3071Peptidomimetic targeting of CavBeta2 improves contractility in models of senescence- or genetically (MYBPC3 KI)-induced heart failure

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
B El-Mathari ◽  
P Briand ◽  
A Corbier ◽  
B Poirier ◽  
S Le-Claire ◽  
...  
Keyword(s):  
Heart Failure ◽  
Heart Rate ◽  
Ejection Fraction ◽  
Stroke Volume ◽  
Dilated Cardiomyopathy ◽  
Diastolic Function ◽  
Myocardial Contractility ◽  
Calcium Release ◽  
Applied Pressure ◽  
Systolic Pressure

Abstract Background L-type calcium channel (LTCC) trafficking controls LTCC density at T-tubule levels for optimal Excitation-Coupling (EC) and resultant adaptive heart work. In some forms of heart failure (HF), abnormalities in calcium-induced calcium-release have been proposed to arise from alteration of T-tubular dyad architecture (LTCC-RyRs) associated with impaired LTCC density. Recently, the R7W-MP peptide, working as a binder of the LTCC Cavβ2 chaperone, was shown to restore the altered density of LTCC current by both promoting forward and reducing reverse trafficking, which consequently improved cellular calcium homeostasis. Accordingly, R7W-MP improved the impaired cardiomyocyte calcium current density and the reduced Ejection Fraction (EF%) in a pharmacologically-induced diabetes model (STZ mice). We aimed to investigate further the benefit to improve LTCC trafficking pathway with R7W-MP in a more physiological model of HF (senescent mice) and in a Dilated Cardiomyopathy (DCM) model (HO MYBPC3 targeted KI mutant). Methods Senescent male C57Bl/6J mice (26 months) or HO MYBPC3 KI male mice (2 months) were treated with R7W-MP (3 mg/kg/d IP for 3 days). Echocardiographies (echo) were conducted before treatment and 4-hours after the last injection. When applied, Pressure-Volume (PV)-loop investigations were conducted one day post-echo 4 hours following an additional R7W-MP injection. Results In senescent mice population, HF was characterized by a midrange ejection fraction (EF%= 43±2 vs 55±1 for young adult mice) associated with enlarged ventricles and decreased cardiac contractility. In contrast to a scrambled peptide (scrP), R7W-MP markedly increased EF% monitored by echo (+38%, 63±3 vs 45±1 for scrP, p≤0.001, n=6–7) without modification of heart rate. EF% improvement was confirmed by PV-loop analysis (78±3 vs 51±4 for scrP (+54%), p≤0.001, n=5), associated with a marked, although not significant, 2.5-fold increase in myocardial contractility [end systolic pressure volume relationship (ESPVR) = 12.1±3.6 vs 4.9±1.3 for scrP, p=0.10, n=4]. Stroke volume, cardiac output and end diastolic volume tended to decrease suggesting an impaired LV filling at this dose regimen. In the DCM model, HF was more severe with a dramatically low EF% (26±1, n=8), impaired myocardial contractility and a pronounced left ventricle enlargement. R7W-MP significantly increased EF% (+17%, reaching 31±1, p≤0.01, n=8) without altering heart rate. Stroke volume was significantly increased by 36% (32±3 vs 24±3 mL at baseline, p≤0.01), without any impairment of diastolic function. All parameters returned to baseline after a 2 week-washout period. Conclusions R7W-MP displays potent positive inotrope properties in senescent or DCM mice models. Although further asses tsments of diastolic function are needed (different dosing and duration), these data underline the potential benefit brought by LTCC trafficking modulation to treat severe dilated cardiomyopathy.

First clinical trial with etomoxir in patients with chronic congestive heart failure

2000 ◽  
Vol 99 (1) ◽  
pp. 27-35 ◽  
Author(s):  
Stephan SCHMIDT-SCHWEDA ◽  
Christian HOLUBARSCH
Keyword(s):  
Heart Failure ◽  
Heart Rate ◽  
Sarcoplasmic Reticulum ◽  
Left Ventricular Ejection Fraction ◽  
Ejection Fraction ◽  
Stroke Volume ◽  
Left Ventricular ◽  
Ventricular Ejection ◽  
Left Ventricular Ejection ◽  
Ventricular Ejection Fraction

