Systolic Ejection Time Research Articles

Regional mechanical dyssynchrony and shortened systole are present in people with Takotsubo syndrome

Background:Takotsubo syndrome is characterized by transient regional systolic dysfunction, left ventricular (LV) dilatation, and edema, often occurring without obstructive coronary artery disease. The mechanisms underlying this stress-induced condition, especially the role of mechanical dyssynchrony in affecting systolic function, remain poorly understood.Methods:In our study, we evaluated global LV function and mechanical dyssynchrony in 24 Takotsubo patients compared to 20 controls by analyzing pressure-volume loops and time-varying elastance. Additionally, we monitored changes in LV segmental volume and internal flow.Results:Here we show a significant reduction in global myocardial contractility and pronounced mechanical dyssynchrony in Takotsubo syndrome, particularly in the mid and apical LV segments, without disturbances in electrical conduction.Conclusions:Our findings reveal substantial mechanical dyssynchrony in Takotsubo patients, characterized by increased internal flow and a shortened systolic ejection time. This indicates a mechanical basis for the inefficient LV function in Takotsubo syndrome, independent of electrical conduction abnormalities.

Association between Left Ventricular Geometry, Systolic Ejection Time, and Estimated Glomerular Filtration Rate in Ambulatory Patients with Preserved Left Ventricular Ejection Fraction

Plain Language SummaryCardiac function is important to quantify for risk stratification. Although left ventricular ejection fraction is commonly used, and identifies patients with poor systolic function, other easily acquired measures of cardiac function are needed. In this retrospective cohort study of 375 patients with increased left ventricular relative wall thickness, an easily derived measure from standard transthoracic echocardiography was independently associated with a surrogate of subclinical systolic dysfunction, left ventricular ejection time, and chronic kidney disease. Left ventricular geometry identifies clinically relevant subclinical systolic dysfunction and patients with worse kidney function.

Association between cardiac time intervals and incident heart failure after acute coronary syndrome

BackgroundCardiac time intervals are sensitive markers of myocardial dysfunction that predispose to heart failure (HF). We aimed to investigate the association between cardiac time intervals and HF in patients with acute coronary syndrome (ACS).MethodsThis study included 386 ACS patients treated with percutaneous coronary intervention (PCI). Patients underwent an echocardiography examination a median of two days after PCI. Cardiac time intervals including isovolumic relaxation time (IVRT), isovolumic contraction time (IVCT), and systolic ejection time (ET), and myocardial performance index (MPI) were obtained by tissue Doppler echocardiography. The outcome was incident HF.ResultsDuring follow-up (median 4.3, IQR:1.0-6.7 years), 140 (36%) developed HF. In unadjusted analyses, IVRT was not associated with HF (HR 1.02 (0.95–1.10), p = 0.61, per 10ms increase), and neither was IVCT (HR 0.07 (0.95–1.22), p = 0.26, per 10ms increase). Increasing MPI was associated with a higher risk of HF (HR 1.20 (1.08–1.34), P = 0.001, per 0.1 increase), and so was decreasing ET (HR 1.13 (1.07–1.18), P < 0.001 per 10ms decrease). After multivariable adjustment for cardiovascular risk factors, MPI (HR 1.13 (1.01–1.27), P = 0.034) and ET (HR 1.09 (1.01–1.17), P = 0.025) remained significantly associated with incident HF. LVEF modified the association between ET and HF (p for interaction = 0.002), such that ET was associated with HF in patients with LVEF ≥ 36% (HR = 1.15 (1.06–1.24), P = 0.001, per 10ms decrease).ConclusionIn patients admitted with ACS, shortened ET and higher MPI were independently associated with an increased risk of incident HF. Additionally, ET was associated with incident HF in patients with LVEF above 36%.Graphical

Assessment of cardiovascular functioning following sport-related concussion: A physiological perspective

There is still much uncertainty surrounding the approach to diagnosing and managing a sport-related concussion (SRC). Neurobiological recovery may extend beyond clinical recovery following SRC, highlighting the need for objective physiological parameters to guide diagnosis and management. With an increased understanding of the connection between the heart and the brain, the utility of assessing cardiovascular functioning following SRC has gained attention. As such, this review focuses on the assessment of cardiovascular parameters in the context of SRC. Although conflicting results have been reported, decreased heart rate variability, blood pressure variability, and systolic (ejection) time, in addition to increased spontaneous baroreflex sensitivity and magnitude of atrial contraction have been shown in acute SRC. We propose that these findings result from the neurometabolic cascade triggered by a concussion and represent alterations in myocardial calcium handling, autonomic dysfunction, and an exaggerated compensatory response that attempts to maintain homeostasis following a SRC. Assessment of the cardiovascular system has the potential to assist in diagnosing and managing SRC, contributing to a more comprehensive and multimodal assessment strategy.

Exploring the Connection Between Relaxed Myosin States and the Anrep Effect.

