scholarly journals Omecamtiv mecarbil evokes diastolic dysfunction and leads to periodic electromechanical alternans

2021 ◽  
Vol 116 (1) ◽  
Author(s):  
Gábor Á. Fülöp ◽  
Attila Oláh ◽  
Tamas Csipo ◽  
Árpád Kovács ◽  
Róbert Pórszász ◽  
...  
Keyword(s):  
Diastolic Dysfunction ◽  
Diastolic Pressure ◽  
Isometric Force ◽  
Systolic Function ◽  
Left Ventricular ◽  
Therapeutic Window ◽  
Clinical Safety ◽  
Omecamtiv Mecarbil ◽  
Isovolumic Relaxation

AbstractOmecamtiv mecarbil (OM) is a promising novel drug for improving cardiac contractility. We tested the therapeutic range of OM and identified previously unrecognized side effects. The Ca2+ sensitivity of isometric force production (pCa50) and force at low Ca2+ levels increased with OM concentration in human permeabilized cardiomyocytes. OM (1 µM) slowed the kinetics of contractions and relaxations and evoked an oscillation between normal and reduced intracellular Ca2+ transients, action potential lengths and contractions in isolated canine cardiomyocytes. Echocardiographic studies and left ventricular pressure–volume analyses demonstrated concentration-dependent improvements in cardiac systolic function at OM concentrations of 600–1200 µg/kg in rats. Administration of OM at a concentration of 1200 µg/kg was associated with hypotension, while doses of 600–1200 µg/kg were associated with the following aspects of diastolic dysfunction: decreases in E/A ratio and the maximal rate of diastolic pressure decrement (dP/dtmin) and increases in isovolumic relaxation time, left atrial diameter, the isovolumic relaxation constant Tau, left ventricular end-diastolic pressure and the slope of the end-diastolic pressure–volume relationship. Moreover, OM 1200 µg/kg frequently evoked transient electromechanical alternans in the rat in vivo in which normal systoles were followed by smaller contractions (and T-wave amplitudes) without major differences on the QRS complexes. Besides improving systolic function, OM evoked diastolic dysfunction and pulsus alternans. The narrow therapeutic window for OM may necessitate the monitoring of additional clinical safety parameters in clinical application.

Load-independent index of diastolic filling: model-based derivation with in vivo validation in control and diastolic dysfunction subjects

2006 ◽  
Vol 101 (1) ◽  
pp. 92-101 ◽  
Author(s):  
Leonid Shmuylovich ◽  
Sándor J. Kovács
Keyword(s):  
Diastolic Dysfunction ◽  
Driving Force ◽  
Diastolic Pressure ◽  
Systolic Function ◽  
Left Ventricular ◽  
Diastolic Filling ◽  
Tilt Table ◽  
Resistive Force ◽  
Force Peak

Maximum elastance is an experimentally validated, load-independent systolic function index stemming from the time-varying elastance paradigm that decoupled extrinsic load from (intrinsic) contractility. Although Doppler echocardiography is the preferred method of diastolic function (DF) assessment, all echo-derived indexes are load dependent, and no invasive or noninvasive load-independent index of filling (LIIF) exists. In this study, we derived and experimentally validated a LIIF. We used a kinematic filling paradigm (the parameterized diastolic filling formalism) to predict and derive the (dimensionless) dynamic diastolic efficiency M, defined by the slope of the peak driving force [maximum driving force ( kx o) ∝ peak atrioventricular (AV) gradient] to maximum viscoelastic resistive force [peak resistive force ( cEpeak)] relation. To validate load independence, we analyzed E-waves recorded while load was varied via tilt table (head up, horizontal, and head down) in 16 healthy volunteers. For the group, linear regression of E-wave derived kx o vs. cEpeak yielded kx o = M ( cEpeak) + B, r2 = 0.98; where M = 1.27 ± 0.09 and B = 5.69 ± 1.70. Effects of diastolic dysfunction (DD) on M were assessed by analysis of preexisting simultaneous cath-echo data in six DD vs. five control subjects. Average M for the DD group ( M = 0.98 ± 0.07) was significantly lower than controls ( M = 1.17 ± 0.05, P < 0.001). We conclude that M is a LIIF because it uncouples intrinsic DF (i.e., the pressure-flow relation) from extrinsic load (left ventricular end-diastolic pressure). Larger M values imply better DF in that increasing AV pressure gradient results in relatively smaller increases in peak resistive losses ( cEpeak). Conversely, lower M implies that increasing AV gradient leads to larger increases in resistive losses. Further prospective validation characterizing M in well-defined pathological states is warranted.

