Systolic Ejection Time Research Articles

Association between systolic ejection time and outcomes in heart failure by ejection fraction.

Worsening heart failure (HF) is associated with shorter left ventricular systolic ejection time (SET), but there are limited data describing the relationship between SET and clinical outcomes. Thus, the objective was to describe the association between SET and clinical outcomes in an ambulatory HF population irrespective of ejection fraction (EF). We identified ambulatory patients with HF with reduced EF (HFrEF) and HF with preserved EF (HFpEF) who had an outpatient transthoracic echocardiogram performed between August 2008 and July 2010 at a tertiary referral centre. Multivariable logistic regression was used to evaluate the association between SET and 1-year outcomes. A total of 545 HF patients (171 HFrEF, 374 HFpEF) met eligibility criteria. Compared with HFpEF, HFrEF patients were younger [median age 60 years (25th-75th percentiles 50-69) vs. 64 years (25th-75th percentiles 53-74], with fewer females (30% vs. 56%) and a similar percentage of African Americans (36% vs. 35%). Median (25th-75th percentiles) EF with HFrEF was 30% (25-35%) and with HFpEF was 54% (48-58%). Median SET was shorter (280ms vs. 315 ms, P < 0.001), median pre-ejection period was longer (114ms vs. 89 ms, P < 0.001), and median relaxation time was shorter (78.7ms vs. 93.3 ms, P < 0.001) among patients with HFrEF vs. HFpEF. Death or HF hospitalization occurred in 26.9% (n=46) HFrEF and 11.8% (n=44) HFpEF patients. After adjustment, longer SET was associated with lower odds of the composite of death or HF hospitalization at 1year among HFrEF but not HFpEF patients. Longer SET is independently associated with improved outcomes among HFrEF patients but not HFpEF patients, supporting a potential role for normalizing SET as a therapeutic strategy with systolic dysfunction.

The Significance of Ventricular Interdependence in Patients with Right Ventricular Hypertrophy and Normal Left Ventricular Function

The aim of the study is to quantify ventricular interactions by comparing tissue and spectral systolic echocardiographic parameters to allow the early identification of ventricular dysfunction. Clinical, paraclinical, electrocardiographic and echocardiographic evaluations were performed. Right ventricular hypertrophy was diagnosed in the M mode subcostal echocardiographic section. RV hypertrophy was defined by a right ventricular free wall thickness of ] 5 mm in diastole. We assessed the following RV and LV tissue and spectral systolic indices: apical systolic excursion of the lateral mitral ring (MAPSE), apical systolic excursion of the lateral tricuspid ring (TAPSE), left (Svs) and right (Svd) ventricular tissue systolic velocities, and RV and LV ejection times. We calculated the following to assess systolic ventricular interdependence: MAPSE/TAPSE, the normal value of which was considered as 0.66 � 0.14, and Svs/Svd, the normal value of which was considered as 0.76 � 0.21. The study group was compared to a control group with the same clinical features but without ventricular hypertrophy. Twenty-one patients were included in the study: 13 men (62%) and eight women (38%) with a mean age of 56 � 3.8 years. We compared the values between the study group and control group, with the following results: TAPSE = 20.4 � 0.9 vs. 24.1 � 0.76 and MAPSE/TAPSE = 0.74 � 0.06 vs. 0.75 � 0.04. MAPSE was comparable between the groups. Svs was comparable between the groups (0.09 � 0.01 vs. 0.12 � 0.02), whereas Svd was different between the groups (0.11 � 0.03 vs 0.16 � 0.03). Svs/Svd was 0.81 � 0.05 in the study group and 0.75 � 0.08 in the control group. LV ejection time was comparable between the two groups (299.8 � 23.6 ms vs. 303.3 � 28 ms), whereas, RV ejection time differed between the groups (275 � 17 ms vs. 245.5 � 28.5). Changes in TAPSE and MAPSE/TAPSE, in addition to Svd and Svs/Svd, are related to right ventricular dysfunction and suggest pathological changes in the interdependence mechanism of the ventricles in patients with RV hypertrophy. In addition, RV free wall thickness was strongly correlated with ventricular interdependence parameters, with the exception of MAPSE. Assessing these parameters and proportions in clinical practice will facilitate the early detection and appropriate treatment of right ventricular dysfunction.

