Decrease In Left Ventricular End-diastolic Pressure Research Articles

Nonsteroidal Mineralocorticoid Receptor Antagonist Finerenone Improves Diastolic Dysfunction in Preclinical Nondiabetic Chronic Kidney Disease.

The mineralocorticoid receptor plays a significant role in the development of chronic kidney disease (CKD) and associated cardiovascular complications. Classic steroidal mineralocorticoid receptor antagonists are a therapeutic option, but their use in the clinic is limited due to the associated risk of hyperkalemia in patients with CKD. Finerenone is a nonsteroidal mineralocorticoid receptor antagonist that has been recently investigated in 2 large phase III clinical trials (FIDELIO-DKD [Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease] and FIGARO-DKD [Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease]), showing reductions in kidney and cardiovascular outcomes. We tested whether finerenone improves renal and cardiac function in a preclinical nondiabetic CKD model. Twelve weeks after 5/6 nephrectomy, the rats showed classic signs of CKD characterized by a reduced glomerular filtration rate and increased kidney weight, associated with left ventricular (LV) diastolic dysfunction and decreased LV perfusion. These changes were associated with increased cardiac fibrosis and reduced endothelial nitric oxide synthase activating phosphorylation (ser 1177). Treatment with finerenone prevented LV diastolic dysfunction and increased LV tissue perfusion associated with a reduction in cardiac fibrosis and increased endothelial nitric oxide synthase phosphorylation. Curative treatment with finerenone improves nondiabetic CKD-related LV diastolic function associated with a reduction in cardiac fibrosis and increased cardiac phosphorylated endothelial nitric oxide synthase independently from changes in kidney function. Short-term finerenone treatment decreased LV end-diastolic pressure volume relationship and increased phosphorylated endothelial nitric oxide synthase and nitric oxide synthase activity. We showed that the nonsteroidal mineralocorticoid receptor antagonist finerenone reduces renal hypertrophy and albuminuria, attenuates cardiac diastolic dysfunction and cardiac fibrosis, and improves cardiac perfusion in a preclinical nondiabetic CKD model.

Delivery of TAPI‐1 via Neutrophil Membrane Fusogenic Liposomal Nanoparticles Can Effectively Ameliorate Cardiac Dysfunction in Heart Failure

Nanomedicine has been widely employed as a site‐specific and target‐oriented drug delivery tactic in treating heart failure (HF). Ischemia‐induced inflammation plays a robust role in the development of HF and neutrophil is one of the main immune cell types that rapidly infiltrate into the inflamed tissues after myocardial infarction (MI). In the present study, we examined the efficacy of a formation of biomimetic nanoparticles that were prepared by fabricated TAPI‐1 loaded liposomes coated with neutrophil membranes in the treatment of HF. Male SD rats underwent coronary artery ligation (CL) to induce HF. These HF rats were treated with intravenous injection of TAPI‐1‐loaded biomimetic nanoparticles (n=6) or TAPI‐1 alone (n=6) for 4 weeks. The left ventricular (LV) function was assessed by echocardiography within 24 hours and 4 weeks after CL. The nanoparticles were evaluated prior to the treatments. Compared with non‐coated formation, neutrophil membrane‐coated nanoparticles have high uptake into LPS‐stimulated cardiac cells or endothelial cells. Moreover, the coated nanoparticles exhibited higher cell‐specific targeting potential and internalization capacity than non‐coated nanoparticles in LPS‐stimulated endothelial cells. Small animal imaging showed that DiR‐labeled nanoparticles were mainly accumulated in the injured heart after MI. Compared with HF rats treated with TAPI‐1 alone, the HF rats treated with TAPI‐1‐loaded nanoparticles had significantly (* p<0.05) improved anatomic indicators with reduced ratio (%) of heart/body weight (0.34 ± 0.042* vs. 0.48± 0.11) and lung/body weight (0.84 ± 0.19* vs. 1.14 ± 0.15). Additionally, one 4‐week treatment with TAPI‐1‐loaded biomimetic nanoparticles reduced LV end systolic volume (0.67±0.032* vs. 0.83±0.036, mL) when compared with the TAPI‐1 alone. While LV stroke volume (LVSV) did not change significantly in IV TAPI‐1‐treated HF animals, LVSV (0.47±0.043* vs. 0.27±0.029, mL) was significantly increased in HF rats treated with TAPI‐1‐loaded nanoparticles at 4 weeks vs. 24 hours after CL. LV end diastolic volume, LV ejection fraction, and LV infarction zone didn’t exhibit significant differences between two treatment groups. Cardiac hemodynamic measurements revealed that the HF rats treated with TAPI‐1‐loaded nanoparticles had decreased LV end diastolic pressure (10.53±1.67* vs. 19.01±3.32, mmHg) and elevated dP/dtmax(8202.65±658.09* vs. 5994.47±630.81) compared with the HF rats‐treated with TAPI‐1 alone. Histological evaluation indicated that the fibrosis areas surrounding the infarction scar were significant reduced (15.97±1.84* vs. 22.86±2.27, %) in HF rats treated with TAPI‐1‐loaded nanoparticles vs. TAPI alone. Flow cytometric analysis also demonstrated that treatment with TAPI‐1‐loaded nanoparticles improved inflammatory conditions indicated by increased ratio of CD4+/CD8+ T Cells (2.40±0.67* vs. 1.56±0.21) in the blood and reduced percentage of leukocytes in the heart of HF. These data indicate that neutrophil membrane fusogenic liposomal nanoparticle is an effective drug delivery approach in treating this devastating disease. (Supported by NIH grants R01 HL‐139521 & HL‐155091 to SGW, S10 OD019941 to RW)