The Anrep effect is an adaptive response that increases left ventricular contractility following an acute rise in afterload. Although the mechanistic origin remains undefined, recent findings suggest a two-phase activation of resting myosin for contraction, involving strain-sensitive and posttranslational phases. We propose that this mobilization represents a transition among the relaxed states of myosin-specifically, from the super-relaxed (SRX) to the disordered-relaxed (DRX)-with DRX myosin ready to participate in force generation. This hypothesis offers a unified explanation that connects myosin's SRX-DRX equilibrium and the Anrep effect as parts of a singular phenomenon. We underscore the significance of this equilibrium in modulating contractility, primarily studied in the context of hypertrophic cardiomyopathy, the most common inherited cardiomyopathy associated with diastolic dysfunction, hypercontractility, and left ventricular hypertrophy. As we posit that the cellular basis of the Anrep effect relies on a two-phased transition of myosin from the SRX to the contraction-ready DRX configuration, any dysregulation in this equilibrium may result in the pathological manifestation of the Anrep phenomenon. For instance, in hypertrophic cardiomyopathy, hypercontractility is linked to a considerable shift of myosin to the DRX state, implying a persistent activation of the Anrep effect. These valuable insights call for additional research to uncover a clinical Anrep fingerprint in pathological states. Here, we demonstrate through noninvasive echocardiographic pressure-volume measurements that this fingerprint is evident in 12 patients with hypertrophic obstructive cardiomyopathy before septal myocardial ablation. This unique signature is characterized by enhanced contractility, indicated by a leftward shift and steepening of the end-systolic pressure-volume relationship, and a prolonged systolic ejection time adjusted for heart rate, which reverses post-procedure. The clinical application of this concept has potential implications beyond hypertrophic cardiomyopathy, extending to other genetic cardiomyopathies and even noncongenital heart diseases with complex etiologies across a broad spectrum of left ventricular ejection fractions.

Effect of the Novel Myotrope Danicamtiv on Cross-Bridge Behavior in Human Myocardium.

Background Omecamtiv mecarbil (OM) and danicamtiv both increase myocardial force output by selectively activating myosin within the cardiac sarcomere. Enhanced force generation is presumably due to an increase in the total number of myosin heads bound to the actin filament; however, detailed comparisons of the molecular mechanisms of OM and danicamtiv are lacking. Methods and Results The effect of OM and danicamtiv on Ca2+ sensitivity of force generation was analyzed by exposing chemically skinned myocardial samples to a series of increasing Ca2+ solutions. The results showed that OM significantly increased Ca2+ sensitivity of force generation, whereas danicamtiv showed similar Ca2+ sensitivity of force generation to untreated preparations. A direct comparison of OM and danicamtiv on dynamic cross-bridge behavior was performed at a concentration that produced a similar force increase when normalized to predrug levels at submaximal force (pCa 6.1). Both OM and danicamtiv-treated groups slowed the rates of cross-bridge detachment from the strongly bound state and cross-bridge recruitment into the force-producing state. Notably, the significant OM-induced prolongation in the time to reach force relaxation and subsequent commencement of force generation following rapid stretch was dramatically reduced in danicamtiv-treated myocardium. Conclusions This is the first study to directly compare the effects of OM and danicamtiv on cross-bridge kinetics. At a similar level of force enhancement, danicamtiv had a less pronounced effect on the slowing of cross-bridge kinetics and, therefore, may provide a similar improvement in systolic function as OM without excessively prolonging systolic ejection time and slowing cardiac relaxation facilitating diastolic filling at the whole-organ level.

Heart rate-corrected systolic ejection time: population-based reference values and differential prognostic utility in acute heart failure.

Systolic ejection time (SET) is discussed as a treatment target in patients with heart failure (HF) and a reduced left ventricular (LV) ejection fraction (EF). We derived reference values for SET correcting for its dependence on heart rate (SETc), and explored its prognostic utility in patients admitted with decompensated HF. SETc was derived in 4836 participants of the population-based STAAB study (mean age 55 ± 12 years, 52% women). There, mean SETc was 328 ± 18 ms, increased with age (+4.7 ms per decade), was shorter in men than women (-14.9 ms), and correlated with arterial elastance (r = 0.30; all P < 0.001). In 134 patients hospitalized with acute HF, SETc at admission was shorter when compared with the general population and differed between patients with HF with reduced EF (HFrEF; LVEF ≤40%; 269 ± 35 ms), HF with mildly reduced EF (HFmrEF; LVEF 41-49%; 294 ± 27 ms), and HF with preserved EF (HFpEF; LVEF ≥50%; 317 ± 35 ms; P < 0.001). In proportional hazard regression, an in-hospital increase in SETc was associated with an age- and sex-adjusted hazard ratio of 0.38 (95% confidence interval 0.18-0.79) in patients with HFrEF, but a hazard ratio of 2.39 (95% confidence interval 1.24-4.64) in patients with HFpEF. In the general population, SETc increased with age and an elevated afterload. SETc was mildly reduced in patients hospitalized with HFpEF, but markedly reduced in patients with HFrEF. In-hospital prolongation of SETc predicted a favourable outcome in HFrEF, but an adverse outcome in HFpEF. Our results support the concept of a U-shaped relationship between cardiac systolic function and risk, providing a rationale for a more individualized treatment approach in patients with HF.