In the failing human myocardium, both impaired calcium homoeostasis and alterations in the levels of contractile proteins have been observed, which may be responsible for reduced contractility as well as diastolic dysfunction. In addition, levels of a key protein in calcium cycling, i.e. the sarcoplasmic reticulum Ca2+-ATPase, and of the α-myosin heavy chain have been shown to be enhanced by treatment with etomoxir, a carnitine palmitoyltransferase inhibitor, in normal and pressure-overloaded rat myocardium. We therefore studied, for the first time, the influence of long-term oral application of etomoxir on cardiac function in patients with chronic heart failure. A dose of 80 mg of etomoxir was given once daily to 10 patients suffering from heart failure (NYHA functional class II–III; mean age 55±4 years; one patient with ischaemic heart disease and nine patients with dilated idiopathic cardiomyopathy; all male), in addition to standard therapy. The left ventricular ejection fraction was measured echocardiographically before and after a 3-month period of treatment. Central haemodynamics at rest and exercise (supine position bicycle) were defined by means of a pulmonary artery catheter and thermodilution. All 10 patients improved clinically; no patient had to stop taking the study medication because of side effects; and no patient died during the 3-month period. Maximum cardiac output during exercise increased from 9.72±1.25 l/min before to 13.44±1.50 l/min after treatment (P < 0.01); this increase was mainly due to an increased stroke volume [84±7 ml before and 109±9 ml after treatment (P < 0.01)]. Resting heart rate was slightly reduced (not statistically significant). During exercise, for any given heart rate, stroke volume was significantly enhanced (P < 0.05). The left ventricular ejection fraction increased significantly from 21.5±2.6% to 27.0±2.3% (P < 0.01). In acute studies, etomoxir showed neither a positive inotropic effect nor vasodilatory properties. Thus, although the results of this small pilot study are not placebo-controlled, all patients seem to have benefitted from etomoxir treatment. Etomoxir, which has no acute inotropic or vasodilatory properties and is thought to increase gene expression of the sarcoplasmic reticulum Ca2+-ATPase and the α-myosin heavy chain, improved clinical status, central haemodynamics at rest and during exercise, and left ventricular ejection fraction.

Abstract 13421: Ventricular and Arterial Elastance During Isometric Handgrip Exercise and Post-exercise Circulatory Arrest in Heart Failure With and Without Preserved Ejection Fraction

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Naoki Fujimoto ◽  
Keishi Moriwaki ◽  
Issei Kameda ◽  
Masaki Ishiyama ◽  
Taku Omori ◽  
...  
Keyword(s):  
Heart Failure ◽  
Blood Pressure ◽  
Heart Rate ◽  
Ejection Fraction ◽  
Circulatory Arrest ◽  
Systolic Pressure ◽  
Left Ventricular ◽  
Isometric Handgrip ◽  
Arterial Elastance ◽  
Post Exercise

Introduction: Isometric handgrip (IHG) training at 30% maximal voluntary contraction (MVC) lowers blood pressure in hypertensive patients. Impacts of IHG exercise and post-exercise circulatory arrest (PECA), which isolates metaboreflex control, have been unclear in heart failure (HF). Purpose: To investigate the impacts of IHG exercise and PECA on ventricular-arterial stiffness and left ventricular (LV) relaxation in HF with preserved (HFpEF) and reduced ejection fraction (HFrEF). Methods: We invasively obtained LV pressure-volume (PV) loops in 20 patients (10 HFpEF, 10 HFrEF) using conductance catheter with microtip-manometer during 3 minutes of IHG at 30%MVC and 3 minutes of PECA. Hemodynamics and LV-arterial function including LV end-systolic elastance (Ees) by the single-beat method, effective arterial elastance (Ea), and time constant of LV relaxation (Tau) were evaluated every minute. Results: At rest, HFpEF had higher LV end-systolic pressure (ESP) and lower heart rate than HFrEF with similar LV end-diastolic pressure (EDP). The coupling ratio (Ees/Ea) was greater in HFpEF than HFrEF (1.0±0.3 vs. 0.6±0.3, p<0.01). IHG for 3minutes similarly increased heart rate in HFpEF (by 10±8 bpm) and HFrEF (by 14±6 bpm). IHG also increased end-diastolic and LVESP (134±21 vs. 158±30 mmHg and 113±25 vs. 139±25 mmHg) in both groups (groupхtime effect p≥0.25). In HFpEF, Ees, Ea and Ees/Ea (1.0±0.3 vs. 1.1±0.4) were unaffected during IHG. In HFrEF, IHG induced variable increases in Ea. LV end-systolic volume and the ESPV volume-axis intercept were larger, and Ees at IHG 3 rd min was greater (1.30±0.7 vs. 3.1±2.1 mmHg/ml, p<0.01) than baseline, resulting in unchanged Ees/Ea at IHG 3 rd min (0.6±0.3 vs. 0.8±0.4, p≥0.37). Tau was prolonged only in HFrEF during IHG and was returned to the baseline value during PECA. During the first 2 minutes of PECA, LVESP was lower than that at IHG 3 rd min only in HFpEF, suggesting less metaboreflex control of blood pressure in HFpEF during IHG. Conclusions: IHG exercise at 30%MVC induced modest increases in LV end-systolic and end-diastolic pressures in HFpEF and HFrEF. Although the prolongation of LV relaxation was observed only in HFrEF, the ventricular and arterial coupling was maintained throughout the IHG exercise in both groups.