Early haemodynamic and structural impact of transcatheter aortic valve replacement in pure aortic regurgitation

Abstract Background Patients with severe aortic regurgitation (AR) are treated by surgery and have variable left-ventricular (LV) “reverse remodelling” after intervention. Transcatheter-aortic-valve replacement (TAVR) might be considered in selected AR patients. Purpose To evaluate the hemodynamic and structural impact of TAVR in patients with pure AR. Methods Consecutive AR patients underwent TAVR in our Institution were identified. Left heart catheterization before and after TAVR and complete echocardiographic assessment before TAVR, after (24–72 hours) TAVR and at follow-up (3–12 months) were systematically performed. Hemodynamic and echocardiographic parameters were compared before and after TAVR. Results Twenty-two patients with severe AR, high surgical risk and advanced heart damage were treated by TAVR using mainly self-expandable prostheses. The procedure was successful in 21 patients (95.5%). An immediate hemodynamic impact of the TAVR procedure was documented by different parameters and included significant decrease in LV end-diastolic pressure (from 26.2 to 20.1 mmHg, P=0.012). Significant reduction in LV size (left ventricular end diastolic diameter (LVEDD): 60.0±8.0 mm vs 54.6±8.1 mm, p=0.002) and mass (left ventricular mass indexed (LVMi): 163.2±58.8 g/m2 vs 140.2±45.6 g/m2, p 0.004) as well as a sharp reduction in systolic-pulmonary-arterial-pressure (48.3±17.6 vs 32.9±7.8 mmHg, p<0.0001) was documented at 24–72 hours. Furthermore, patients with baseline moderate-to-severe mitral and tricuspid regurgitation showed a significant, early, valvular regurgitation reduction. All favourable changes persisted at follow-up. More pronounced LVEDD reduction was predicted by baseline LVEDD (p=0.019). Conclusions In patients with severe AR, TAVR determines a profound impact on heart remodelling, which is early detectable and durable. Impact of TAVR in pure AR Funding Acknowledgement Type of funding source: None

Chronic dantrolene treatment attenuates cardiac dysfunction and reduces atrial fibrillation inducibility in a rat myocardial infarction heart failure model.

BackgroundCardiac ryanodine receptor 2 (RyR2) dysfunction and elevated diastolic Ca2+ leak have been linked to arrhythmogenesis not only in inherited arrhythmia syndromes but also in acquired forms of heart disease including heart failure (HF) and atrial fibrillation (AF). Thus, stabilizing RyR2 may exert therapeutic effects in these conditions.ObjectiveThe purpose of this study was to investigate the effects of stabilizing RyR2 with chronic dantrolene treatment on HF development and AF inducibility in a myocardial infarction (MI)–induced HF model in rats.MethodsMI was induced in adult Sprague-Dawley rats by ligation of the left anterior descending coronary artery. Two weeks after MI surgery, rats with large MI (≥40%) were randomly assigned to MI-vehicle (n = 14) or MI-dantrolene (10 mg/kg/d; n = 13) groups. Sham-surgery rats (n = 7) served as controls.ResultsCompared to the MI-vehicle group, 4-week dantrolene treatment significantly improved cardiac function, with increased left ventricular (LV) fractional shortening (19.48% ± 3.61% vs 15.43% ± 2.65%; P <.01), and decreased LV end-diastolic pressure (12.58 ± 8.52 mm Hg vs 21.91 ± 7.25 mm Hg; P <.01), left atrial diameter (4.97 ± 0.75 mm vs 6.09 ± 1.53 mm; P <.05), and fibrosis content (6.42% ± 0.78% vs 9.76% ± 2.25%; P <.001). Dantrolene significantly decreased AF inducibility (69% in MI-vehicle vs 23% in MI-dantrolene; P <.05). Dantrolene treatment was associated with reduced RyR2 phosphorylation and favorably altered gene expression involving ion channels, sympathetic signaling, oxidative stress, and inflammatory markers.ConclusionChronic dantrolene treatment attenuated LV dysfunction and reduced AF inducibility, which was associated with decreased RyR2 phosphorylation and normalization of many adverse changes in gene expression. Thus, stabilizing RyR2 with chronic dantrolene treatment is a promising novel strategy for decreasing AF in HF.

Short-and long-term administration of imeglimin counters cardiorenal dysfunction in a rat model of metabolic syndrome.

