 0.02 vs 0.1 ± 0.02 mm, P ≤ 0.01). A decrease in eNOS was seen with both the IR and NIR of the LV (20.8± 3.8 intensity unit (IU)/50 μg of tissue vs 11.1 ± 3.3 IU/50 μg, P = 0.04) and (26.7 ± 4.8 vs 8.14 ± 1.6 IU/50 μg, P = 0.002), respectively after MI. Conversely, CM was increased in both IR and NIR of the LV (10.3 ± 2.4 IU/25 μg vs 26.2 ± 4.6 IU/25 μg, P = 0.0005) and (9.3 ± 1.8 vs 18.5 ± 3.7 IU/25 μg, P = 0.003), respectively. Conclusion Decreases in δ strain occurred in both IR and NIR of the LV acutely after MI. This is accompanied by alterations in eNOS and CM levels throughout the LV immediately after MI. Our data demonstrate that physical and biomarkers signaling LV remodeling occur immediately after MI, rather than over time.

Background Female patients with chest pain pose unique problems to clinicians. Traditionally, epidemiological evidence has demonstrated low sensitivity and specificity in physiologic stress testing leading to poor accuracy in the ability of these tests to predict coronary artery disease (CAD) among women with chest pain We evaluated the accuracy of clinical symptoms, dobutamine stress echo (DSE) and nuclear stress testing (NST) in predicting presence of CAD among women presenting with chest pain in a large, tertiary referral center. Methods We evaluated 30 female patients that have undergone cardiac catheterization within the past two years. These patients proceeded to cath after having a positive DSE, NST or due to strong clinical suspicion. Patients with acute myocardial infarction, planned valvular surgery or coronary bypass were excluded from statistical analyses. Presence of CAD was defined as any stenotic lesions greater than 50% of coronary luminal diameter. Differences among groups were analyzed by ANOVA, paired and unpaired Student9s t tests for significance. Data reported as percent accuracy. Results All patients underwent cardiac catherization as a result of strong clinical suspicion, positive DSE or nuclear stress myocardial imaging. The accuracy of DSE in predicting presence of CAD is 67%, significantly (P≤ 0.05) higher than nuclear stress myocardial imaging (accuracy = 18%). There was a trend towards a significant difference between DSE and clinical suspicion in predicting presence of CAD, (67% vs. 42%, P = NS). Clinical suspicion is more accurate than nuclear stress imaging in predicting CAD (42% vs. 18%, P ≤ 0.05). Conclusions Female patients with chest pain pose unique problems to clinicians. From our single center study, the data demonstrate that DSE is superior to clinical suspicion and nuclear stress imaging in accurately predicting presence of CAD among women presenting with chest pain.