The Novel Cardiac Myosin Activator Danicamtiv Improves Cardiac Systolic Function at the Expense of Diastolic Dysfunction In Vitro and In Vivo: Implications for Clinical Applications.

Recent cardiotropic drug developments have focused on cardiac myofilaments. Danicamtiv, the second direct myosin activator, has achieved encouraging results in preclinical and clinical studies, thus implicating its potential applicability in the treatment of heart failure with reduced ejection fraction (HFrEF). Here, we analyzed the inotropic effects of danicamtiv in detail. To this end, changes in sarcomere length and intracellular Ca2+ levels were monitored in parallel, in enzymatically isolated canine cardiomyocytes, and detailed echocardiographic examinations were performed in anesthetized rats in the absence or presence of danicamtiv. The systolic and diastolic sarcomere lengths decreased; contraction and relaxation kinetics slowed down with increasing danicamtiv concentrations without changes in intracellular Ca2+ transients in vitro. Danicamtiv evoked remarkable increases in left ventricular ejection fraction and fractional shortening, also reflected by changes in systolic strain. Nevertheless, the systolic ejection time was significantly prolonged, the ratio of diastolic to systolic duration was reduced, and signs of diastolic dysfunction were also observed upon danicamtiv treatment in vivo. Taken together, danicamtiv improves cardiac systolic function, but it can also limit diastolic performance, especially at high drug concentrations.

Abstract 10050: Omecamtiv Mecarbil and Its Effects on Cardiac Parameters in Heart Failure With Reduced Ejection Fraction (HFrEF). A Meta-Analysis of Randomized Controlled Trials

Introduction: Omecamtiv mecarbil (OM) is a novel selective cardiac myosin activator that has been shown to improve cardiac function in patients with HFrEF. Proposed mechanism of action suggests that it increases myocardial systolic function and systolic ejection time without associated increases in intracellular concentrations of calcium or the rate of change in left ventricular pressure or any direct effects on vascular tissue, cardiovascular receptors, or ion channels. Methods: Systematic review identified phase II/III randomized controlled trials (RCTs) evaluating OM versus placebo. Mean Difference (MD) of different echocardiographic parameters from baseline and Odds Ratios (OR) of cardiovascular (CV) death (along with 95% confidence intervals; CI) were extracted to compute pooled MD and OR using RevMan v.5.3. Random effects model was employed when there was significant heterogeneity (&gt;40%, as assessed by I-squared). Results: Four RCTs were finalized (n=9331; OM: 4722, placebo: 4609). Majority of the patients were males (n=7359; 79%), of white ethnicity (n=7345; 78.7%), and had ischemic heart failure (n=5109; 54.7%). All patients had EF &lt;40% and were on guideline-directed therapy. When patients were pooled for stroke volume; OM increased mean SV to 4.34 ml from baseline as compared to placebo (MD 4.34, 95% CI 2.03-6.65; p=0.0002; I 2 =0%). Mean LV ejection time increased to 32 milliseconds (ms) (MD 32.60, 27.34-37.87; p&lt;0.00001; I 2 =84%). OM resulted in 1.68 mm reduction in mean LV end-systolic diameter (MD -1.68; -2.73 to -0.62; p=0.002; I 2 =0%)). However, reduction in mean end-diastolic diameter (MD -1.05; -1.98 to -0.12; p=0.34; I 2 =42%) was statistically non-significant. Mean LV Fractional Shortening improved to 2% with OM but was statistically insignificant (MD 2.18; 0.54-3.82; p=0.09; I 2 =42%). OM resulted in slightly decreased heart rate (MD -1.77 beats/min; -2.29 to -1.24; p&lt;0.00001; I 2 =0%) with no effect on mean systolic BP (MD -0.05; -0.73 to 0.64; p=0.89; I 2 =0%). In terms of CV mortality, OM decreased the odds for mortality but results were statistically non-significant (OR 0.93, 95% CI 0.80 to 1.08; p=0.34; I 2 = 0%). Conclusion: Omecamtiv mecarbil improved the echocardiographic parameters in patients with HFrEF.