IntroductionImeglimin, a glucose‐lowering agent targeting mitochondrial bioenergetics, decreases reactive oxygen species (ROS) overproduction and improves glucose homeostasis. We investigated whether this is associated with protective effects on metabolic syndrome‐related left ventricular (LV) and vascular dysfunctions.MethodsWe used Zucker fa/fa rats to assess the effects on LV function, LV tissue perfusion, LV oxidative stress and vascular function induced by imeglimin administered orally for 9 or 90 days at a dose of 150 mg/kg twice daily.ResultsCompared to untreated animals, 9‐ and 90‐day imeglimin treatment decreased LV end‐diastolic pressure and LV end‐diastolic pressure‐volume relation, increased LV tissue perfusion and decreased LV ROS production. Simultaneously, imeglimin restored acetylcholine‐mediated coronary relaxation and mesenteric flow‐mediated dilation. One hour after imeglimin administration, when glucose plasma levels were not yet modified, imeglimin reduced LV mitochondrial ROS production and improved LV function. Ninety‐day imeglimin treatment reduced related LV and kidney fibrosis and improved kidney function.ConclusionIn a rat model, mimicking Human metabolic syndrome, imeglimin immediately countered metabolic syndrome‐related cardiac diastolic and vascular dysfunction by reducing oxidative stress/increased NO bioavailability and improving myocardial perfusion and after 90‐day treatment myocardial and kidney structure, effects that are, at least in part, independent from glucose control.

A dipeptidyl peptidase-IV inhibitor improves diastolic dysfunction in Dahl salt-sensitive rats

To date, there is no established treatment for heart failure with preserved ejection fraction (HFpEF). Dipeptidyl peptidase-IV (DPP-IV) inhibitors reportedly have improved not only diabetes mellitus but also heart failure with systolic dysfunction in experimental models. We investigated the effects of a DPP-IV inhibitor on HFpEF in rats. Dahl salt-sensitive rats were fed either high-salt (high-salt diet (HSD): 8% NaCl) or low-salt diets (0.3% NaCl) from 6.5 weeks of age. They were then treated with or without a DPP-IV inhibitor, vildagliptin (10 mg/kg/day, orally), from 11 weeks of age for 9 weeks and analyzed at the age of 20 weeks. HSD rats mimicked the pathophysiology of HFpEF. There were no differences in heart rate, blood pressure, left ventricular (LV) systolic function, or the extent of LV hypertrophy between HSD rats with or without vildagliptin. However, vildagliptin decreased LV end-diastolic pressure, the most reliable hemodynamic parameter of HFpEF in HSD rats. Vildagliptin also decreased the LV distensibility index, a sensitive marker of LV diastolic function in HSD rats. Vildagliptin decreased the expression of collagen genes in HSD hearts and attenuated LV interstitial fibrosis (HSD with vehicle and vildagliptin, 2.9% vs. 1.9%; P < 0.05). Furthermore, vildagliptin administration reduced both plasma renin activity and aldosterone concentrations in HSD rats. A DPP-IV inhibitor, vildagliptin, improved the severity of LV fibrosis, and thus, diastolic dysfunction of HFpEF in Dahl salt-sensitive hypertensive rats. DPP-IV inhibitors are promising medicines for treatment of HFpEF in patients with diabetes mellitus.

The role of PI3-K/Akt signal pathway in the antagonist effect of CEPO on CHF rats.

The possible role of phosphoinositide 3-kinase (PI3-K)/protein kinase B (Akt) signal pathway in the antagonist effect of carbamylated erythropoietin (CEPO) on chronic heart failure (CHF) in rats was investigated. Twenty of 120 rats were randomly selected as the control group, and the remaining rats as the model group. Rats in the model group received intraperitoneal injection of isoproterenol, those in the control group underwent intraperitoneal injection of equivalent normal saline. Rats with successful model establishment were divided into 4 groups, i.e. CHF group, CEPO group, LY294002 (LY) group and CEPO + LY group. Rats in the CEPO group underwent intraperitoneal injection of CEPO, while those in the CHF group received intraperitoneal injection of equivalent normal saline at the same time, those in the LY group received intraperitoneal injection of LY after model establishment, and those in the CEPO + LY group received the combined intraperitoneal injection of CEPO and LY simultaneously. Indicators for hemodynamics were determined using BL-410S bio-functional experiment system, including heart rate (HR), left ventricular end-diastolic pressure (LVEDP), left ventricular systolic pressure (LVSP) and maximal increased rate of left ventricular pressure (LVP)/maximal reduced rate of LVP (±dp/dtmax). Western blotting assay was utilized to determine the changes in activity of PI3-K/Akt signal pathway. LVSP and ±dp/dtmax in the CHF, the CEPO, the CEPO + LY and the LY groups were significantly lower than those in the control group (P<0.05); LVSP and ±dp/dtmax in the CEPO group were also elevated significantly compared with CHF, LY and CEPO + LY groups (P<0.05) with significant decreases in LVEDP and HR (P<0.05); compared with the CHF group, LVSP and ±dp/dtmax in the LY group were each significantly decreased (P<0.05), in the LY group, pAkt level was significantly lower than that in the CHF group (P<0.05). In conclusion, CEPO can generate the antagonist effect on CHF in rats through activation of PI3-K/Akt signal pathway.