scholarly journals SAT-470 When The Heart Can’t Clap To The Thyroid’s Beat

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Aditi Thakkar ◽  
Maria Camila Trejo-Parades ◽  
Anantha Sriharsha Madgula ◽  
Margaret Stevenson
Keyword(s):  
Heart Failure ◽  
Atrial Fibrillation ◽  
Heart Rate ◽  
Ejection Fraction ◽  
Dilated Cardiomyopathy ◽  
Ischemic Cardiomyopathy ◽  
Left Ventricular ◽  
Reduced Ejection Fraction ◽  
Tachycardia Induced Cardiomyopathy

Abstract Hyperthyroidism is associated with multiple cardiac pathologies including dilated cardiomyopathy, isolated right ventricular heart failure, and atrial fibrillation (AF). Long standing untreated hyperthyroidism in conjunction with AF can cause severe dilated cardiomyopathy with reduced ejection fraction that is completely reversible with treatment. We present the case of a previously healthy male who presented with florid congestive heart failure (CHF) as an initial presentation for hyperthyroidism. A 37-year-old male presented to the emergency department with progressively worsening dyspnea on exertion and lower extremity edema for one month. His heart rate was noted to be 172 bpm and an EKG was done that showed AF. He was clinically noted to be in heart failure and was admitted for further management. He was started on metoprolol with good heart rate control and was started on furosemide for diuresis. A transthoracic echocardiogram was done and showed severe global hypokinesis with left ventricular ejection fraction reduced to 20% along with bi-atrial enlargement and dilated left ventricular cavity. Ischemic cardiomyopathy was ruled out with left heart catheterization. A TSH level was checked as a part of workup for non-ischemic cardiomyopathy and atrial fibrillation and was markedly reduced to &lt;0.01mIU/L with free T4 of 1.49ng/dL and free T3 of 6.7ng/dL. A diagnosis of hyperthyroid cardiomyopathy with concomitant tachycardia induced cardiomyopathy was made. Autoimmune workup was negative for anti-thyroid-peroxidase and anti-thyroid-stimulating antibodies. Ultrasound of his thyroid gland revealed multiple thyroid nodules concerning for toxic multinodular goiter. He was started on methimazole and discharged after volume optimization with diuresis to closely follow up with endocrinology and cardiology for further management. CHF can be the primary presentation in about 6% of patients with hyperthyroidism. T3 is the main thyroid hormone that binds to cardiomyocytes. It increases the expression of beta-adrenergic receptors on cardiomyocytes and subsequently increases heart rate and contractility. T3 can also cause atrial arrhythmias such as AF by decreasing the parasympathetic tone. Concomitant AF and hyperthyroidism can cause reduced ejection fraction due to tachycardia induced cardiomyopathy and dilated cardiomyopathy. Treatment mainly is with beta-blockers that slow down the heart as well decrease serum T3 levels by blocking 5-monodeiodinase which converts T4 to T3. Our patient was started on beta-blocker and methimazole with good reduction in heart rate and improvement of symptoms. Recovery of cardiac function will be assessed with longitudinal follow up. As hyperthyroidism is one of the few causes of CHF that is completely reversible, clinicians must maintain low degree of suspicion in patients with new onset heart failure especially when associated with AF.