The Significance of Ventricular Interdependence in Patients with Right Ventricular Hypertrophy and Normal Left Ventricular Function

The aim of the study is to quantify ventricular interactions by comparing tissue and spectral systolic echocardiographic parameters to allow the early identification of ventricular dysfunction. Clinical, paraclinical, electrocardiographic and echocardiographic evaluations were performed. Right ventricular hypertrophy was diagnosed in the M mode subcostal echocardiographic section. RV hypertrophy was defined by a right ventricular free wall thickness of &gt; 5 mm in diastole. We assessed the following RV and LV tissue and spectral systolic indices: apical systolic excursion of the lateral mitral ring (MAPSE), apical systolic excursion of the lateral tricuspid ring (TAPSE), left (Svs) and right (Svd) ventricular tissue systolic velocities, and RV and LV ejection times. We calculated the following to assess systolic ventricular interdependence: MAPSE/TAPSE, the normal value of which was considered as 0.66 ± 0.14, and Svs/Svd, the normal value of which was considered as 0.76 ± 0.21. The study group was compared to a control group with the same clinical features but without ventricular hypertrophy. Twenty-one patients were included in the study: 13 men (62%) and eight women (38%) with a mean age of 56 ± 3.8 years. We compared the values between the study group and control group, with the following results: TAPSE = 20.4 ± 0.9 vs. 24.1 ± 0.76 and MAPSE/TAPSE = 0.74 ± 0.06 vs. 0.75 ± 0.04. MAPSE was comparable between the groups. Svs was comparable between the groups (0.09 ± 0.01 vs. 0.12 ± 0.02), whereas Svd was different between the groups (0.11 ± 0.03 vs 0.16 ± 0.03). Svs/Svd was 0.81 ± 0.05 in the study group and 0.75 ± 0.08 in the control group. LV ejection time was comparable between the two groups (299.8 ± 23.6 ms vs. 303.3 ± 28 ms), whereas, RV ejection time differed between the groups (275 ± 17 ms vs. 245.5 ± 28.5). Changes in TAPSE and MAPSE/TAPSE, in addition to Svd and Svs/Svd, are related to right ventricular dysfunction and suggest pathological changes in the interdependence mechanism of the ventricles in patients with RV hypertrophy. In addition, RV free wall thickness was strongly correlated with ventricular interdependence parameters, with the exception of MAPSE. Assessing these parameters and proportions in clinical practice will facilitate the early detection and appropriate treatment of right ventricular dysfunction. Keywords: interdependence, ventricular hypertrophy, MAPSE, TAPSE, systolic tissue velocities

P5440Systolic/diastolic effects of chronic treatment with omecamtiv mecarbil in minipigs with post-myocardial infarction Heart Failure with reduced Ejection Fraction (HFrEF)

Abstract Background Omecamtiv mecarbil (OM), a novel myosin ATPase activator, is currently developed for the treatment of Heart Failure with reduced Ejection Fraction (HFrEF). Phase I in healthy volunteers and patients showed that the positive inotropic effect of OM was associated with an impairment of diastolic function as assessed by change in E peak, e' wave and E/e' ratio. Purpose The diastolic impact of chronic treatment with OM has not been described yet. This study investigates the balance between positive inotropic effect and the diastolic impairment after chronic treatment with OM in a post-myocardial infarction (Post-MI) swine model of HFrEF. Methods HFrEF was induced in minipigs after myocardial infarction caused by a 150-min left anterior descending (LAD) artery occlusion performed under angiography. HFrEF minipigs were treated with OM at 3 mg/kg PO BID for 15 days (n=4), a dose known to increase systolic ejection time (SET) by ∼50 ms as achieved in healthy volunteers and patients at plasma levels between 200–300 ng/ml. Echocardiogram was performed before and after 15 days of treatment with OM. An additional echocardiogram was conducted 7 days after the last administration. Results One year after MI, minipigs displayed increased left ventricular end-diastolic volume index (LVEDVi 151±3.7ml/m2 vs 100±8.9ml/m2 before infarction) and decreased LVEF (42±2.5% vs 68±4.4% before infarction) associated with a pseudo-normal mitral pattern. A two-week treatment with OM increased SET by 64ms (p&lt;0.0001 vs before treatment) and EF to 49±3.8% (p=0.07 vs before treatment) as well as it improved SVi by 13%. This inotropic effect was associated with a decrease of mitral E peak (p=0.01 vs before treatment) and e' waves, and with the prolongation of deceleration time (p&lt;0.05 vs before treatment). OM treatment was associated with marked reduction of LVEDVi to 117±13.2ml/m2 (p&lt;0.05 vs before treatment) concomitant with a ∼20% increase in diastolic septum and posterior wall thicknesses. None of these systolic or diastolic effects remained 7 days post OM treatment completion. Conclusion Similarly to clinical description, OM treatment increased LVEF and SVi principally through extension of SET. It provides positive inotropic effects associated with diastolic impairment resulting in impaired ventricular filling as assessed by LVEDVi decrease and the thickening of ventricular wall in diastole. Whether this profile will allow a beneficial reverse remodeling, needs to be investigated in a longer chronic study. Acknowledgement/Funding Sanofi sponsored study

Improvement of abnormal systolic motion of the interventricular septum with cardiac resynchronization therapy.

