Treatment Of Congestive Heart Failure Research Articles

Readmissions after Implantation of Continuous Flow Left Ventricular Assist Device

Background: Based on the REMATCH (Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure) study experience, readmissions after LVAD implantation are thought to be frequent. The purpose of this study was to determine the occurrence and causes of readmissions after implantation of axial flow left ventricular assist device (LVAD).

FasL expression in cardiomyocytes activates the ERK1/2 pathway, leading to dilated cardiomyopathy and advanced heart failure.

Increase in the apoptotic molecule Fas ligand (FasL) in serum and cardiomyocytes has been shown to be associated with progressive dilated cardiomyopathy (DCM) and congestive heart failure (CHF) in humans. However, the underlying mechanism(s) of FasL-related deterioration of heart function remain obscure. The aim of the present study is to determine roles of myocardial FasL in the activation of alternative pathways such as extracellular-signal-regulated kinase 1/2 (ERK1/2), inflammation or fibrosis and to identify effective treatments of progressive DCM and advanced CHF. Transgenic mice with cardiomyocyte-specific overexpression of FasL were investigated and treated with an ERK1/2 inhibitor (U-0126), losartan (los), prednisolone (pred) or placebo. Morpho-histological and molecular studies were subsequently performed. FasL mice showed significantly higher mortality compared with wild-type (WT) littermates due to DCM and advanced CHF. Prominent perivascular and interstitial fibrosis, increased interleukin secretion and diffuse CD3-positive cell infiltration were evident in FasL hearts. Up-regulation of the short form of Fas-associated death domain (FADD)-like interleukin 1β-converting enzyme (FLICE) inhibitory protein (s-FLIP), RIP (receptor-interacting protein) and ERK1/2 and down-regulation of transforming growth factor beta 1 (TGFβ1) and nuclear factor-κB (NF-κB) was determined in the myocardium, whereas expression of ERK1/2, periostin (Postn) and osteopontin increased in cardiac fibroblasts. U-0126 and los increased CHF survival by 75% compared with pred and placebo groups. U-0126 had both anti-fibrotic and anti-apoptotic effects, whereas los reduced fibrosis only. Myocardial FasL expression in mice activates differential robust fibrotic, apoptotic and inflammatory responses via ERK1/2 in cardiomyocytes and cardiac fibroblasts inducing DCM and CHF. Blocking the ERK1/2 pathway prevented progression of FasL-induced DCM and CHF by reducing fibrosis, inflammation and apoptosis in the myocardium.

Optimal Use of Beta-Blockers for Congestive Heart Failure.

Beta-blockers are the cornerstone treatment for congestive heart failure (HF). Current HF guidelines commonly recommend β-blockers for the treatment of HF with reduced left ventricular ejection fraction (LVEF). The effect of β-blockers, however, is less clear for HF patients with preserved LVEF, unstable severe acute HF, or right ventricular failure. This review summarizes the effect of β-blockers in various clinical situations and suggests a strategy for optimal use. (Circ J 2016; 80: 565-571).

Effect of myocardial dysfunction in cardiac morbidity and all cause mortality in childhood cancer subjects treated with anthracycline therapy.