Abstract 205: Cryopreserved Cardiac Tissue Graft (MyCardia) Improved Cardiac Function in Rats With Heart Failure

Introduction: There are currently 2M patients with NYHA Class II-IV heart failure of ischemic etiology in the United States. Cell-based therapies hold tremendous potential to provide therapeutic benefit for treating degenerative diseases such as chronic heart failure (CHF). Therapeutic adoption of engineered grafts will require ease of use and demonstration of cost-effectiveness. Here we describe for the first time the ability to cryopreserve an engineered tissue (MyCardia™) and demonstrate functional recovery in a rat model of CHF. Methods: MyCardia grafts were cultured with human dermal fibroblasts (hNDF) and human iPSC derived cardiomyocytes (hiPSC-CMs) (FCDI) into a bioabsorbable mesh (Novus Scientific). Grafts were cryopreserved at -196C for 2-4weeks, thawed, reconstituted and implanted into rats with CHF. Myocardial infarction (MI) were generated in immune competent rats by ligating the left coronary artery. Three weeks after MI, rats received graft implants via median sternotomy. Echocardiography was performed at 3 and 7 weeks post graft implantation. In addition, terminal hemodynamics were performed. Results: MyCardia maintained spontaneous and synchronous contractions pre-freeze (65±10bpm) and post thaw (60±10bpm). Grafts were maintained to 40 days post thaw with no deterioration in composition or beat rate. MyCardia reversed maladaptive left ventricular (LV) remodeling by decreasing (p&lt;0.05) LV volume systole/diastole, LV diameter systole/diastole with trending improvement in EF and FS from 3 and 7 weeks post implantation as compared to CHF controls. Grafts decreased LV end diastolic pressure, 24±6 mmHg vs. 18±3mmHg and showed trending improvements in LV dP/dt(-) and dP/dt(+) as compared to controls. In addition, MyCardia results in 36% reduction in LV EDP operating volume as demonstrated by a leftward shift of the diastolic pressure-volume relationship. Conclusion: MyCardia can be cryopreserved, reconstituted and implanted in rats with CHF. Treated rats demonstrated reversal of maladaptive LV remodeling and continued functional improvement from 3 to 7 weeks post treatment. We anticipate that the ability to cryopreserve will allow long-term storage after large batch manufacture, providing cost and utility advantages.

Renal Sympathetic Denervation in Rats Ameliorates Cardiac Dysfunction and Fibrosis Post-Myocardial Infarction Involving MicroRNAs.

BackgroundThe role of renal sympathetic denervation (RSD) in ameliorating post-myocardial infarction (MI) left ventricular (LV) fibrosis via microRNA-dependent regulation of connective tissue growth factor (CTGF) remains unknown.Material/MethodsMI and RSD were induced in Sprague–Dawley rats by ligating the left coronary artery and denervating the bilateral renal nerves, respectively. Norepinephrine, renin, angiotensin II and aldosterone in plasma, collagen, microRNA21, microRNA 101a, microRNA 133a and CTGF in heart tissue, as well as cardiac function were evaluated six weeks post-MI.ResultsIn the RSD group, parameters of cardiac function were significantly improved as evidenced by increased LV ejection fraction (p<0.01), LV end-systolic diameter (p<0.01), end-diastolic diameter (p<0.05), LV systolic pressure (p<0.05), maximal rate of pressure rise and decline (dP/dtmax and dP/dtmin, p<0.05), and decreased LV end-diastolic pressure (p<0.05) when compared with MI rats. Further, reduced collagen deposition in peri-infarct myocardium was observed in RSD-treated rats along with higher microRNA101a and microRNA133a (p<0.05) and lower microRNA21 expression (p<0.01) than in MI rats. CTGF mRNA and protein levels were decreased in LV following RSD (p<0.01), accompanied by decreased expression of norepinephrine, renin, angiotensin II and aldosterone in plasma (p<0.05) compared with untreated MI rats.ConclusionsThe potential therapeutic effects of RSD on post-MI LV fibrosis may be partly mediated by inhibition of CTGF expression via upregulation of microRNA 101a and microRNA 133a and downregulation of microRNA21.