A Narrative Review of Clinical Applications of Systolic Time Intervals

Systolic time interval (STI) estimation is an established noninvasive method for the quantifiable assessment of left ventricular (LV) performance in well-being and disease states; it stays valuable for clinical application and forms no burden to the subjects. This manuscript reviews the potential clinical applications and prognostic value of STI for the assessment of LV systolic function in cardiovascular disease (CVD). STIs could be obtained by several noninvasive imaging modalities such as transthoracic echocardiography, tissue Doppler imaging M-mode echocardiography, conventional echocardiography, and so on. In view of that, a literature review for studies reporting the clinical applications of STI in assessing LV systolic function among CVD patients was carried out using PubMed search. Accordingly, the current review describes how STI can be measured; reliability of cardiac time interval measurement in patients with CVD and its role in a clinical setting. With the advent of modern techniques, STI could be easily measured in a clinical setting. Likewise, STI parameter, particularly preejection period and LV ejection time ratio (PEP/LVET), has got the highest degree of correlation with LV ejection fraction (LVEF) in assessing LV performance. Furthermore, reproducibility of systolic ejection time (SET) achieved by the TDI M-mode method is outstanding and better when compared with the reproducibility of SET obtained by the conventional pulsed Doppler method. Furthermore, prolonged SET is independently related with enhanced outcomes among heart failure with reduced EF (HFrEF, i.e., EF ≤40%) but not HF with preserved EF (HFpEF, i.e., EF &gt;40%) patients, indicating that stabilizing SET would be helpful in the case of systolic dysfunction. Clinically, tissue Doppler-derived time intervals could be beneficial to analyze abnormal cases in comparison with other invasive and noninvasive methods of ventricular function examination. Furthermore, phonoelectrocardiography-derived STI parameters, particularly electromechanical activation time-to-LVET ratio, may have a significant role in the diagnostic approach of heart failure (HF) in patients with undifferentiated dyspnea. In addition, in HF patients, PEP/LVET of &gt;0.43 helps to detect LVEF &lt;35% by pulsed Doppler echocardiography. Moreover, LVET continues to be an independent predictor of incident HF and provides incremental prognostic value on the future HF risk and death but not myocardial infarction. In conclusion, STI measurement could be useful, particularly in identifying LVEF &lt;35% in the case of refractory HF patients. This could be beneficial in the selection of patients requiring cardiac resynchronization, specifically when accurate LVEF evaluation by echocardiography proves challenging in atrial fibrillation or if the evaluation is done by a trainee echocardiographer. Furthermore, the cardiac time intervals including SET can be acquired irrespective of rhythm. Good image quality is required for the assessment of LVEF. In contrast, evaluation of SET could be useful in the case of echocardiograms with poor quality images. As a final point, the present review suggests using an echocardiographic parameter like STIs to procure additional information regarding the risk of mortality in patients with HFrEF along with LVEF measurement.

Abstract 9604: Pulmonary Artery Systolic Blood Pressure Predicted From Cardiac MR Image Data Without Requiring Calibration; A Virtual RHC?

Introduction: Despite decades of initiatives, assessment of absolute pulmonary arterial pressures (PAP) by CMR has remained an elusive goal. We introduce a means to predict the PAP from routine image data easily obtained by CMR. The image data is directly used to calculate the impedance between the LV and the aorta (IMP LV ) and between the RV and the main PA (IMP RV ) which are combined to predict PAP. Methods: Patients (n=33, 82% F), 51 ±12 yrs) with a diagnosis of (PHTN) underwent evaluation by CMR to assess the blood flow through the aorta and PA at the interface to the LV and RV, respectively. Phase velocity mapping flow data at single plane (acquisition time 2min) was used to calculate the previously described and validated impedance for the LV and RV: IMP LV and IMP RV . IMP was calculated using the formula:IMP = (end systolic ejection time) x (mean blood velocity) / (vessel diameter). Systolic PAP was measured during a right heart cath examination performed within one week of the CMR. A multiple linear regression model was generated to predict systolic PAP, with parameters retained with a significance &lt;0.05. Results: The parameters that best predicted the systolic PAP were IMP LV , IMP RV and the distance of the measured IMP LV from the center position of the data range of IMP LV (r = 0.69, p&lt;0.001), Fig 1. The standard major-axis line was fitted to the data (p&lt;0.001). Conclusions: This is the first demonstration of the utility of a CMR-measured left and right ventricular impedance value to directly predict systolic PAP. Critically, the correlation coefficient, identical to Echo, holds over a very wide physiologic range, and has never been demonstrated before by CMR. Of central importance is the distinguishing feature that no calibration of the data is required, thus, unlike typical Echo-derived estimates of PAP or newer implanted pressure monitors, no estimate of CVP or RAP is required. Thus, this is the first-in-man CMR demonstration of a virtual RHC.