Abstract 16091: Cardiac Mechanical Determinants of Exercise Function in Differing Fontan Heart Failure Phenotypes

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Shahryar M Chowdhury ◽  
carolyn taylor ◽  
Andrew M ATZ
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Stroke Volume ◽  
Diastolic Dysfunction ◽  
Diastolic Function ◽  
Cardiac Mechanics ◽  
Arterial Elastance ◽  
Cross Sectional ◽  
Reduced Ejection Fraction ◽  
Fontan Patients

Introduction: The objective of this study was to investigate the association of contractility, afterload, and diastolic dysfunction to exercise function between patients with heart failure and preserved ejection fraction (HFpEF) versus heart failure with reduced ejection fraction (HFrEF). Hypothesis: Cardiac mechanical determinants of exercise would be different in HFrEF versus HFpEF Methods: Core-lab echocardiograms were obtained from the publically-available Pediatric Heart Network Fontan Cross-sectional Study database. Ejection fraction was considered abnormal if < 50%. Diastolic function was defined as abnormal if the diastolic pressure:volume quotient (lateral E:e’/end-diastolic volume) was > 10 th percentile. Patients were divided into three groups: 1 = normal EF and normal diastolic function, 2 = decreased EF with normal diastolic function (HFrEF), 3 = normal EF with abnormal diastolic function (HFpEF). End-systolic elastance (Ees), a measure of contractility, and arterial elastance (Ea), a measure of afterload, were calculated. Results: 238 patients were included. Differences between groups are reported in the Table. In group 1, there were no significant correlations between exercise and echocardiographic measures. In patients with HFrEF, Ea was correlated with percent predicted max O 2 pulse (ppO 2 P-max) (r = -0.40, p = 0.03). In patients with HFpEF, lateral E:e’/EDV was correlated with ppO 2 P-max (r = -0.57, p = 0.02). No measures correlated with percent predicted peak VO 2 in either group. Conclusions: As Fontan patients progress to heart failure, stroke volume during exercise is limited by afterload in patients with HFrEF. Alternatively, stroke volume is limited by diastolic dysfunction in HFpEF patients. These measures of cardiac mechanics may be useful in identifying the mechanisms that drive exercise dysfunction in Fontan patients of varying heart failure phenotypes.

scholarly journals 2D Echocardiographic features in low T3 syndrome in chronic heart failure

2014 ◽  
Vol 5 (3) ◽  
pp. 35-39
Author(s):  
Arun Kumar ◽  
YL Shivamurthy ◽  
V Mohan Kumar ◽  
SS Ramesh ◽  
AG Ravi Shankar ◽  
...  
Keyword(s):  
Heart Failure ◽  
Chronic Heart Failure ◽  
Ejection Fraction ◽  
Dilated Cardiomyopathy ◽  
Medical Science ◽  
Systolic Pressure ◽  
Low T3 Syndrome ◽  
Heart Failure Patients ◽  
Low T3 ◽  
Number Of Patients

Background: Thyroid abnormalities are common in chronic heart failure. Severity of heart failure rises by several fold in patients with thyroid dysfunction. Objectives: The purpose of this prospective study is to determine the correlation between low T3 syndrome and chronic heart failure with 2D echocardiography features & predicting the severity of chronic heart failure. Methods: In this descriptive, prospective cross sectional study, all patients who presented to the department of medicine with chronic heart failure during this study period of 12 months from January 2010-December 2011 in K.R.Hospital, Mysore were included. Patients were grouped into Low T3 chronic heart failure, hypothyroid chronic heart failure and chronic heart failure. Results: Mean age of low T3 chronic heart failure patients was higher than other two groups [60.50±6.15(SD) years, Systolic dysfunction on 2D Echo was more in low T3 dilated cardiomyopathy (20%), Diastolic dysfunction on 2D Echo was more in low T3 dilated cardiomyopathy group (30%), Pericardial effusion was seen in more number of patients with low T3 dilated cardiomyopathy (10%). Global hypokinesia was seen in more number of patients with low T3 dilated cardiomyopathy (30%). Segmental hypokinesia was seen in more number of patients with low T3 dilated cardiomyopathy (3%). Mean ejection fraction was seen in more number of patients with low T3 dilated cardiomyopathy [36.78±5.08 (SD) %]. Mean ejection fraction was lower in low T3 dilated cardiomyopathy [34.8±3.293 (SD) %].The high pulmonary artery systolic pressure was seen in more number of patients in low T3 dilated cardiomyopathy (70%). Conclusion: There is significant percentage of chronic heart failure patients having low T3 alone as biochemical parameter. It is important to recognize patients with chronic heart failure as it is associated with increased severity of heart failure. Asian Journal of Medical Science, Volume-5(3) 2014: 35-39 http://dx.doi.org/10.3126/ajms.v5i3.9522      

scholarly journals COMPARISON OF EJECTION FRACTION AND END VOLUMES OF THE LEFT VENTRICLE AS INDICATORS OF THE SEVERITY OF HEART FAILURE