BackgroundSubacute cardiotoxicity, consisting of acute myocyte damage and associated left ventricular dysfunction, occurs early during anthracycline therapy. We investigated the impact of myocardial dysfunction, defined herein by a shortening fraction (SF) < 29 % at any time during or after anthracycline therapy, on late onset cardiomyopathy and all-cause mortality, among childhood cancer survivors exposed to anthracyclines. In addition, we sought to identify subpopulations of subjects at highest risk for cardiomyopathy and death from all causes.MethodsFive hundred thirty-one childhood cancer survivors exposed to anthracyclines were enrolled and studied on average 10 (1.4–27.3) years following their initial exposure. The medical records were reviewed to identify known risk factors associated with cardiotoxicity, including cumulative anthracycline dose, length of post-therapy interval, administration of other cardiotoxic medications (vinca alkaloids), previous heart disease, radiation dose to the heart, history of bone marrow transplantation, age at treatment, gender, systolic dysfunction, and history of congestive heart failure during anthracycline therapy.ResultsNinety subjects (16.9 %) developed SF < 29 % and 71 patients (13.4 %) died on average 10 years after initial exposure (range 1.4–27.3 years). Total cumulative dose (OR 3.27, 95 % CI 1.94, 5.49, p < 0.001) and bone marrow transplantation (OR 2.57, 95 % CI 1.24, 5.30, p = 0.01) were found to be statistically significant risk factors for development of myocardial dysfunction. There was a 3-fold increase in the odds of having a SF < 29 % at any point during or following cancer therapy if a subject underwent bone marrow transplantation or had a total cumulative dose anthracycline therapy ≥ 240 mg/m2. The all-cause mortality ratio was almost seven-fold higher (95 % CI, 2.40-fold to 17.81-fold higher) if a subject developed systolic dysfunction, defined by a previous SF < 29 % anytime during or after anthracycline therapy. Nine deaths (12.7 %) were attributed to cardiovascular disease. The risk of dying as a result of cardiac disease also was significantly higher in individuals who had a SF < 29 % at any time during or after therapy.ConclusionsThis study demonstrates an almost seven-fold increase in all cause mortality in pediatric cancer survivors with a history of anthracycline induced myocardial dysfunction defined as SF < 29 %.

Abstract 19201: Clinical Impact of Cardiac Regenerative Therapy With Autologous Skeletal Stem Cell Sheet Implantation on Treating Severe Heart Failure

Background: Transplantation of autologous somatic tissue-derived cells into the heart has been shown to yield functional recovery of the failing heart via “paracrine effects” that enhance the native regenerative process. We have introduced skeletal stem cell (SSC) sheet methods for treating severe heart failure (HF), in which scaffold-free cell-sheets are attached on the epicardial surface to maximize the paracrine effects. We herein report feasibility, safety and efficacy of SSC sheet transplantation for treating advanced HF. Methods: This study enrolled 27 patients (mean age, 51±15 years, DCM in 15 patients and ICM in 12 patients) with chronic advanced HF despite optimum treatments. Scaffold-free cell-sheets containing SSC (average: 3.5±1.9х108 cells) was transplanted over the left ventricular (LV) free wall via the left thoracotomy. Average follow-up was 2.5 (0.6-5.1) years. Results: All patients discharged from the hospital without procedure-related complications. Re-In-hospital treatment for congestive HF was required in 8 patients, who we defined as non-responder (Group N: n=8), while the other patients who were free from in-hospital cardiac treatments were defined as responder (Group R: n=19). The Group R exhibited decreased NYHA functional class (2.8±0.6 to 1.6±1.1 p&lt;0.05) and increased 6-minute walk test (444±110 to 499±114m p&lt;0.05) at 6 months, while these values maintained until the latest follow-up. Echocardiographically, LV systolic and diastolic diameters significantly decreased and ejection fraction significantly increased. In addition, both LV end-systolic and diastolic wall stress, assessed by cardiac CT scanning, significantly decreased (systolic: 377±76 to 317±88, diastolic: 116±98 to 51±32 kdynes/cm2, p&lt;0.05 respectively) in the Group R. Multivariate analysis showed that preoperative duration of HF was a single independent risk factor for Group N with its hazard ratio 1.8 (p&lt;0.05). Three-year freedom from cardiac death was 92%, while that from recurrence of HF was 70%. Conclusions: SSC sheet transplantation was feasible and safe in advanced HF patients. Functional recovery, including reduced LV wall stress, was gained in the selected patients, who received this treatment in early stage of advanced HF.