73. OMECAMTIV MECARBIL, A NOVEL THERAPEUTIC AGENT FOR HEART FAILURE WITH REDUCED EJECTION FRACTION: A SYSTEMATIC REVIEW

Background: At least half of the millions of heart failure patients have heart failure with reduced ejection fraction (HFrEF). There have been many drugs used to treat heart failure, but these drugs don’t directly work on the target pathogenesis of HFrEF. Improving systolic function will prevent neurohormonal activation and ventricular remodeling, which clinically will provide better results from hospitalization and causes of death. Omecamtive mecarbil (OM) is a novel selective cardiac myosin activator, it will improve cardiac function in patients with HFrEF. Objective: We aim to assess the latest evidence on the outcome of OM in heart failure patients. Method: We performed a comprehensive search on topics that assesses OM outcomes in heart failure patients from inception up until January 2021. Results: There were 17.712 HFrEF patients from six studies. Three studies showed the decrease of heart rate, two studies prove that OM increase the stroke volume and systolic ejection time, while each of one study showed increase of left ventricular ejection fraction and decrease left ventricular end systolic volume, left ventricular end diastolic volume, left ventricular fraction shortening, left ventricular end systolic dimension and left ventricular end diastolic dimension from the baseline. The route via intravena maximum tolerated by dose 0,5 mg/kg per h, while via orally start with dose 25 mg twice daily. No significant side effects were found. One randomized controlled trial study also showed a lower risk of a composite heart failure events and cardiovascular death than those who received placebo. Conclusion: Omecamtiv mecarbil improved cardiac function in heart failure and could be the first in class of a new therapeutic agent. Further controlled studies are warranted for definite conclusion.

24. OMECAMTIVE MECARBIL, A NOVEL THERAPEUTIC AGENT FOR HEART FAILURE WITH REDUCED EJECTION FRACTION: A SYSTEMATIC REVIEW

Background: At least half of the millions of heart failure patients have heart failure with reduced ejection fraction (HFrEF). There have been many drugs used to treat heart failure, but these drugs don’t directly work on the target pathogenesis of HFrEF. Improving systolic function will prevent neurohormonal activation and ventricular remodeling, which clinically will provide better results from hospitalization and causes of death. Omecamtive mecarbil (OM) is a novel selective cardiac myosin activator, it will improve cardiac function in patients with HFrEF. Objective: We aim to assess the latest evidence on the outcome of OM in heart failure patients. Method: We performed a comprehensive search on topics that assesses OM outcomes in heart failure patients from inception up until January 2021. Results: There were 17.712 HFrEF patients from six studies. Three studies showed the decrease of heart rate, two studies prove that OM increase the stroke volume and systolic ejection time, while each of one study showed increase of left ventricular ejection fraction and decrease left ventricular end systolic volume, left ventricular end diastolic volume, left ventricular fraction shortening, left ventricular end systolic dimension and left ventricular end diastolic dimension from the baseline. The route via intravena maximum tolerated by dose 0,5 mg/kg per h, while via orally start with dose 25 mg twice daily. No significant side effects were found. One randomized controlled trial study also showed a lower risk of a composite heart failure events and cardiovascular death than those who received placebo. Conclusion: Omecamtive mecarbil improved cardiac function in heart failure and could be the first in class of a new therapeutic agent. Further controlled studies are warranted for definite conclusion.

April 2021 at a glance: focus on systolic function, quality of life and treatment in heart failure.

Left ventricular (LV) systolic ejection time is a prognostic marker in patients with heart failure (HF) and reduced ejection fraction (HFrEF).1, 2 Alhakak et al.3 reviewed the definition and methods of measurement of LV ejection time, the mechanisms behind its shortening in HFrEF, its role as a prognostic marker and in the assessment of the response to medical treatment. Left ventricular ejection fraction (LVEF) remains the landmark parameter of LV systolic function. It is a major prognostic marker both in acute and chronic HF.4, 5 Strange et al.5, 6 furthered their previous findings showing in a large cohort of 117 275 subjects followed up by echocardiography that even modest LVEF changes over time, i.e. at least 6 months, have a significant prognostic impact. Five-year all-cause mortality increased from 12% to 29% among subjects with the smallest to the largest decrease in LVEF (from <5 units to >30 units). Health-related quality of life (QoL) scores are clinically relevant in patients with HF.7-9 In a recent analysis of BIOSTAT-CHF, Ravera et al.10 reported worse QoL scores in women with HFrEF as compared with men, both when assessed with the Kansas City Cardiomyopathy Questionnaire (KCCQ) overall score (median 44 vs. 53; P < 0.001) and the EuroQol 5 dimensions utility score (median 0.62 vs. 0.73; P < 0.001). Of note, QoL was independently associated with subsequent outcome both in women and men. Turgeon et al.11 synthetized evidence regarding the impact of HFrEF pharmacotherapy on QoL in a comprehensive systematic review and meta-analysis. QoL was improved by angiotensin receptor blockers, angiotensin receptor–neprilysin inhibitor, sodium–glucose co-transporter 2 inhibitors, ivabradine, hydralazine–nitrate, and intravenous iron whereas findings were inconclusive for angiotensin-converting enzyme inhibitors, beta-blockers, digoxin, and oral iron. Sodium–glucose co-transporter 2 inhibitors have a pivotal role in the treatment of patients with HFrEF.12-14 Their cost-effectiveness has also been shown.15 Despite differences in the pathophysiology of ischaemic and non-ischaemic HF,16 dapagliflozin had similar effects on the risk of worsening HF or cardiovascular death as well as on symptoms and QoL in patients with HFrEF of ischaemic and non-ischaemic aetiology in DAPA-HF.17 Comorbidities have a major role in patients with HF, including those enrolled in clinical trials.18 Two analyses from DAPA-HF reported that patients with concomitant anaemia or chronic obstructive pulmonary disease had poorer outcomes. However, the benefit of dapagliflozin on cardiovascular events was independent of their presence.19, 20 Rivaroxaban 2.5 mg twice daily may be considered among treatment options for patients with HF, coronary artery disease and LVEF >30%.14 An analysis of COMMANDER-HF demonstrated that high plasma D-dimer levels (>515 ng/mL) identify patients at high risk of stroke who can benefit from rivaroxaban administration.21 Iron deficiency is a major therapeutic target in HF.9, 14, 22 In a non-randomized, open-label, prospective pilot study, oral sucrosomial iron improved exercise capacity and QoL in patients with HFrEF and Iron deficiency, with significant improvement in 6-min walk distance and KCCQ at 3 and 6 months (all adjusted P-values <0.01).23 The MSC-HF trial reported a positive effect of intramyocardial injection of autologous bone marrow-derived mesenchymal stromal cells (MSCs) in patients with ischaemic HF.24 The Phase II CONCERT-HF trial demonstrated that the combination of MSCs and c-kit positive cardiac cells was associated with further improvement in clinical outcome and QoL.25