There is no consensus in the literature regarding what is the responsible mechanism of left ventricular dyssynchrony; septal dyskinesia or late movement of left ventricle (LV) lateral wall. We aim to evaluate the abnormal systolic motion in each myocardial segment and the improvement of LV systolic function with pulsed tissue Doppler imaging (TDI) in patients undergoing cardiac resynchronization therapy (CRT) with left bundle branch block (LBBB). A total of 26 patients undergoing CRT implantation with LBBB, wide QRS duration (≥120ms), and low ejection fraction (EF) (<35%) were included. Pulsed TDI was taken from apical 4-chamber view and parasternal short axis view (PSAX). All echocardiographic parameters were measured when CRT is on and off. Systolic ejection time (ET) of anteroseptal and posterolateral wall of LV in PSAX was statistically significantly longer in CRT on group (321.6±62.7vs 237.5±59.3 ms, P<.001; 323.9±58.0vs 289.4±43.7 ms, P=.015, respectively). In apical 4-chamber view, septal annulus systolic ET is significantly longer in CRT on group than CRT off group (315.8±57.2vs 287.3 ± 42.2, P=.014). Also, there was a strong correlation between systolic ET of the septum in PSAX with aortic velocity time integral (VTI), QRS duration and EF (r=.587, P=.002; r=.479, P=.013; r=.440, P=.025; respectively). Circumferential contraction of septal myocardial fibers is improved with CRT and it is strongly correlated with increase of aortic VTI and shortening of QRS duration. These findings predict the deterioration of septal contraction as the main mechanism in patients with LBBB pattern and, CRT may improves myocardial contraction by correcting septal systolic motion.

Estimation of Beat-to-Beat Interval and Systolic Time Intervals Using Phono- and Seismocardiograms.

Systolic time intervals Pre-Ejection Period (PEP) and Left Ventricular Ejection Time (LVET) are widely used indicators of cardiac functions. While accurate assessment of them requires costly equipment such as echocardiography devices, a satisfactory estimation can be done by analyzing signals from simple accelerometer and microphone attached to human chest. This paper reports a study where heart rate and the systolic intervals were derived from phonocardiogram (PCG) and seismocardiogram (SCG) simultaneously. Both sensors, the microphone for PCG and the accelerometer for SCG were attached on the chest wall, close to sternum (PCG) and apex of the heart (SCG). The signals were acquired from 10 participants in a 33-minute laboratory protocol with synchronized ECG measurements. Both signals went through an identical processing path: band pass filtering, envelope extraction with Hilbert transformation and peak detection from the envelope signal. In heart rate estimation, PCG and SCG reached 84% and 93% accuracy, respectively. The systolic interval accuracy estimation was based on deviation analysis as the absolute reference values for PEP and LVET were not available. In PEP estimation, the average standard deviations during the rest periods of the protocol were 4 ms for PCG and 8 ms for SCG. In LVET estimation, the deviations were nearly 10 fold compared to PEP. However, the results show that both methods can be used for accurate heart rate estimation and with careful mechanical attachment also PEP can be accurately derived from both. Due to sharper envelope signal waveform, PEP estimation was more accurate with PCG than with SCG.

Machine learning detection of obstructive hypertrophic cardiomyopathy using a wearable biosensor

Hypertrophic cardiomyopathy (HCM) is a heritable disease of heart muscle that increases the risk for heart failure, stroke, and sudden death, even in asymptomatic patients. With only 10–20% of affected people currently diagnosed, there is an unmet need for an effective screening tool outside of the clinical setting. Photoplethysmography uses a noninvasive optical sensor incorporated in commercial smart watches to detect blood volume changes at the skin surface. In this study, we obtained photoplethysmography recordings and echocardiograms from 19 HCM patients with left ventricular outflow tract obstruction (oHCM) and a control cohort of 64 healthy volunteers. Automated analysis showed a significant difference in oHCM patients for 38/42 morphometric pulse wave features, including measures of systolic ejection time, rate of rise during systole, and respiratory variation. We developed a machine learning classifier that achieved a C-statistic for oHCM detection of 0.99 (95% CI: 0.99–1.0). With further development, this approach could provide a noninvasive and widely available screening tool for obstructive HCM.