scholarly journals Tachycardia-induced myocardial ischemia and diastolic dysfunction potentiate secretion of ANP, not BNP, in hypertrophic cardiomyopathy

2006 ◽  
Vol 290 (3) ◽  
pp. H1064-H1070 ◽  
Author(s):  
Shinsuke Kido ◽  
Naoyuki Hasebe ◽  
Yoshinao Ishii ◽  
Kenjiro Kikuchi
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Myocardial Ischemia ◽  
Diastolic Dysfunction ◽  
Diastolic Pressure ◽  
Systolic Function ◽  
Left Ventricular ◽  
Atrial Pacing ◽  
Catheter Tip ◽  
Lv Systolic Function ◽  
Lv Diastolic Dysfunction

The aim of this study was to investigate what factor determines tachycardia-induced secretion of atrial and brain natriuretic peptides (ANP and BNP, respectively) in patients with hypertrophic cardiomyopathy (HCM). HCM patients with normal left ventricular (LV) systolic function and intact coronary artery ( n = 22) underwent rapid atrial pacing test. The cardiac secretion of ANP and BNP and the lactate extraction ratio (LER) were evaluated by using blood samples from the coronary sinus and aorta. LV end-diastolic pressure (LVEDP) and the time constant of LV relaxation of tau were measured by a catheter-tip transducer. These parameters were compared with normal controls ( n = 8). HCM patients were divided into obstructive (HOCM) and nonobstructive (HNCM) groups. The cardiac secretion of ANP was significantly increased by rapid pacing in HOCM from 384 ± 101 to 1,268 ± 334 pg/ml ( P < 0.05); however, it was not significant in control and HNCM groups. In contrast, the cardiac secretion of BNP was fairly constant and rather significantly decreased in HCM ( P < 0.01). The cardiac ANP secretion was significantly correlated with changes in LER ( r = −0.57, P < 0.01) and tau ( r = 0.73, P < 0.001) in HCM patients. Tachycardia potentiates the cardiac secretion of ANP, not BNP, in patients with HCM, particularly when it induces myocardial ischemia and LV diastolic dysfunction.

scholarly journals Genetic inhibition of calcineurin induces diastolic dysfunction in mice with chronic pressure overload

2009 ◽  
Vol 297 (5) ◽  
pp. H1814-H1819 ◽  
Author(s):  
Ricardo J. Gelpi ◽  
Shumin Gao ◽  
Peiyong Zhai ◽  
Lin Yan ◽  
Chull Hong ◽  
...  
Keyword(s):  
Diastolic Dysfunction ◽  
Diastolic Function ◽  
Systolic Function ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Aortic Banding ◽  
Lv Systolic Function ◽  
Calcineurin Inhibition ◽  
Lv Diastolic Function ◽  
Isovolumic Relaxation