Importance of Angina in Patients With Coronary Disease, Heart Failure, and Left Ventricular Systolic Dysfunction: Insights From STICH

BackgroundPatients with left ventricular (LV) systolic dysfunction, coronary artery disease (CAD), and angina are often thought to have a worse prognosis and a greater prognostic benefit from coronary artery bypass graft (CABG) surgery than those without angina. ObjectivesThis study investigated: 1) whether angina was associated with a worse prognosis; 2) whether angina identified patients who had a greater survival benefit from CABG; and 3) whether CABG improved angina in patients with LV systolic dysfunction and CAD. MethodsWe performed an analysis of the STICH (Surgical Treatment for Ischemic Heart Failure) trial, in which 1,212 patients with an ejection fraction ≤35% and CAD were randomized to CABG or medical therapy. Multivariable Cox and logistic models were used to assess long-term clinical outcomes. ResultsAt baseline, 770 patients (64%) reported angina. Among patients assigned to medical therapy, all-cause mortality was similar in patients with and without angina (hazard ratio [HR]: 1.05; 95% confidence interval [CI]: 0.79 to 1.38). The effect of CABG was similar whether the patient had angina (HR: 0.89; 95% CI: 0.71 to 1.13) or not (HR: 0.68; 95% CI: 0.50 to 0.94; p interaction = 0.14). Patients assigned to CABG were more likely to report improvement in angina than those assigned to medical therapy alone (odds ratio: 0.70; 95% CI: 0.55 to 0.90; p < 0.01). ConclusionsAngina does not predict all-cause mortality in medically treated patients with LV systolic dysfunction and CAD, nor does it identify patients who have a greater survival benefit from CABG. However, CABG does improve angina to a greater extent than medical therapy alone. (Comparison of Surgical and Medical Treatment for Congestive Heart Failure and Coronary Artery Disease [STICH]; NCT00023595)

The preventive role of levosimendan against bleomycin-induced pulmonary fibrosis in rats

In this study, the effects of levosimendan used in the treatment of acute congestive heart failure upon pulmonary fibrosis in rats induced with bleomycin (BL) were analyzed. A total of 33 male Sprague-Dawley type rats were categorized into five groups randomly. About 2.5U/kg BL was intratracheally administered to the rats in the BL, BL+L1, BL+L2, and BL+L3 groups, and 0.9% saline was intratracheally administered at the same rate to the control group. 0.3, 1, and 3mg/kg levosimendan was intraperitoneally administered to the BL+L1, BL+L2, and BL+L3 groups, respectively. Blood and tissue samples were taken from the rats euthanized to determine the changes in erythrocyte enzyme activities and to conduct histopathological evaluations after 14 days. With values between 0 and 3, histopathological scoring damage was assessed by the presence of inflammation and fibrosis in a semiquantitative manner. Compared with those in the C group, glutathione reductase (GR) and Catalase (CAT) enzymes decreased in the BL group; compared with that in the BL group, GR increased in the BL+L1 and BL+L3 groups, 6-phosphogluconate dehydrogenase (6PGD) increased in the BL+L3 group, and CAT increased in the BL+L2 and BL+L3 groups (p<0.05). In the histopathological evaluation, fibrosis occurred in all rats in the BL group, and tissue damage was noticed to be generally less in the BL+L1, BL+L2, and BL+L3 groups (p<0.001). The results obtained from biochemical and histopathological evaluations indicate that levosimendan had an anti-fibrotic effect without a dose-dependent response on pulmonary fibrosis.