February 2021 at a glance: focus on amyloidosis, myocarditis and cardiomyopathy

Cardiac amyloidosis (CA) is emerging as a major cause of heart failure (HF).1-3 Castiglione et al.4 reviewed the role of circulating biomarkers as tools to guide diagnosis, prognostic stratification, and therapy in CA. The independent prognostic role of cardiopulmonary exercise testing in patients with light chain or transthyretin CA (TTR-CA) was shown by Nicol et al.5 in a multicentre study. Both peak oxygen consumption (VO2) ≤13 mL/kg/min and N-terminal pro B-type natriuretic peptide (NT-proBNP) ≥1800 ng/L had independent prognostic value with a hazard ratio (HR) of 2.7 [95% confidence interval (CI) 1.6–4.8] and 2.2 (95% CI 1.1–4.3), respectively. No events occurred in patients with peak VO2 >13 mL/kg/min and NT-proBNP <1800 ng/L during a median follow-up of 20 months, despite overall 25% mortality and 29% hospitalization rates. Amyloidosis may be present in patients with severe aortic stenosis.2, 6 TTR-CA was detected in 13% of patients with severe aortic stenosis undergoing transcatheter aortic valve replacement. It had no impact on mortality but was associated with a higher HF hospitalization rate during a 3-year follow-up.3 Tafamidis has emerged as an effective treatment option to improve prognosis in patients with TTR-CA.7, 8 A single-centre study in 648 real-world patients with TTR-CA matching the inclusion criteria of the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT) showed a significant benefit of tafamidis on major cardiovascular outcomes (HR after propensity score matching 0.546, P = 0.0132).9 In an analysis of the long-term extension of ATTR-ACT, both tafamidis 80 mg and 20 mg reduced all-cause mortality and cardiovascular hospitalizations at 30 months compared with placebo, with the higher dose associated with better outcomes without safety issues in the long-term extension.10 Sinagra et al.11 reviewed data about the role of viral detection for immunomodulation in acute lymphocytic myocarditis, highlighting current limitations of this approach and providing a framework for future dedicated studies. The Authors pointed out that the value of viral presence to guide immunosuppressive treatment in lymphocytic myocarditis requires more evidence and remains a subject of debate. As a further support, intravenous immunoglobulin did not improve cardiac systolic function or functional status in patients with chronic inflammatory cardiomyopathy, namely idiopathic dilated cardiomyopathy with parvovirus B19 persistence, in a randomized controlled trial.12 Over the last years, improvement in survival was observed in patients with dilated cardiomyopathy, with many patients with new-onset cardiomyopathy who may show reverse remodelling.13, 14 In TRED-HF, withdrawal of pharmacological treatment for HF in patients with recovered dilated cardiomyopathy was associated with relapses in 44% of patients.15 In a further analysis by cardiac magnetic resonance, treatment withdrawal resulted in early ventricular remodelling with an increase in myocardial mass and a reduction in global longitudinal strain. Interestingly, these changes may also occur in patients who do not show clinical deterioration.16 Shorter left ventricular systolic ejection time has been identified as a marker of worse prognosis among patients with HF with reduced ejection fraction (HFrEF).17 Alhakak et al.18 confirmed the prognostic impact of left ventricular systolic ejection time on mortality in a large HFrEF population (per 10 ms decrease: adjusted HR 1.06, 95% CI 1.01–1.11, P = 0.030), hence supporting its use to stratify patients' risk and to guide therapeutic response. Heightened chemosensitivity has a major role in the excessive ventilatory response to exercise and sleep breathing abnormalities in patients with HF. Buspirone, a 5HT1A receptor agonist that inhibits serotonergic chemoreceptor neuron firing, reduced carbon dioxide chemosensitivity and improved central apnoeas in patients with HF.19 A relatively large number of patients with advanced HF may benefit from long-term mechanical circulatory support.20 This indication might be further expanded if this device therapy may cause regression of myocardial fibrosis. Unfortunately, such hypothesis was not proven in a recent study in 125 patients.21

Omecamtiv Mecarbil: A Novel Mechanistic and Therapeutic Approach to Chronic Heart Failure Management.