Intake Duration Effects of New Zealand Blackcurrant Extract on Cardiovascular Responses During Moderate Intensity Exercise in Males (P23-015-19)

ObjectivesNew Zealand blackcurrant (NZBC) is an anthocyanin-rich berry with potential effects on cardiovascular health (e.g., 7-day NZBC extract lowered total peripheral resistance at rest). We examined effects of 7- and 14-day intake of NZBC extract on cardiovascular responses during moderate intensity exercise. MethodsFifteen healthy men (mean ± SD, age: 24 ± 6 yr, body mass: 79 ± 16 kg, height: 178 ± 6 cm, BMI: 24.7 ± 4.3 kg·m−2, IPAQ score: 4534 ± 1576 MET·week−1) volunteered. Resting metabolic equivalent (1-MET) was measured using Douglas bags (1-MET: 3.97 ± 0.66 ml·kg−1·min−1) with an incremental walking test to determine the relationship between walking speed and MET. A randomised, cross-over experimental design was used for baseline, 7-day and 14-day intake. Participants consumed 2 capsules of NZBC extract (600 mg and containing 210 mg of anthocyanins, CurraNZ™ Health Currancy Ltd., UK) with breakfast with a 14-day washout. On the morning of testing, the final 2 capsules were ingested 2-hr before the 30-min walk at 4 (n = 3) or 5 (n = 12) METs (speed: 5.68 ± 0.67 km·hr−1). Cardiovascular responses were measured at 7–10, 17–20 and 27–30 min during the walk (Portapres Model 2), averaged and analysed (ANOVA and post-hoc t-tests). ResultsIntake duration had no effect on heart rate (e.g., baseline: 102 ± 18 beats·min−1), systolic blood pressure (e.g., baseline 158 ± 18 mm Hg) and ejection time (e.g., baseline: 0.28 ± 0.03 s). Cardiac output (baseline: 11.7 ± 2.0, 7-day: 12.7 ± 2.5, 14-day: 12.7 ± 2.1 L·min−1, P = 0.012) and stroke volume (baseline: 114 ± 13, 7-day: 123 ± 22, 14-day: 126 ± 21 mL·min−1, P = 0.017) were increased, and total peripheral resistance (baseline: 0.51 ± 0.11, 7-day: 0.46 ± 0.17, 14-day: 0.44 ± 0.12 mmHg·L−1·min−1, P = 0.018) and diastolic blood pressure (baseline 71 ± 9, 7-day: 66 ± 10, 14-day: 63 ± 11 mm Hg, P = 0.002) were lower for 7- and 14-day intake. Only 14-day intake resulted in lower mean arterial pressure (baseline: 93 ± 10, 7-day: 89 ± 9, 14-day: 87 ± 11 mm Hg, P = 0.034). ConclusionsBeneficial effects of anthocyanin-rich NZBC extract intake on cardiovascular responses during moderate intensity exercise do not require long-duration intake. Funding SourcesHealth Currancy (UK) Ltd and CurraNZ (NZ) Ltd provided supplements and support for conference attendance with Blackcurrant New Zealand Inc. (NZ).

Effects of Daily and Intermittent Intake of New Zealand Blackcurrant Extract on Cardiovascular Responses During Moderate Intensity Exercise in Males (P23-011-19)

ObjectivesSeven-day intake of anthocyanin-rich New Zealand blackcurrant extract affected exercise-induced cardiovascular responses by vasodilation. It is not known whether daily intake of NZBC extract is required for effectiveness. Effects of daily and intermittent NZBC extract intake on cardiovascular responses were examined during brisk walking. MethodsFifteen healthy men (mean ± SD age: 24 ± 6 yr, body mass: 79 ± 16 kg, height: 178 ± 6 cm, BMI: 24.7 ± 4.3 kg·m−2, IPAQ score: 4534 ± 1576 MET·week−1) volunteered. Resting metabolic equivalent (1-MET) was measured using Douglas bags (1-MET: 3.97 ± 0.66 ml·kg−1·min−1) and an incremental walking test to determine the relationship between walking speed and MET. A randomised, cross-over (14-day washout) experimental design was used for baseline, 14-day intermittent (14I, every other day), and 14-day continuous (14C, daily) intake. Participants consumed 2 capsules of NZBC extract (600 mg and containing 210 mg of anthocyanins, CurraNZ™ Health Currancy Ltd., Surrey, UK) with breakfast. On the morning of testing, the final 2 capsules were ingested 2-hr before the 30-min brisk walk at 4 (n = 3) or 5 (n = 12) METs (walking speed: 5.68 ± 0.67 km·hr−1). Cardiovascular responses were measured at 7–10, 17–20 and 27–30 min during the walk by Portapres Model 2, averaged and analysed (ANOVA and post-hoc t-tests). ResultsThere were no changes in heart rate (e.g., baseline: 102 ± 18 beats·min-1), systolic blood pressure (e.g., baseline: 158 ± 18 mm Hg) and ejection time (e.g., baseline: 0.28 ± 0.03 s). Cardiac output (baseline: 11.7 ± 2.0, 14I: 12.5 ± 2.0, 14C: 12.7 ± 2.1 L·min-1, P = 0.009) and stroke volume (baseline: 114 ± 13, 14I: 123 ± 17, 14C: 126 ± 21 mL·min-1, P = 0.004) were higher, and total peripheral resistance (baseline 0.51 ± 0.11, 14I: 0.45 ± 0.09, 14C: 0.44 ± 0.12 mmHg·L-1·min-1, P = 0.001), diastolic blood pressure (baseline: 71 ± 9, 14I: 66 ± 9, 14C: 63 ± 11 mm Hg, P < 0.001) and mean arterial pressure (baseline 93 ± 10, 14I: 88 ± 9, 14C: 87 ± 11 mm Hg P = 0.006) were lower for 14I and 14C intake. ConclusionsDaily intake of anthocyanin-rich NZBC extract is not required to obtain beneficial cardiovascular responses during walking. Funding SourcesHealth Currancy (UK) Ltd and CurraNZ (NZ) Ltd provided supplements and support for conference attendance with Blackcurrant New Zealand Inc. (NZ).