Abstract 13813: Intravascular Vagal Nerve Stimulation in Acute Myocardial Infarction Markedly Reduced Infarct Size and Improved Cardiac Function in the Long Term

Backgrounds: In acute myocardial infarction (AMI), the extent of myocardial damage governs the progression to heart failure in the long-term. Therefore, reducing the myocardial damage is prerequisite to prevent chronic heart failure. Although vagal nerve stimulation (VNS) has been repeatedly demonstrated to have the powerful anti-infarct effect, technical difficulties preclude its clinical applications. Recently we developed an new percutaneous, intravascular VNS (iVNS). In this study, we investigated whether iVNS reduces the infarct size and prevents heart failure one month after ischemia reperfusion (IR). Methods: In mongrel dogs, we ligated the left anterior descending coronary artery for 3 hours and reperfused. We transvascularly stimulated the right vagal nerve with a pacing catheter in the superior vena cava. We maximized the intensity of iVNS that did not deteriorate hemodynamics (amplitude; 5.1±2.1 V, pulse width; 0.2ms, frequency; 10 Hz). We started iVNS at the onset of ischemia (iVNS0, n=7) or 90 min after the onset of ischemia (iVNS90, n=7) and continued to 60 min after reperfusion. One month after IR, we compared the infarct size, left ventricular (LV) function and hormonal responses among 3 groups including the no treatment group (IR, n=10). Results: Both iVNS0 and iVNS90 significantly reduced the infarct size (IR: 11.6±3.1, iVNS0: 2.4±2.1, iVNS90: 4.5±1.9%, p&lt;0.05, Figure), improved LV ejection fraction (IR: 50±7, iVNS0: 61±6, iVNS90: 60±5.1%, p&lt;0.05) and decreased LV end-diastolic pressure (IR: 14.6±1.9, iVNS0: 4.2±1.0, iVNS90: 5.0±2.8mmHg, P&lt;0.05). The benefits were larger in iVNS0 than iVNS90. Conclusion: Short term iVNS delivered prior to coronary reperfusion markedly reduced the infarct size and preserved LV function one month after ischemia. Since we can transvascularly deliver iVNS, it may serve as a new non-pharmacological therapeutic strategy and contribute to improve the long term survival in patients with AMI.

Disturbance effects of PM₁₀ on iNOS and eNOS mRNA expression levels and antioxidant activity induced by ischemia-reperfusion injury in isolated rat heart: protective role of vanillic acid.

Myocardial infarction is the acute condition of myocardial necrosis that occurs as a result of imbalance between coronary blood supply and myocardial demand. Air pollution increases the risk of death from cardiovascular diseases (CVDs). The aim of this study was to investigate the effects of particulate matter (PM) on oxidative stress, the expression of inducible nitric oxide synthase (iNOS) and endothelial nitric oxide synthase (eNOS) messenger RNA (mRNA) level induced by ischemia-reperfusion injury, and the protective effects of vanillic acid (VA) in the isolated rat heart. Male Wistar rats were randomly divided into eight groups (n = 10), namely control, VAc, sham, VA, PMa (0.5 mg/kg), PMb (2.5 mg/kg), PMc (5 mg/kg), and PMc + VA groups. Particles with an aerodynamic diameter <10 μm (PM10) was instilled into the trachea through a fine intubation tube. Two days following the PM10 instillation, the animal's hearts were isolated and transferred to a Langendorff apparatus. The hearts were subjected to 30 min of global ischemia followed by 60 min of reperfusion. The activities of superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT), xanthine oxidase (XOX), and lactate dehydrogenase (LDH) were measured using special kits. Reverse transcription polymerase chain reaction (RT-PCR) was used to determine levels of iNOS and eNOS mRNA. An increase in left ventricular end-diastolic pressure (LVEDP), S-T elevation, and oxidative stress in PM10 groups was observed. Ischemia-reperfusion (I/R) induction showed a significant augment in the expression of iNOS mRNA level and a significant decrease in the expression eNOS mRNA level. This effect was more pronounced in the PM groups than in the control and sham groups. Vanillic acid caused a significant decrease in LVEDP, S-T elevation, and also a significant difference in eNOS mRNA expression level, antioxidant enzymes, iNOS mRNA expression level, and oxidative stress occurred on myocardial dysfunction after I/R in isolated rat hearts. This study showed that PM10 exposure had devastating effects on the myocardial heart, oxidative stress, and eNOS and iNOS mRNA expression levels. Vanillic acid was able to improve these parameters. Vanillic acid as a potent antioxidant could also provide protection against particulate matter-induced toxicity.

Abstract 15989: Intracoronary Infusion of Multicellular Cardiospheres Can Be Safely Used to Prevent Adverse Remodeling in a Pig Model of Myocardial Infarction