Heart failure (HF) is a major public health problem in the United States as well as worldwide. Chronic heart failure is a syndrome of reduced cardiac output resulting from impaired ventricular function, impaired filling, or a combination of both. Associated symptoms include dyspnea, fatigue, and decreased exercise tolerance. HF has a marked effect on morbidity and mortality, given limited therapeutic choices. The first line of therapeutic agents indicated in heart failure are beta-blockers. Other drugs and therapeutic modalities employed in HF treatment include angiotensin-receptor blockers (ARBs), sacubitril (neprilysin inhibitor) combination with the ARB, valsartan, small doses of aldosterone receptor antagonists (ARAs) in the setting of angiotensin-converting enzyme (ACE) inhibitors, and beta-blockers. Additionally, the sodium-glucose transporter-2 inhibitor, dapagliflozin in the setting of ACE inhibitors, ARBs, or sacubitril-valsartan plus beta-blocker have been employed. Other therapeutic modalities have included loop diuretics, digoxin, the hydralazine-isosorbide dinitrate combination, ivabradine, the inotropes, dobutamine, milrinone, and dopamine. Decreased cardiac contractility is central to the systolic HF. Therapeutic agents employed to increase cardiac contractility in HF are limited because of their mechanistic-related adverse effect profiles. Omecamtiv mecarbil (OM) is a first of its class cardiac myosin activator that increases the cardiac contractility by specifically binding to the catalytic S1 domain of cardiac myosin, to be employed in heart failure treatment. This agent has demonstrated benefit in reducing heart rate, peripheral vascular resistance, mean left arterial pressure, and left ventricular end-diastolic pressure in the animal models. Additionally, OM is known to improve systolic wall thickening, stroke volume (SV), and cardiac output (CO). OM increases systolic ejection time (SET), cardiac myocyte fractional shortening without significant increase of LV dP/dtmax, myocardial oxygen consumption, and myocyte intracellular calcium. The benefits of OM have been demonstrated through key trials, as (i) The Acute Treatment with Omecamtiv mecarbil to Increase Contractility in Acute Heart Failure (ATOMIC-AHF), and (ii) The Chronic Oral Study of Myosin Activation to Increase Contractility in Heart Failure (COSMIC-HF). The Global Approach to Lowering Adverse Cardiac Outcomes Through Improving Contractility in Heart Failure (GALACTIC-HF) trial is ongoing and can help provide further clinical data. OM provides a novel mechanism and therapeutic approach to managing patients with HF. Preclinical and clinical data suggest that OM capability can improve cardiac function, decrease ventricular wall stress, reverse ventricular remodeling, and promote sympathetic withdrawal.

Cardiac Myosin Activation for the Treatment of Systolic Heart Failure.

Left ventricular systolic dysfunction is the hallmark pathology in heart failure with reduced ejection fraction. Increasing left ventricular contractility with beta-adrenergic receptor agonists, phosphodiesterase-3 inhibitors, or levosimendan has failed to improve clinical outcomes and, in some situations, increased the risk of sudden cardiac death. Beta-adrenergic receptor agonists and phosphodiesterase-3 inhibitors retain an important role in advanced heart failure. Thus, there remains an unmet need for safe and effective therapies to improve left ventricular systolic function. Two novel cardiac myotropes, omecamtiv mecarbil and danicamtiv, target cardiac myosin to increase left ventricular systolic performance. Neither omecamtiv mecarbil nor danicamtiv affects cardiomyocyte calcium handling, the proposed mechanism underlying the life-threatening arrhythmias associated with cardiac calcitropes and calcium sensitizers. Phase 2 clinical trials have demonstrated that these cardiac myosin activators prolong left ventricular systolic ejection time and promote left ventricular and atrial reverse remodeling. At higher plasma concentrations, these agents may be associated with myocardial ischemia and impaired diastolic function. An ongoing phase 3 clinical trial will estimate the clinical efficacy and safety of omecamtiv mecarbil. An additional study of these agents, which have minimal hemodynamic and renal effects, is warranted in patients with advanced heart failure refractory to guideline-directed neurohormonal blockers.

Left ventricular systolic ejection time is an independent predictor of all-cause mortality in heart failure with reduced ejection fraction.