Cardiac myosin activators for heart failure therapy: focus on omecamtiv mecarbil

Heart failure continues to be a major global health problem with a pronounced impact on morbidity and mortality and very limited drug treatment options especially with regard to inotropic therapy. Omecamtiv mecarbil is a first-in-class cardiac myosin activator, which increases the proportion of myosin heads that are tightly bound to actin and creates a force-producing state that is not associated with cytosolic calcium accumulation. Phase I and phase II studies have shown that it is safe and well tolerated. It produces dose-dependent increases in systolic ejection time (SET), stroke volume (SV), left ventricular ejection fraction (LVEF), and fractional shortening. In the ATOMIC-AHF trial, intravenous (IV) omecamtiv mecarbil did not improve dyspnoea overall but may have improved it in a high-dose group of acute heart failure patients. It did, however, increase SET, decrease left ventricular end-systolic diameter, and was well tolerated. The COSMIC-HF trial showed that a pharmacokinetic-based dose-titration strategy of oral omecamtiv mecarbil improved cardiac function and reduced ventricular diameters compared to placebo and had a similar safety profile. It also significantly reduced plasma N-terminal-pro B-type natriuretic peptide compared with placebo. The GALACTIC-HF trial is now underway and will compare omecamtiv mecarbil with placebo when added to current heart failure standard treatment in patients with chronic heart failure and reduced LVEF. It is expected to be completed in January 2021. The ongoing range of preclinical and clinical research on omecamtiv mecarbil will further elucidate its full range of pharmacological effects and its clinical usefulness in heart failure.

Dose-Dependent Effects of the Myosin Activator Omecamtiv Mecarbil on Cross-Bridge Behavior and Force Generation in Failing Human Myocardium

Omecamtiv mecarbil (OM) enhances systolic function in vivo by directly binding the myosin cross-bridges (XBs) in the sarcomere. However, the mechanistic details governing OM-induced modulation of XB behavior in failing human myocardium are unclear. The effects of OM on steady state and dynamic XB behavior were measured in chemically skinned myocardial preparations isolated from human donor and heart failure (HF) left ventricle. HF myocardium exhibited impaired contractile function as evidenced by reduced maximal force, magnitude of XB recruitment (Pdf), and a slowed rate of XB detachment (krel) at submaximal Ca2+ activations. Ca2+ sensitivity of force generation (pCa50) was higher in HF myocardium when compared with donor myocardium, both prior to and after OM incubations. OM incubation (0.5 and 1.0 μmol/L) enhanced force generation at submaximal Ca2+ activations in a dose-dependent manner. Notably, OM induced a slowing in krel with 1.0 μmol/L OM but not with 0.5 μmol/L OM in HF myocardium. Additionally, OM exerted other differential effects on XB behavior in HF myocardium as evidenced by a greater enhancement in Pdf and slowing in the time course of cooperative XB recruitment (Trec), which collectively prolonged achievement of peak force development (Tpk), compared with donor myocardium. Our findings demonstrate that OM augments force generation but also prolongs the time course of XB transitions to force-bearing states in remodeled HF myocardium, which may extend the systolic ejection time in vivo. Optimal OM dosing is critical for eliciting enhanced systolic function without excessive prolongation of systolic ejection time, which may compromise diastolic filling.

Metoprolol Reduces Hemodynamic and Metabolic Overload in Asymptomatic Aortic Valve Stenosis Patients: A Randomized Trial.