Change in Renal Perfusion by Treatment of Congestive Heart Failure Using Contrastenhanced Ultrasonography

Change in Renal Perfusion by Treatment of Congestive Heart Failure Using Contrastenhanced Ultrasonography

Successful Treatment of Congestive Heart Failure Due to Severe Aortic Valve Stenosis with Low Dose Tolvaptan in Old Patients

BackgroundSymptomatic patients with severe aortic stenosis (AS) are usually are operative candidates because medical therapy has little to offer. Tolvaptan (TLV) treatment resulted in favorable but modest changes in filling pressures associated with a significant increase in urine output. Therefore, TLV is a potential candidate to improve decompensated heart failure due to severe AS without hemodynamic instability.MethodsWe retrospectively investigated 5 patients over 80 years of age who admitted due to decompensated congestive heart failure with severe AS and treated with tolvaptan from April 2014 to March 2015.ResultsFour females and a male were examined. Mean age was 90.6±6.6 years. Compared to total urine volume of the day before treatment, those of the first day were increased (928±478 vs. 1203±517 ml, P=0.03). Urine osmolality tended to be increased in the first day of treatment (408±137 vs. 261±155 mOsm, P=0.06). NYHA classification was significantly improved 1 week after treatment (3.8±0.4 vs. 3.0±0.0, P=0.02). BNP levels were decreased 1 week after TLV treatment and at discharge (1264±796 vs. 635±470 pg/mL, P=0.03, vs. 538±343 pg/mL, P=0.03, respectively). Severe adverse events, including death, cardiogenic shock did not occur during TLV treatment.ConclusionsTLV treatment safely improved decompensated heart failure due to AS in old patients. Further prospective studies are warranted to confirm these results. BackgroundSymptomatic patients with severe aortic stenosis (AS) are usually are operative candidates because medical therapy has little to offer. Tolvaptan (TLV) treatment resulted in favorable but modest changes in filling pressures associated with a significant increase in urine output. Therefore, TLV is a potential candidate to improve decompensated heart failure due to severe AS without hemodynamic instability. Symptomatic patients with severe aortic stenosis (AS) are usually are operative candidates because medical therapy has little to offer. Tolvaptan (TLV) treatment resulted in favorable but modest changes in filling pressures associated with a significant increase in urine output. Therefore, TLV is a potential candidate to improve decompensated heart failure due to severe AS without hemodynamic instability. MethodsWe retrospectively investigated 5 patients over 80 years of age who admitted due to decompensated congestive heart failure with severe AS and treated with tolvaptan from April 2014 to March 2015. We retrospectively investigated 5 patients over 80 years of age who admitted due to decompensated congestive heart failure with severe AS and treated with tolvaptan from April 2014 to March 2015. ResultsFour females and a male were examined. Mean age was 90.6±6.6 years. Compared to total urine volume of the day before treatment, those of the first day were increased (928±478 vs. 1203±517 ml, P=0.03). Urine osmolality tended to be increased in the first day of treatment (408±137 vs. 261±155 mOsm, P=0.06). NYHA classification was significantly improved 1 week after treatment (3.8±0.4 vs. 3.0±0.0, P=0.02). BNP levels were decreased 1 week after TLV treatment and at discharge (1264±796 vs. 635±470 pg/mL, P=0.03, vs. 538±343 pg/mL, P=0.03, respectively). Severe adverse events, including death, cardiogenic shock did not occur during TLV treatment. Four females and a male were examined. Mean age was 90.6±6.6 years. Compared to total urine volume of the day before treatment, those of the first day were increased (928±478 vs. 1203±517 ml, P=0.03). Urine osmolality tended to be increased in the first day of treatment (408±137 vs. 261±155 mOsm, P=0.06). NYHA classification was significantly improved 1 week after treatment (3.8±0.4 vs. 3.0±0.0, P=0.02). BNP levels were decreased 1 week after TLV treatment and at discharge (1264±796 vs. 635±470 pg/mL, P=0.03, vs. 538±343 pg/mL, P=0.03, respectively). Severe adverse events, including death, cardiogenic shock did not occur during TLV treatment. ConclusionsTLV treatment safely improved decompensated heart failure due to AS in old patients. Further prospective studies are warranted to confirm these results. TLV treatment safely improved decompensated heart failure due to AS in old patients. Further prospective studies are warranted to confirm these results.