Colour tissue Doppler imaging (TDI) M-mode through the mitral leaflet is an easy and precise method to obtain cardiac time intervals including isovolumic contraction time (IVCT), isovolumic relaxation time (IVRT) and systolic ejection time (SET). The myocardial performance index (MPI) is defined as [(IVCT + IVRT)/SET]. Whether cardiac time intervals obtained by the TDI M-mode method can be used to predict outcome in patients with heart failure with reduced ejection fraction (HFrEF) remains unknown. A total of 997 patients with HFrEF (mean age 67 ± 11 years, 74% male) underwent an echocardiographic examination including TDI. During a median follow-up of 3.4 years (interquartile range 1.9-4.8 years), 165 (17%) patients died. The risk of mortality increased by 9% per 10ms decrease in SET [per 10ms decrease: hazard ratio (HR) 1.09, 95% confidence interval (CI) 1.06-1.13; P< 0.001]. The association remained significant even after multivariable adjustment for clinical and echocardiographic parameters (per 10 ms decrease: HR 1.06, 95% CI 1.01-1.11; P=0.030). The MPI was a significant predictor in an unadjusted model (per 0.1 increase: HR 3.06, 95% CI 1.16-8.06; P=0.023). However, the association did not remain significant after multivariable adjustment. No significant associations between IVCT or IVRT and mortality were found in unadjusted nor adjusted models. Additionally, SET provided incremental prognostic information with regard to predicting mortality when added to established clinical predictors of mortality in patients with HFrEF. In patients with HFrEF, SET provides independent and incremental prognostic information regarding all-cause mortality.

Determining the Properties of Omecamtiv Mecarbil on Human Explanted Cardiac Trabeculae and Its Interaction with Current Inotropes via the Beta 1-Adrenoceptor

Omecamtiv mecarbil (OM) is a first in class selective myosin activator, developed to increase contractile force without altering intracellular calcium concentrations in patients with advanced heart failure (AHF). We sought to investigate the effect of OM on contractility, arrhythmia genesis and interaction with Beta 1-adrenoceptor (B1AR) inotropes directly on explanted human failing heart. Trabeculae from 7 explanted hearts with AHF were dissected and set up to contract at 1 Hz. Trabeculae were incubated with or without OM (600 nM or 2 µM) for 120 mins. Cumulative concentration-effect curves were established to (-)-noradrenaline at B1ARs in the presence of the B2AR blocker (50 nM ICI 118,551) and phenoxybenzamine to block α1ARs and neuronal uptake. Contractile force and duration were recorded and observed for spontaneous contractions. OM prevented time dependent reduction (fade) in contractile force (Fig A, P=0.013 at 120mins). Trabeculae exhibited a concentration dependent increase in systolic ejection time (SET), associated with increased stroke volume, but this reduces the time for diastole. (Fig B). The concentration of (-)-noradrenaline required for 50% of maximal contractile force, the LogEC50, remained unchanged in the presence of OM (Mean LogEC50: -6.1 (control), -6.2 (600 nM), -6.1 (2 µM); P=0.7). (-)-Noradrenaline reversed OM mediated increases in SET. There was no significant increase in spontaneous contractions with OM concentrations up to 2 µM. OM maintains contractile force, independent of a B1AR mediated mechanism, without an increase in spontaneous contraction. In isolation OM increases SET at the cost of diastolic performance. Concomitant B1AR activation by (-)-noradrenaline normalises SET, improving ventricular filling. This finding may prove clinically relevant, especially when titrating traditional inotropes which increase metabolic demand.

The C-Terminal End Peptide of Troponin I as a Myofilament Ca2+Desensitizer

The C-terminal end segment of troponin I (TnI) is a highly conserved structure. Mutation in this segment impairs cardiac muscle relaxation. This segment is a Ca2+-regulated allosteric structure in troponin complex and binds tropomyosin in low Ca2+state, indicating a role in the inhibitory activity of TnI during muscle relaxation. The C-terminal end peptide forms a conserved epitope recognized by a monoclonal antibody. We characterized the C-terminal 27 amino acid peptide of human cardiac TnI (HcTnI-C27) for its effect on modulating muscle contractility. Biologically or chemically synthesized HcTnI-C27 free peptide in physiological solution retains the native epitope recognized by the anti-TnI C-terminus monoclonal antibody. HcTnI-C27 peptide also retains the binding affinity for tropomyosin as that residing in intact TnI. A restrictive cardiomyopathy mutation inHcTnI-C27 peptide (R192H) abolishes its bindings to the anti-TnI C-terminus monoclonal antibody and tropomyosin, demonstrating a pathogenic destruction with loss of function. Contractility studies using skinned muscle preparations demonstrated that addition of free HcTnI-C27 peptide reduces Ca2+-sensitivity of myofibrils at high Ca2+state without decreasing the maximum force production. The results indicate that the C-terminal end segment of TnI is a regulatory element of troponin, which retains the native configuration in the form of free peptide to confer a physiological effect on myofilament Ca2+-desensitization. Without negative inotropic impact, this short peptide may be developed into a novel reagent to selectively facilitate cardiac muscle relaxation in the activated state as a potential treatment for diastolic dysfunction and heart failure. This notion is supported by previous findings that a conformational modulation of the T subunit of troponin (TnT) to add a TnI C-terminus-like element in the contractile machinery of transgenic mouse cardiac muscle selectively prolongs ventricular end systolic ejection time to increase stroke volume without increase in pressure development.