Currently, no pharmacological treatment can modify the natural history of aortic valve stenosis (AS). This underlines the critical need to explore novel treatment strategies, which could postpone or prevent the need for aortic valve replacement in patients with asymptomatic AS. The objectives of this study were to investigate whether metoprolol reduce the hemodynamic and metabolic burden imposed by AS. In a double-blinded design, 40 patients with moderate-severe asymptomatic AS (aortic valve area, 0.5±0.1 cm2/m2; peak gradient, 53±19 mm Hg) were randomized to placebo or metoprolol treatment for 22 weeks. Patients were evaluated by echocardiography, cardiovascular magnetic resonance, and 11C-acetate positron emission tomography. Compared with placebo, metoprolol (100±53 mg/d) decreased heart rate; mean difference (95% confidence interval) -8 minute-1 (-13, -3; P=0.003) and increased ejection time 26 ms (2, 50; P=0.03). Furthermore, metoprolol reduced aortic valve peak -7 mm Hg (-13, 0; P=0.05) and mean -4 mm Hg (-7, -1; P=0.03) gradients, without affecting stroke volume 3 mL/m2 (-2, 8; P=0.16). Valvuloarterial impedance (ie, global afterload) and myocardial oxygen consumption were reduced by -11% and -12% (P=0.03 and 0.01), respectively; and decreased heart rate correlated with lower valvuloarterial impedance, myocardial oxygen consumption, and improved myocardial efficiency defined as stroke work/myocardial oxygen consumption (r=0.63-0.65; all P<0.01). There were 2 adverse cardiovascular events in the metoprolol group and none in the placebo group. In patients with asymptomatic AS, metoprolol increases systolic ejection time and reduces aortic valve gradients, global afterload, and myocardial oxygen requirements. Thus, metoprolol displays favorable hemodynamic and metabolic effects and could improve outcome in patients with asymptomatic AS. URL: http://www.clinicaltrials.gov. Unique identifier: NCT02076711.

Central diastolic pressure exponential decay constant and subendocardial flow supply.

Central diastolic pressure exponential decay constant and subendocardial flow supply.

Frequency-dependent effects of omecamtiv mecarbil on cell shortening of isolated canine ventricular cardiomyocytes.

Omecamtiv mecarbil (OM) is a myosin activator agent developed for the treatment of heart failure. OM was reported to increase left ventricular ejection fraction and systolic ejection time, but little is known about the effect of heart rate on the action of OM. The present study, therefore, was designed to investigate the effects of OM on unloaded cell shortening and intracellular Ca2+ ([Ca2+]i) transients as a function of the pacing frequency. Isolated cardiomyocytes were stimulated at various frequencies under steady-state conditions. Cell length was monitored by an optical edge detector and changes in [Ca2+]i were followed using the Ca2+-sensitive dye Fura-2. At the pacing frequency of 1Hz, OM (1-10μM) significantly decreased both diastolic and systolic cell length, however, fractional shortening was augmented only by 1μM OM. Time to peak tension and time of 90% relaxation were progressively increased by OM. At the frequency of 2Hz, diastolic cell length was reduced by 10μM OM to a larger extent than systolic cell length, resulting in a significantly decreased fractional shortening under these conditions. OM had no effect on the parameters of the [Ca2+]i transient at any pacing frequency. The results suggest that supratherapeutic concentrations of OM may decrease rather than increase the force of cardiac contraction especially in tachycardic patients.

The effect of exercises on left ventricular systolic and diastolic heart function in sedentary women: Step-aerobic vs core exercises

The purpose of this study is to investigate the effect of 16 weeks step-aerobic exercises and core exercises on left ventricular structure and function with some physiological parameters in sedentary women. MethodsTo achieve the purpose of this study, a total of 45 volunteers including (step-aerobic group (SAG, n = 25), core exercise group (CEG, n = 20) were selected as participants. Two different exercises were applied for 4 days a week, throughout 16 weeks, within 60 minutes for each exercise with the intensity of heart rate (HR) 60-70 percent. The HR was measured using a heart rate monitor for each subject. The physical, biochemical and echocardiographic characteristics of the women were measured before and after the exercise. ResultsDuring the exercise periods, there were a meaningful decrease in the body weight, BMI, value of waist region and hip circumference of the women in both intervention groups as well as in the values of HR, DBP, SBP (p < 0,05). In addition, serum homocysteine (Hcy) and high-sensitivity C-reactive protein (Hs-CRP) levels decreased and the VO2max and left ventricular diastolic end-diastolic dimension increased in both SAG and CEG (p < 0.05). The left ventricular diastolic functions of the SAG improved more than CEG. Left ventricular systolic ejection time and fractional shortening meaningfully improved in both SAG and CEG (p < 0.01). Conclusion16 weeks of step-aerobic and core exercise showed significant changes of inflammatory and lipid markers with cardiac dimensions and had favorable effects on both left ventricular systolic function. Left ventricular diastolic function had more improved in SAG than the CEG.