Severity of Remodeling, Myocardial Viability, and Survival in Ischemic LV Dysfunction After Surgical Revascularization

ObjectivesThis study sought to test the hypothesis that end-systolic volume (ESV), as a marker of severity of left ventricular (LV) remodeling, influences the relationship between myocardial viability and survival in patients with coronary artery disease and LV systolic dysfunction. BackgroundRetrospective studies of ischemic LV dysfunction suggest that the severity of LV remodeling determines whether myocardial viability predicts improved survival with surgical compared with medical therapy, with coronary artery bypass grafting (CABG) only benefitting patients with viable myocardium who have smaller ESV. However, this has not been tested prospectively. MethodsInteractions of end-systolic volume index (ESVI), myocardial viability, and treatment with respect to survival were assessed in patients in the prospective randomized STICH (Comparison of Surgical and Medical Treatment for Congestive Heart Failure and Coronary Artery Disease) trial of CABG versus medical therapy who underwent viability assessment (n = 601; age 61 ± 9 years; ejection fraction ≤35%), with a median follow-up of 5.1 years. Median ESVI was 84 ml/m2. Viability was assessed by single-photon emission computed tomography or dobutamine echocardiography using pre-specified criteria. ResultsMortality was highest among patients with larger ESVI and nonviability (p < 0.001), but no interaction was observed between ESVI, viability status, and treatment assignment (p = 0.491). Specifically, the effect of CABG versus medical therapy in patients with viable myocardium and ESVI ≤84 ml/m2 (hazard ratio [HR]: 0.85; 95% confidence interval [CI]: 0.56 to 1.29) was no different than in patients with viability and ESVI >84 ml/m2 (HR: 0.87; 95% CI: 0.57 to 1.31). Other ESVI thresholds yielded similar results, including ESVI ≤60 ml/m2 (HR: 0.87; 95% CI: 0.44 to 1.74). ESVI and viability assessed as continuous rather than dichotomous variables yielded similar results (p = 0.562). ConclusionsAmong patients with ischemic cardiomyopathy, those with greater LV ESVI and no substantial viability had worse prognosis. However, the effect of CABG relative to medical therapy was not differentially influenced by the combination of these 2 factors. Lower ESVI did not identify patients in whom myocardial viability predicted better outcome with CABG relative to medical therapy. (Comparison of Surgical and Medical Treatment for Congestive Heart Failure and Coronary Artery Disease [STICH]; NCT00023595)

Towards destination therapy with left ventricular assist devices in Japan.

Medical and electrical therapies for systolic heart failure have improved outcomes and altered the natural history of the disease. Although heart transplantation remains the most successful treatment option for patients with advanced heart failure refractory for these treatment, cardiac transplantation is available for only a minority of patients because of the lack of suitable donor hearts. As a consequence of limited donor availability, left ventricular assist device (LVAD) therapy has become an established treatment for patients with advanced heart failure as either a bridge to transplantation (BTT) or as a permanent alternative to transplantation, i.e., destination therapy (DT). The Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH) trial provided a firm albeit inauspicious proof of concept for the use of blood pumps as an alternative to medical therapy in patients not eligible for transplantation. Small continuous-flow LVADs improved the probability of survival and reduced the risk of device failure compared to larger pulsatile-flow LVADs. Axialflow LVADs have been the most popular option for mechanical circulatory support. Along with axial-flow blood pumps, some centrifugal blood pumps have also been developed aiming at achieving mechanical circulatory support as well as long-term durability.