2019 ◽  
Vol 26 (3) ◽  
pp. 33-40
Author(s):  
Dinara Sh. Gazizova
Keyword(s):  
Heart Failure ◽  
Heart Rate ◽  
Left Ventricle ◽  
Ejection Fraction ◽  
Dilated Cardiomyopathy ◽  
Pathological Condition ◽  
Severe Heart Failure ◽  
Volume Index ◽  
Stroke Index ◽  
Reduced Ejection Fraction

Aim. To demonstrate that the end volumes are indicative of the severity of the left ventricle pathological condition not only under preserved, but also under reduced ejection fraction. Material and methods. 32 patients with dilated cardiomyopathy and severe heart failure, as well as with complete monitor and computer and echocardiographic control were examined. Results. The sensitivity of the ejection fraction and end volumes to the severity of heart failure (stroke index from 15.3 to 57.2, average 29.5±1.6; ejection fraction from 16.5 to 48.0, average 27.4±127; heart rate from 52 tо 113, average 81.8±2.4) was established. It is shown that the percentage change (sensitivity) of the ejection fraction (55%) is much lower than that of the end diastolic volume index (190%) and that of the end systolic volume index (438%) to the severity of heart failure. Conclusion. Indices of end-diastolic and end-systolic volumes of critical patients with dilated cardiomyopathy are more sensitive to the severity of heart failure than the ejection fraction. It is advisable to use end volumes as indicators of heart failure. An adequate quantitative assessment of the severity of heart failure should include the heart rate (duration of the cardiac cycle T).

Hemodynamic effects of epinephrine: concentration-effect study in humans

1985 ◽  
Vol 58 (4) ◽  
pp. 1199-1206 ◽  
Author(s):  
J. R. Stratton ◽  
M. A. Pfeifer ◽  
J. L. Ritchie ◽  
J. B. Halter
Keyword(s):  
Heart Rate ◽  
Ejection Fraction ◽  
Stroke Volume ◽  
Systemic Vascular Resistance ◽  
Vascular Resistance ◽  
Systolic Pressure ◽  
Left Ventricular ◽  
Hemodynamic Effects ◽  
Plasma Epinephrine ◽  
Ventricular Performance

The hemodynamic effects of three different infusion rates of epinephrine (25, 50, or 100 ng X kg-1 X min-1 for 14 min) were examined in 10 normal human subjects. Ejection fraction and changes in cardiac volumes were assessed by radionuclide ventriculography. Plasma epinephrine was increased to levels that spanned the normal physiological range (178 +/- 15, 259 +/- 24, and 484 +/- 69 pg/ml, respectively). Epinephrine infusions resulted in dose-dependent increases in heart rate (8 +/- 3, 12 +/- 2, and 17 +/- 1 beats/min, mean +/- SE) and systolic pressure (8 +/- 1, 18 +/- 2, and 30 +/- 6 mmHg). Although epinephrine infusions had minimal effects on end-diastolic volume, there were significant increases in stroke volume (+26 +/- 2, 31 +/- 4, and 40 +/- 4%), ejection fraction (+0.10 +/- 0.01, 0.14 +/- 0.02 and 0.16 +/- 0.03 ejection fraction units), and cardiac output (+41 +/- 4, 58 +/- 5, and 74 +/- 1%). These increases in left ventricular performance were associated with a decreased systemic vascular resistance (-31 +/- 3, -42 +/- 2, and -48 +/- 8%). Supine bicycle exercise resulted in similar plasma epinephrine levels (417 +/- 109 pg/ml) and similar changes in stroke volume, ejection fraction, and systemic vascular resistance but greater increases in heart rate and systolic blood pressure. Since infusion-associated hemodynamic changes occurred at plasma epinephrine levels commonly achieved during many types of physical and emotional stress, epinephrine release may have an important role in regulating systemic vascular resistance, stroke volume, and ejection fraction responses to stress in man.

Sign in / Sign up

Export Citation Format

Share Document