Lower Transaortic Flow Rate Is Associated With Increased Mortality in Aortic Valve Stenosis

ObjectivesThe association of transaortic flow rate (FR) with outcomes was tested in 1,661 patients with aortic valve stenosis (AS) in the SEAS (Simvastatin and Ezetimibe in Aortic Stenosis) study. BackgroundLow transaortic flow may complicate grading of AS. However, the association of lower transaortic FR with adverse outcomes has not been reported. MethodsTransaortic FR was calculated from Doppler-derived stroke volume in milliliters divided by systolic ejection time in seconds and considered low if <200 ml/s. The association of transaortic FR with cardiovascular and all-cause mortality during 4.3-year follow-up was tested in time-varying Cox regression models run with aortic valve replacement as competing risk and reported as hazard ratio (HR) and 95% confidence interval (CI). ResultsLow transaortic FR was found in 21% of patients at baseline. Patients with low transaortic FR were older, had lower systemic arterial compliance and left ventricular mass, and included more women and patients with inconsistently graded severe AS and low stroke volume index (<35 ml/m2) (p < 0.01 for all). Low in-study transaortic FR was associated with higher rates of cardiovascular and all-cause mortality both in unadjusted analyses (HR: 2.56 [95% CI: 1.62 to 4.04]; and HR: 1.93 [95% CI: 1.35 to 2.75], respectively; p < 0.001 for both) and after adjustment for age, sex, randomized study treatment, hypertension, stroke volume index <35 ml/m2, LV mass, and mean aortic gradient (HR: 2.79 [95% CI: 1.65 to 4.73]; and HR: 1.90 [95% CI: 1.27 to 2.84], respectively; p < 0.01 for both). ConclusionsIn patients with AS without known cardiovascular disease or diabetes, low transaortic FR was independently associated with higher rates of cardiovascular and all-cause mortality. (An Investigational Drug on Clinical Outcomes in Patients With Aortic Stenosis (Narrowing of the Major Blood Vessel of the Heart) (MK-0653A-043 AM4); NCT00092677)

Acute Treatment With Omecamtiv Mecarbil to Increase Contractility in Acute Heart Failure: The ATOMIC-AHF Study

BackgroundOmecamtiv mecarbil (OM) is a selective cardiac myosin activator that increases myocardial function in healthy volunteers and in patients with chronic heart failure. ObjectivesThis study evaluated the pharmacokinetics, pharmacodynamics, tolerability, safety, and efficacy of OM in patients with acute heart failure (AHF). MethodsPatients admitted for AHF with left ventricular ejection fraction ≤40%, dyspnea, and elevated plasma concentrations of natriuretic peptides were randomized to receive a double-blind, 48-h intravenous infusion of placebo or OM in 3 sequential, escalating-dose cohorts. ResultsIn 606 patients, OM did not improve the primary endpoint of dyspnea relief (3 OM dose groups and pooled placebo: placebo, 41%; OM cohort 1, 42%; cohort 2, 47%; cohort 3, 51%; p = 0.33) or any of the secondary outcomes studied. In supplemental, pre-specified analyses, OM resulted in greater dyspnea relief at 48 h (placebo, 37% vs. OM, 51%; p = 0.034) and through 5 days (p = 0.038) in the high-dose cohort. OM exerted plasma concentration-related increases in left ventricular systolic ejection time (p < 0.0001) and decreases in end-systolic dimension (p < 0.05). The adverse event profile and tolerability of OM were similar to those of placebo, without increases in ventricular or supraventricular tachyarrhythmias. Plasma troponin concentrations were higher in OM-treated patients compared with placebo (median difference at 48 h, 0.004 ng/ml), but with no obvious relationship with OM concentration (p = 0.95). ConclusionsIn patients with AHF, intravenous OM did not meet the primary endpoint of dyspnea improvement, but it was generally well tolerated, it increased systolic ejection time, and it may have improved dyspnea in the high-dose group. (Acute Treatment with Omecamtiv Mecarbil to Increase Contractility in Acute Heart Failure [ATOMIC-AHF]; NCT01300013)

Omecamtiv mecarbil: a new cardiac myosin activator for the treatment of heart failure