Background: Pre-clinical studies in rodents and pigs indicate that the self-assembling microtissues known as cardiospheres (CSp), when administered intramyocardially, may be more effective than dispersed CSp-derived cells (CDCs). However, the more desirable intracoronary (IC) route has been assumed to be unsafe for CSp delivery: CSp are large (&gt;35 μm), raising concerns about likely microembolization. Objective: We sought to evaluate the safety and efficacy of IC delivery of allogeneic CSp in a porcine model of convalescent MI. Methods: Dosage was optimized by infusing CSp (3.25x10 5 particles [n=2], 6.5 x10 5 [n=3] and 1.3x10 6 [n=2], size=44±23, 29%&gt;50μm) in the LAD of naïve pigs, looking for acute adverse effects (troponin I [TnI] leak, low TIMI flow, stunning). We next tested the efficacy of IC allogeneic Csp (1.3x10 6 ; n=7) or vehicle (n=8) in a minipig model of chronic MI. Animals underwent MRI before infusion and 1 month later. Left ventricular (LV) ejection fraction (EF), scar mass and viable mass were evaluated at both time points. Results: In the dosing study, we observed no impairment of TIMI flow or LVEF after CSp infusion. TnI at 24 hours was 0.7±0.5ng/mL and did not differ among groups (P=0.11). In the post-MI study, EF was identical in the two groups at baseline. One month post-infusion, LV function was preserved in the CSp group but not in controls (ΔEF=+0.5±1.6% vs. -4.5±1.8%, p&lt;0.001). CSp reduced scar mass (P&lt;0.001) and increased viable mass (+17±8% vs. +6±6% from baseline, P=0.04) compared to controls. IC CSp also decreased LV end diastolic pressure (-7±4mmHg vs. -1±4 mmHg in control, P&lt;0.01)) and increased cardiac output (+0.5±0.4 mL/min vs. -0.1±0.3mL/min, P&lt;0.01. Conclusions: IC delivery of allogeneic CSp is safe and preserves LV function after MI. In addition, global hemodynamic improvement is observed, which may have significant clinical implications. The decision to use CDCs or CSp is not forced, therefore, by an inability to infuse CSp safely via the IC route.

Coronary Blood Flow in Patients With Severe Aortic Stenosis Before and After Transcatheter Aortic Valve Implantation

Patients with severe aortic stenosis and no obstructed coronary arteries are reported to have reduced coronary flow. Doppler evaluation of proximal coronary flow is feasible using transesophageal echocardiography. The present study aimed to assess the change in coronary flow in patients with severe aortic stenosis undergoing transcatheter aortic valve implantation (TAVI). The left main coronary artery was visualized using transesophageal echocardiography in 90 patients undergoing TAVI using the Edwards SAPIEN valve. The peak systolic and diastolic velocities of the coronary flow and the time-velocity integral were obtained before and after TAVI using pulse-wave Doppler. Mean aortic gradients decreased from 47.1 ± 15.7 mm Hg before TAVI to 3.6 ± 2.6 mm Hg after TAVI (p <0.001). The aortic valve area increased from 0.58 ± 0.17 to 1.99 ± 0.35 cm(2) (p <0.001). The cardiac output increased from 3.4 ± 1.1 to 3.8 ± 1.0 L/min (p <0.001). Left ventricular end-diastolic pressure (LVEDP) decreased from 19.8 ± 5.4 to 17.3 ± 4.1 mm Hg (p <0.001). The following coronary flow parameters increased significantly after TAVI: peak systolic velocity 24.2 ± 9.3 to 30.5 ± 14.9 cm/s (p <0.001), peak diastolic velocity 49.8 ± 16.9 to 53.7 ± 22.3 cm/s (p = 0.04), total velocity-time integral 26.7 ± 10.5 to 29.7 ± 14.1 cm (p = 0.002), and systolic velocity-time integral 6.1 ± 3.7 to 7.7 ± 5.0 cm (p = 0.001). Diastolic time-velocity integral increased from 20.6 ± 8.7 to 22.0 ± 10.1 cm (p = 0.04). Total velocity-time integral increased >10% in 43 patients (47.2%). Pearson's correlation coefficient revealed the change in LVEDP as the best correlate of change in coronary flow (R = -0.41, p = 0.003). In conclusion, TAVI resulted in a significant increase in coronary flow. The change in coronary flow was associated mostly with a decrease in LVEDP.

Mineralocorticoid and AT1 receptors in the paraventricular nucleus contribute to sympathetic hyperactivity and cardiac dysfunction in rats post myocardial infarct.

Intracerebroventricular infusion of a mineralocorticoid receptor (MR) or angiotensinII type1 receptor (AT1R) blocker in rats attenuates sympathetic hyperactivity and progressive left ventricular (LV) dysfunction post myocardial infarction (MI). The present study examined whether knockdown of MRs or AT1Rs specifically in the paraventricular nucleus (PVN) contributes to these effects, and compared cardiac effects with those of systemic treatment with the β1-adrenergic receptor blocker metoprolol. The PVN of rats was infused with adeno-associated virus carrying small interfering RNA against either MR (AAV-MR-siRNA) or AT1R (AAV-AT1R-siRNA), or as control scrambled siRNA. At 4weeks post MI, AT1R but not MR expression was increased in the PVN, excitatory renal sympathetic nerve activity and pressor responses to air stress were enhanced, and arterial baroreflex function was impaired; LV end-diastolic pressure (LVEDP) was increased and LV peak systolic pressure (LVPSP), ejection fraction (EF) and dP/dtmax decreased. AAV-MR-siRNA and AAV-AT1R-siRNA both normalized AT1R expression in the PVN, similarly ameliorated sympathetic and pressor responses to air stress, largely prevented baroreflex desensitization, and improved LVEDP, EF and dP/dtmax as well as cardiac interstitial (but not perivascular) fibrosis. In a second set of rats, metoprolol at 70 or 250mgkg(-1)day(-1) in the drinking water for 4weeks post MI did not improve LV function except for a decrease in LVEDP at the lower dose. These results suggest that in rats MR-dependent upregulation of AT1Rs in the PVN contributes to sympathetic hyperactivity, and LV dysfunction and remodelling post MI. In rats, normalizing MR-AT1R signalling in the PVN is a more effective strategy to improve LV dysfunction post MI than systemic β1 blockade.