Abstract 3795: Cardiac glycoside digitoxin and its monosaccharide analogue MonoD inhibit NFκB to induce apoptotic cell death in ER+ MCF7 and triple-negative MDAMB-468 breast cancer cells

Abstract Digitoxin, a cardiac glycoside well appreciated in the treatment of congestive heart failure, has been poorly understood and appreciated as an anti-cancer therapeutic due to its narrow therapeutic potential. Using a patented palladium-catalyzed de novo synthesis method, we have developed a library of digitoxin analogs, which alleviate the toxic side effects of digitoxin while maintaining its chemical activity. We have evaluated MonoD, a digitoxin analog with a single sugar moiety, in a variety of NCI-60 panel of cell lines, with a significant tumoristatic effect observed in estrogen receptor positive and triple negative breast cancer cells. Therefore, in order to determine the efficacy of digitoxin and MonoD, delineate its mode of action and identify molecular targets we chose to test this novel compound in ER+ MCF7 and TN MDAMB-468 breast cancer cells. Digitoxin and MonoD showed a dose dependent decrease in cell viability in MCF7 and MDAMB-468 cell lines. Further characterization of cell death using the Hoechst assay showed that MonoD induced significantly higher apoptosis at the same dose as digitoxin. Both drugs induce oxidative stress in the form of superoxide as assayed using Dihydroethidium (DHE). In vitro scratch migration assay showed a five-fold decrease in rate of cell migration in the presence of test drugs. MCF7 and MDAMB-468 cells were analyzed for cell cycle progression in the presence of digitoxin and MonoD. We observed that the drugs induced cell cycle arrest in G0/G1 phase at the expense of S and G2/M phases. Increased expression of p27Kip1 in the presence of drugs provided further validation, as increased p27 expression is known to block cell cycle progression through G1-S transition. In addition to cell cycle arrest, apoptosis is another widely accepted mechanism by which anti-cancer drugs inhibit tumor formation. We observed that these drugs induced apoptosis as indicated by cleaved PARP and cleaved caspase-9, in addition to down-regulation of pro-survival factor Bcl-2. NFκB has been reported to be constitutively active in many types of cancer by controlling the expression of several genes involved in cellular proliferation and apoptosis. We observed that NFκB expression was down-regulated in both cell lines with digitoxin and MonoD treatment. IKKβ, a critical kinase involved in regulating NFκB pathway showed significant down-regulation, thereby suggesting that these drugs exert their anti-cancer therapeutic potential through the inhibition of NFκB pathway. While additional work is required to establish their mode of action, we have sufficient evidence to hypothesize that down-regulation of NFκB is critical to the mode of action of these drugs. Further, it is evident from densitometric analyses of western blots, MTT and Hoechst assays that MonoD shows higher efficacy as compared to digitoxin in inducing cancer cell death. Citation Format: Yogesh Kulkarni, Vivek Kaushik, Raj Venkatadri, Clayton Wright, Juan Sebastian Yakisich, George O'Doherty, Neelam Azad, Anand Iyer. Cardiac glycoside digitoxin and its monosaccharide analogue MonoD inhibit NFκB to induce apoptotic cell death in ER+ MCF7 and triple-negative MDAMB-468 breast cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3795. doi:10.1158/1538-7445.AM2015-3795

Toward hybrid force/position control for the Cerberus epicardial robot.

Gene therapies have emerged as a promising treatment for congestive heart failure, yet they lack a method for minimally invasive, uniform delivery. To address this need we developed Cerberus, a minimally invasive parallel wire robot for cardiac interventions. Prior work on Cerberus was limited to controlling the device using only position feedback. In order to ensure safety for both the patient and the device, as well as to improve the performance of the device, this paper presents work on enhancing the existing system with force feedback capabilities. By modeling the statics of the system and developing a tension distribution optimization technique, existing position control schemes were modified to a hybrid force/position controller. Experimental results show that using a hybrid force-position control scheme as opposed to position decreases positioning error by 38%.

Serum Level of Heart-Type Fatty Acid Binding Protein (H-FABP) Before and After Treatment of Congestive Heart Failure in Children.