Introduction: Current available inotropic agents increase cardiac contractility, but are associated with myocardial ischemia, arrhythmias, and mortality. A novel selective cardiac myosin activator, omecamtiv mecarbil (CK-1827452/ AMG-423) is a small molecule that activates the sarcomere proteins directly, resulting in prolonged systolic ejection time and increased cardiac contractility.Areas covered: This paper discusses the chemistry, pharmacokinetics, clinical efficacy and safety of omecamtiv mecarbil. Omecamtiv mecarbil represents a novel therapeutic approach to directly improve cardiac function and is therefore proposed as a potential new treatment of patients with systolic heart failure. The authors review results of previous studies investigating the effect of omecamtiv mecarbil in heart failure animal models, healthy volunteers, and patients with acute and chronic systolic heart failure.Expert opinion: Results of phase I and phase II studies demonstrate that omecamtiv mecarbil is safe and well tolerated both as an intravenous and oral formulation. In healthy volunteers and chronic systolic heart failure patients, administration of omecamtiv mecarbil resulted in a concentration-dependent increase of left ventricular ejection time, ejection fraction, fractional shortening, and stroke volume. The first results of a double-blind, randomized, placebo-controlled phase IIb dose-finding study with the oral formulation of omecamtiv mecarbil demonstrated beneficial effects on cardiac function and N-terminal pro-brain natriuretic peptide levels. This study will provide essential dosing information for the requisite phase III trials which will investigate whether the beneficial effects of omecamtiv mecarbil translate into improved clinical outcomes.

Systolic Ejection Time is an Independent Predictor of Incident Heart Failure in a Community Based Cohort Free of Heart Failure

Introduction: Cardiac time intervals are sensitive markers of cardiac dysfunction. The usefulness of the systolic ejection time (SET) to predict incident heart failure (HF), however, is unknown. Hypothesis: We hypothesized that SET is a strong predictor of incident HF in a community based cohort free of HF. Methods: We studied middle-aged African-Americans from the Jackson cohort of the Atherosclerosis Risk in Communities study (n52,077) who underwent echocardiography between 1993 and 1995 and were free of heart failure. SET was measured by pulsed-wave Doppler. Results: The mean age of the participants was 59 years, 37% were men, 58% had hypertension, 22% diabetes and 4% prevalent coronary heart disease (CHD). SET ranged from 194 to 778 ms (mean 341 6 35 ms)(Figure 1). During median follow-up of 16.7 years, 394 (19%) had incident HF. In unadjusted analyses, the risk of incident HF increased with decreasing SET below the mean of the population (Figure 1); HF risk was approximately 40% higher for participants with a SET below the mean vs. above the mean (Hazard Ratio (HR) 1.41 [1.16; 1.73], p50.001). Lower SET was also significantly associated with higher age, male gender, higher blood pressure (BP) and heart rate, lower fractional shortening (FS) and lower E/A-ratio (p for trend ! 0.001 for all). The SETwas similarly prognostic of FS and left atrium diameter (LAD) when assessed by c-statistics (0.58 for SET, 0.57 for FS and 0.59 for LAD). SET remained an independent predictor of incident HF after adjustment for age, gender, heart rate, body mass index, hypertension, diabetes, CHD, systolic and diastolic BP and conventional measures of systolic and diastolic function (FS, LAD and E/A-ratio)(HR 1.06 [1.01; 1.11], p50.013, per 10 ms decrease). Conclusion: SET is an independent predictor of incident HF in a community based cohort and provides similar prognostic information on the risk of future HF when compared to conventional measures of systolic and diastolic function.

Population pharmacokinetic‐pharmacodynamic modeling of omecamtiv mecarbil, a cardiac myosin activator, in healthy volunteers and patients with stable heart failure

Data from 3 clinical trials of omecamtiv mecarbil in healthy volunteers and patients with stable heart failure (HF) were analyzed using a nonlinear mixed-effects model to investigate omecamtiv mecarbil's pharmacokinetics and relationship between plasma concentration and systolic ejection time (SET) and Doppler-derived left ventricular outflow tract stroke volume (LVOTSV). Omecamtiv mecarbil pharmacokinetics were described by a linear 2-compartment model with a zero-order input rate for intravenous administration and first-order absorption for oral administration. Oral absorption half-life was 0.62 hours, and absolute bioavailability was estimated as 90%; elimination half-life was approximately 18.5 hours. Variability in pharmacokinetic parameters was not explained by patient baseline characteristics. Omecamtiv mecarbil plasma concentration was directly correlated with increases in SET and LVOTSV between healthy volunteers and patients with HF. The maximum increase from baseline in SET (delta SET) estimated by an Emax model was 137 milliseconds. LVOTSV increased linearly from baseline by 1.6 mL per 100 ng/mL of omecamtiv mecarbil. Model-based simulations for several immediate-release oral dose regimens (37.5, 50, and 62.5 mg dosed every 8, 12, and 24 hours) showed that a pharmacodynamic effect (delta SET ≥20 milliseconds) could be maintained in the absence of excessive omecamtiv mecarbil plasma concentrations.