Calcineurin is a Ca2+/calmodulin-dependent protein phosphatase that induces myocardial growth in response to several physiological and pathological stimuli. Calcineurin inhibition, induced either via cyclosporine or genetically, can decrease myocardial hypertrophy secondary to pressure overload without affecting left ventricular (LV) systolic function. Since hypertrophy can also affect LV diastolic function, the goal of this study was to examine the effects of chronic pressure overload (2 wk aortic banding) in transgenic (Tg) mice overexpressing Zaki-4β (TgZ), a specific endogenous inhibitor of calcineurin, on LV diastolic function. As expected, in the TgZ mice with calcineurin inhibitor overexpression, aortic banding reduced the degree of LV hypertrophy, as assessed by LV weight-to-body weight ratio (3.5 ± 0.1) compared with that in non-Tg mice (4.6 ± 0.2). LV systolic function remained compensated in both groups with pressure overload. However, the LV end-diastolic stress-to-LV end-diastolic dimension ratio, an index of diastolic stiffness and LV pressure half-time and isovolumic relaxation time, two indexes of isovolumic relaxation, increased significantly more in TgZ mice with aortic banding. Protein levels of phosphorylated phospholamban (PS16), sarco(endo)plasmic reticulum Ca2+-ATPase 2a, phosphorylated ryanodine receptor, and the Na+/Ca2+ exchanger were also reduced significantly ( P < 0.05) in the banded TgZ mice. As expected, genetic calcineurin inhibition inhibited the development of LV hypertrophy with chronic pressure overload but also induced LV diastolic dysfunction, as reflected by both impaired isovolumic relaxation and increased myocardial stiffness. Thus genetic calcineurin inhibition reveals a new mechanism regulating LV diastolic function.

scholarly journals A common mechanism for concurrent changes of diastolic muscle length and systolic function in intact hearts

2001 ◽  
Vol 280 (4) ◽  
pp. H1513-H1518 ◽  
Author(s):  
Li Lu ◽  
Ya Xu ◽  
Peili Zhu ◽  
Clifford Greyson ◽  
Gregory G. Schwartz
Keyword(s):  
Diastolic Pressure ◽  
Systolic Function ◽  
Muscle Length ◽  
Left Ventricular ◽  
Segment Length ◽  
Common Mechanism ◽  
External Work ◽  
Cross Bridge ◽  
Cross Bridges

Mechanical properties of the myocardium at end diastole have been thought to be dominated by passive material properties rather than by active sarcomere cross-bridge interactions. This study tested the hypothesis that residual cross-bridges significantly contribute to end-diastolic mechanics in vivo and that changes in end-diastolic cross-bridge interaction parallel concurrent changes in systolic cross-bridge interaction. Open-chest anesthetized pigs were treated with intracoronary verapamil ( n = 7) or 2,3-butanedione monoxime (BDM; n = 8). Regional left ventricular external work and end-diastolic pressure (EDP) versus end-diastolic segment length (EDL) relations were determined in the treated and untreated regions of each heart. Both agents reduced external work of treated regions to 31–38% of baseline and concurrently shifted EDP versus EDL relations to the right (i.e., greater EDL at a given EDP) by an average of 5% ( P < 0.05). During washout of the drugs, EDP versus EDL returned to baseline in parallel with recovery of external work. Sarcomere length, measured by transmission electron microscopy in BDM-treated and untreated regions of the same hearts after diastolic arrest and perfusion fixation, was 8% greater in BDM-treated regions ( P < 0.01). We concluded that residual diastolic cross-bridges significantly and reversibly influence end-diastolic mechanics in vivo. Alterations of end-diastolic and systolic cross-bridge interactions occur in parallel.

scholarly journals HDAC inhibition improves cardiopulmonary function in a feline model of diastolic dysfunction

2020 ◽  
Vol 12 (525) ◽  
pp. eaay7205 ◽  
Author(s):  
Markus Wallner ◽  
Deborah M. Eaton ◽  
Remus M. Berretta ◽  
Laura Liesinger ◽  
Matthias Schittmayer ◽  
...  
Keyword(s):  
Diastolic Dysfunction ◽  
Diastolic Pressure ◽  
Ex Vivo ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Blood Oxygenation ◽  
Hdac Inhibition ◽  
Major Health Problem ◽  
Feline Model