Acute Intravenous Infusion of an Adenosine Regulating Agent Improves Left Ventricular Function in Dogs with Advanced Heart Failure

GP531 is a second generation adenosine regulating agent (ARA) that increases concentrations of endogenous adenosine, a natural cardioprotective agent, in ischemic/hypoxic tissue. This study examined the effects of acute intravenous infusions of GP531 on left ventricular (LV) systolic and diastolic function in dogs with advanced chronic heart failure (HF) (LV ejection fraction, EF <30%). Six dogs with intracoronary microembolization-induced HF received a constant intravenous infusion of GP531 (10μg/kg/min) or vehicle (normal saline) for 6h in random order 1week apart. Hemodynamic measurements were made at baseline and at 1, 2, 3, 4, 5 and 6h after initiating drug infusion. Myocardial oxygen consumption (MVO2) was measured at baseline and 4 and 6h. LV pressure-volume relationship (PVR) was measured at baseline and 6h. Vehicle infusions had no effect on indexes of LV systolic and diastolic function. GP531 infusion had no effect on heart rate or mean aortic pressure but significantly decreased LV end-diastolic pressure, end-diastolic volume, end-systolic volume and end-diastolic wall stress. GP531 significantly increased LV EF (27 ± 1 at baseline to 34 ± 1 after 6h of drug infusion, p < 0.05), deceleration time of early mitral inflow velocity and the slope of end-systolic PVR without increasing MVO2. Results of the study indicate that approaches which increase the local release of adenosine in failing LV myocardium, such as ARAs, have a favorable impact on LV performance. These observations support the continued development of ARA's for the treatment of acute HF syndromes.

Possible mechanism of the cardio-renal protective effects of AVE-0991, a non-peptide Mas-receptor agonist, in diabetic rats

This study was designed to investigate the cardio-renal protective effect of AVE-0991, a non-peptide Mas-receptor agonist, and A-779, a Mas-receptor antagonist, in diabetic rats. Wistar rats treated with streptozotocin (50 mg/kg, i.p., once), developed diabetes mellitus after 1 week. After 8 weeks, myocardial functions were assessed by measuring left ventricular developed pressure (LVDP), rate of left ventricular pressure development (dp/dt (max)), rate of left ventricular pressure decay (dp/dt (min)) and left ventricular end diastolic pressure (LVEDP) on an isolated Langendorff's heart preparation. Further, mean arterial blood pressure (MABP) was measured by using the tail-cuff method. Assessment of renal functions and lipid profile was carried out using a spectrophotometer. The administration of streptozotocin to rats produced persistent hyperglycaemia, dyslipidaemia and hypertension which consequently produced cardiac and renal dysfunction in 8 weeks. AVE0991 treatment produced cardio-renal protective effects, as evidenced by a significant increase in LVDP, dp/dt (max), dp/dt (min) and a significant decrease in LVEDP, BUN, and protein urea. Further, AVE-0991 treatment for the first time has been shown to reduce dyslipidaemia and produced antihyperglycaemic activity in streptozotocin-treated rats. However, MABP and creatinine clearance remained unaffected with AVE-0991 treatment. AVE-0991 produced cardio-renal protection possibly by improving glucose and lipid metabolism in diabetic rats, independent of its blood pressure lowering action.

Soluble epoxide hydrolase inhibition improves myocardial perfusion and function in experimental heart failure

The study addressed the hypothesis that soluble epoxide hydrolase (sEH) inhibition, which increases cardiovascular protective epoxyeicosatrienoic acids (EETs), exerts beneficial effects in an established chronic heart failure (CHF) model. In CHF rats, left ventricular (LV) function, perfusion and remodeling were assessed using MRI and invasive hemodynamics after 42-day (starting 8days after coronary ligation) and delayed 3-day (starting 47days after coronary ligation) treatments with the sEH inhibitor AUDA (twice 0.25mg/day). Delayed 3-day and 42-day AUDA increased plasma EETs demonstrating the effective inhibition of sEH. Delayed 3-day and 42-day AUDA enhanced cardiac output without change in arterial pressure, thus reducing total peripheral resistance. Both treatment periods increased the slope of the LV end-systolic pressure–volume relation, but only 42-day AUDA decreased LV end-diastolic pressure, relaxation constant Tau and the slope of the LV end-diastolic pressure–volume relation, associated with a reduced LV diastolic volume and collagen density. Delayed 3-day and, to a larger extent, 42-day AUDA increased LV perfusion associated with a decreased LV hypoxia-inducible factor-1alpha. Both treatment periods decreased reactive oxygen species level and increased reduced-oxidized glutathione ratio. Finally, MSPPOH, an inhibitor of the EET-synthesizing enzyme cytochrome epoxygenases, abolished the beneficial effects of 3-day AUDA on LV function and perfusion. Augmentation of EET availability by pharmacological inhibition of sEH increases LV diastolic and systolic functions in established CHF. This notably results from short-term processes, i.e. increased LV perfusion, reduced LV oxidative stress and peripheral vasodilatation, but also from long-term effects, i.e. reduced LV remodeling.