Remodeling of the heart following injury affects the morbidity and mortality in children presented with heart failure (HF). Heart-type fatty acid binding protein (H-FABP) is a novel biomarker that could be of help to predict the prognosis and risk stratification in those children. We aimed to evaluate the diagnostic and prognostic value of H-FABP in children with heart failure before and after treatment. The study was conducted as a prospective cohort study. It included 30 children with HF as a patient group and 20 healthy children matched for age and sex as a control group. Echocardiographic assessment of the heart was done using conventional Doppler echocardiography. Serum levels of (H-FABP) were measured using enzyme-linked immunosorbent assay before and after treatment of HF. All patients were observed during follow-up period of 3months. There was a significant difference in the serum level of H-FABP in our patients before treatment (5.278±3.253ng/ml) compared with after treatment (2.089±0.160ng/ml) with significant difference compared with the control group. There was a significant increase in the serum level of H-FABP with increase in the severity of heart failure according to Ross classification. Significant increase in the H-FABP was associated with adverse outcome. Serum levels of H-FABP strongly correlated with clinical and echocardiographic assessment of LV performance of children with HF, and its levels significantly increased in children with adverse outcome suggesting its value as a useful diagnostic and prognostic predictor (with high sensitivity and specificity).

Перспективы блокады ренин-ангиотензин-альдестероновой системы и модуляции системы натрийуретических пептидов в лечении артериальной гипертонии и сердечной недостаточности

Перспективы блокады ренин-ангиотензин-альдестероновой системы и модуляции системы натрийуретических пептидов в лечении артериальной гипертонии и сердечной недостаточности

Cardiohemodynamic and electrophysiological effects of a selective EP4 receptor agonist ONO­-AE1­-329 in the halothane-anesthetized dogs

Cardiovascular effects of a highly selective prostaglandin E2 type 4 (EP4) receptor agonist ONO-AE1-329 were assessed with the halothane-anesthetized dogs (n=6). ONO-AE1-329 was intravenously infused in three escalating doses of 0.3, 1 and 3ng/kg/min for 10min with a pause of 20min between the doses. The low dose of 0.3ng/kg/min significantly increased maximum upstroke velocity of left ventricular pressure by 18% at 20min, indicating increase of ventricular contractility. The middle dose of 1ng/kg/min significantly decreased total peripheral resistance by 24% and left ventricular end-diastolic pressure by 32% at 10min, indicating dilation of arteriolar resistance vessels and venous capacitance ones, respectively; and increased cardiac output by 25% at 10min in addition to the change induced by the low dose. The high dose of 3ng/kg/min increased heart rate by 34% at 10min; decreased mean blood pressure by 14% at 10min and atrioventricular nodal conduction time by 13% at 5min; and shortened left ventricular systolic period by 8% at 10min and electromechanical coupling defined as an interval from completion of repolarization to the start of ventricular diastole by 39% at 10min in addition to the changes induced by the middle dose. No significant change was detected in a ventricular repolarization period. These results indicate that ONO-AE1-329 may possess a similar cardiovascular profile to typical phosphodiesterase 3 inhibitors as an inodilator, and suggest that EP4 receptor stimulation can become an alternative strategy for the treatment of congestive heart failure.

Cardiac CT Angiography in Congestive Heart Failure.

Cardiac CT angiography has become an important tool for the diagnosis and treatment of congestive heart failure. Differentiation of ischemic from nonischemic cardiomyopathy; evaluation of myocardial perfusion; characterization of hypertrophic cardiomyopathy, left ventricular noncompaction, and arrhythmogenic right ventricular dysplasia; and delineation of congenital heart defects and valvular abnormalities are the primary diagnostic applications. Therapeutic use includes visualization of the coronary venous anatomy for optimal implementation of cardiac resynchronization therapy and evaluation of left ventricular assist devices and transplant vasculopathy.

Pharmacokinetics and cardiovascular effects following a single oral administration of a nonaqueous pimobendan solution in healthy dogs.