The Acute Hemodynamic Effects of MitraClip Therapy

The objective of this study was to evaluate the acute hemodynamic consequences of mitral valve (MV) repair with the MitraClip device (Abbott Vascular, Menlo Park, California). Whether surgical correction of mitral regurgitation (MR) results in a low cardiac output (CO) state because of an acute increase in afterload remains controversial. The acute hemodynamic consequences of MR reduction with the MitraClip device have not been studied. We evaluated 107 patients with cardiac catheterization before and immediately following percutaneous MV repair with the MitraClip device. In addition, pre- and post-procedural hemodynamic parameters were studied by transthoracic echocardiography. MitraClip treatment was attempted in 107 patients, and in 96 (90%) patients, a MitraClip was deployed. Successful MitraClip treatment resulted in: 1) an increase in CO from 5.0 ± 2.0 l/min to 5.7 ± 1.9 l/min (p = 0.003); 2) an increase in forward stroke volume (FSV) from 57 ± 17 ml to 65 ± 18 ml (p < 0.001); and 3) a decrease in systemic vascular resistance from 1,226 ± 481 dyn·s/cm(5) to 1,004 ± 442 dyn·s/cm(5) (p < 0.001). In addition, there was left ventricular (LV) unloading manifested by a decrease in LV end-diastolic pressure from 11.4 ± 9.0 mm Hg to 8.8 ± 5.8 mm Hg (p = 0.016) and a decrease in LV end-diastolic volume from 172 ± 37 ml to 158 ± 38 ml (p < 0.001). None of the patients developed acute post-procedural low CO state. Successful MV repair with the MitraClip system results in an immediate and significant improvement in FSV, CO, and LV loading conditions. There was no evidence of a low CO state following MitraClip treatment for MR. These favorable hemodynamic effects with the MitraClip appear to reduce the risk of developing a low CO state, a complication occasionally observed after surgical MV repair for severe MR.

Chronic electrical stimulation of the carotid sinus baroreflex improves left ventricular function and promotes reversal of ventricular remodeling in dogs with advanced heart failure.

Autonomic abnormalities exist in heart failure and contribute to disease progression. Activation of the carotid sinus baroreflex (CSB) has been shown to reduce sympathetic outflow and augment parasympathetic vagal tone. This study tested the hypothesis that long-term electric activation of the CSB improves left ventricular (LV) function and attenuates progressive LV remodeling in dogs with advanced chronic heart failure. Studies were performed in 14 dogs with coronary microembolization-induced heart failure (LV ejection fraction ≈25%). Eight dogs were chronically instrumented for bilateral CSB activation using the Rheos System (CVRx Inc, Minneapolis, Minn) and 6 were not and served as controls. All dogs were followed for 3 months, and none received other background therapy. During follow-up, treatment with CSB increased LV ejection fraction 4.0±2.4% compared with a reduction in control dogs of −2.8±1.0% (P<0.05). Similarly, treatment with CSB decreased LV end-systolic volume -2.5±2.7 mL compared with an increase in control dogs of 6.7±2.9 mL (P<0.05). Compared with control, CSB activation significantly decreased LV end-diastolic pressure and circulating plasma norepinephrine, normalized expression of cardiac β(1)-adrenergic receptors, β-adrenergic receptor kinase, and nitric oxide synthase and reduced interstitial fibrosis and cardiomyocyte hypertrophy. In dogs with advanced heart failure, CSB activation improves global LV function and partially reverses LV remodeling both globally and at cellular and molecular levels.

Cardiac resynchronization therapy for the causal treatment of heart failure with preserved ejection fraction: insight from a pressure–volume loop analysis

This case describes a middle-aged patient with normal ejection fraction (64%) and significant dyspnoea which could not be explained by results from routine examinations. A pressure-volume loop analysis revealed severe left ventricular (LV) dyssynchrony to be the underlying mechanism of heart failure. The patient underwent implantation of a biventricular pacemaker. Cardiac resynchronization therapy (CRT) was associated with an immediate reduction in LV dyssynchrony from 32 to 13%, decrease in LV end-diastolic pressure from 19 to 8 mmHg, and increased exercise tolerance during follow-up. Thus, CRT may be considered a causal therapy in selected patients with heart failure and preserved ejection fraction.