Pimobendan is an inodilator used in the treatment of canine congestive heart failure (CHF). The aim of this study was to investigate the pharmacokinetics and cardiovascular effects of a nonaqueous oral solution of pimobendan using a single-dose, operator-blinded, parallel-dose study design. Eight healthy dogs were divided into two treatment groups consisting of water (negative control) and pimobendan solution. Plasma samples and noninvasive measures of cardiovascular function were obtained over a 24-h period following dosing. Pimobendan and its active metabolite were quantified using an ultra-high-performance liquid chromatography-mass spectrometer (UHPLC-MS) assay. The oral pimobendan solution was rapidly absorbed [time taken to reach maximum concentration (Tmax ) 1.1 h] and readily converted to the active metabolite (metabolite Tmax 1.3 h). The elimination half-life was short for both pimobendan and its active metabolite (0.9 and 1.6 h, respectively). Maximal cardiovascular effects occurred at 2-4 h after a single oral dose, with measurable effects occurring primarily in echocardiographic indices of systolic function. Significant effects persisted for <8 h. The pimobendan nonaqueous oral solution was well tolerated by study dogs.

192. Regulated Atrial Natriuretic Peptide Expression with a Novel Spatiotemporal AAV Vector Cassette for Treating Congestive Heart Failure

Patients suffering from congestive heart failure (CHF) are vulnerable to a fluid overloaded state, contributing to significant morbidity and the mortality of ~287,000 patients per year in the US. This vulnerability is in part mediated by a dysregulation of atrial natriuretic peptide (ANP) – a molecule acting on kidneys to induce diuresis. Multiple preclinical studies show that injecting pre-synthesized ANPs can induce diuresis, however pre-synthesized ANPs degrade rapidly making their impact only transient. Sustained ANP-mediated diuresis may provide a novel approach to curb fluid retention. To this end, we hypothesize that the use of AAV9 vectors will mediate delivery of a more biologically active version of ANP (aka mANP) in the context of a cardiomyocyte-specific, tetracycline-regulated expression cassette. Methodology – For temporal regulation we inserted a Tet-On 3G System into an AAV cassette (AAV-Tet). For cardiac restricted expression we also introduced a cardiomyocyte specific regulatory element. Preliminary Data – Doxycycline specifically induces expression in vitro of all tested genes, i.e. mANP, EGFP, and firefly luciferase (Luc). Regulation is tight, showing Luc expression increases of ~2000-fold over baseline. Using murine models we are currently accessing the pharmacokinetics of the AAV9-Tet vectors. Finally, diuretic potentials will be assessed in murine models of CHF. Conclusion – The spatiotemporally regulated mANP AAV vectors being developed herein could represent a new paradigm for treatment in CHF.

Endogenous Digitalis-Like Factors: An Overview of the History

The sodium pump is a ubiquitous cell surface enzyme, a Na, K ATPase, which maintains ion gradients between cells and the extracellular fluid (ECF). The extracellular domain of this enzyme contains a highly conserved binding site, a receptor for a plant derived family of compounds, the digitalis glycosides. These compounds inhibit the enzyme and are used in the treatment of congestive heart failure and certain cardiac arrhythmias. The highly conserved nature of this enzyme and its digitalis receptor led to early suggestions that endogenous regulators might exist. Recent examination of this hypothesis emerged from research in two separate areas: the regulation of ECF volume by a natriuretic hormone (NH), and the regulation of peripheral vascular resistance by a circulating inhibitor of vascular Na, K ATPase. These two areas merged with the hypothesis that NH and the vascular Na, K ATPase inhibitor were in fact the same entity, and that it played a causative role in the pathophysiology of certain types of hypertension. The possibility that multiple endogenous digitalis-like factors (EDLFs) exist emerged from efforts to characterize the circulating enzyme inhibitory activity. In this review, the development of this field from its beginnings is traced, the current status of the structure of EDLFs is briefly discussed, and areas for future development are suggested.