Heart failure with preserved ejection fraction (HFpEF) is a major health problem without effective therapies. This study assessed the effects of histone deacetylase (HDAC) inhibition on cardiopulmonary structure, function, and metabolism in a large mammalian model of pressure overload recapitulating features of diastolic dysfunction common to human HFpEF. Male domestic short-hair felines (n = 31, aged 2 months) underwent a sham procedure (n = 10) or loose aortic banding (n = 21), resulting in slow-progressive pressure overload. Two months after banding, animals were treated daily with suberoylanilide hydroxamic acid (b + SAHA, 10 mg/kg, n = 8), a Food and Drug Administration–approved pan-HDAC inhibitor, or vehicle (b + veh, n = 8) for 2 months. Echocardiography at 4 months after banding revealed that b + SAHA animals had significantly reduced left ventricular hypertrophy (LVH) (P < 0.0001) and left atrium size (P < 0.0001) versus b + veh animals. Left ventricular (LV) end-diastolic pressure and mean pulmonary arterial pressure were significantly reduced in b + SAHA (P < 0.01) versus b + veh. SAHA increased myofibril relaxation ex vivo, which correlated with in vivo improvements of LV relaxation. Furthermore, SAHA treatment preserved lung structure, compliance, blood oxygenation, and reduced perivascular fluid cuffs around extra-alveolar vessels, suggesting attenuated alveolar capillary stress failure. Acetylation proteomics revealed that SAHA altered lysine acetylation of mitochondrial metabolic enzymes. These results suggest that acetylation defects in hypertrophic stress can be reversed by HDAC inhibitors, with implications for improving cardiac structure and function in patients.

Hyperhomocysteinemia leads to adverse cardiac remodeling in hypertensive rats

2002 ◽  
Vol 283 (6) ◽  
pp. H2567-H2574 ◽  
Author(s):  
Jacob Joseph ◽  
Abeer Washington ◽  
Lija Joseph ◽  
Laura Koehler ◽  
Louis M. Fink ◽  
...  
Keyword(s):  
Diastolic Dysfunction ◽  
Cardiac Remodeling ◽  
Dietary Intervention ◽  
Diastolic Pressure ◽  
Systolic Function ◽  
Myocardial Dysfunction ◽  
Left Ventricular ◽  
Hypertensive Rats ◽  
Volume Curve

Hyperhomocysteinemia (Hhe), linked to cardiovascular disease by epidemiological studies, may be an important factor in adverse cardiac remodeling in hypertension. Specifically, convergence of myocardial and vascular alterations promoted by Hhe and hypertension may exacerbate cardiac remodeling and myocardial dysfunction. We studied male spontaneously hypertensive rats fed one of three diets: control, intermediate Hhe inducing, or severe Hhe inducing. After 10 wk of dietary intervention, cardiac function was assessed in vitro, and cardiac and coronary arteriolar remodeling were monitored by histomorphometric, immunohistochemical, and biochemical techniques. Results showed that Hhe induced diastolic dysfunction, as characterized by the diastolic pressure-volume curve, without significant changes in baseline systolic function. Perivascular collagen levels were increased by Hhe, and there was an increase in left ventricular hydroxyproline levels. Myocyte size was not affected. Coronary arteriolar wall thickness increased with Hhe due to smooth muscle hyperplasia. Mast cells increased in parallel with Hhe and collagen accumulation. In summary, 10 wk of Hhe caused coronary arteriolar remodeling, myocardial collagen deposition, and diastolic dysfunction in hypertensive rats.

Effect of lidocaine on left ventricular pressure-volume curves during demand ischemia in pigs

1998 ◽  
Vol 274 (6) ◽  
pp. H2100-H2109 ◽  
Author(s):  
Masao Tayama ◽  
Steven B. Solomon ◽  
Stanton A. Glantz
Keyword(s):  
Diastolic Dysfunction ◽  
Diastolic Pressure ◽  
Systolic Function ◽  
Left Ventricular ◽  
Volume Curve ◽  
Pressure Volume Curve ◽  
Volume Relationship ◽  
Before And After ◽  
Lidocaine Injection ◽  
Pressure Volume Relationship

The diastolic pressure-volume curve shifts upward during demand ischemia, most likely because of changes in Ca2+ dynamics within the sarcomere. It is possible that agents that affect Na+/Ca2+exchange, such as lidocaine, a class 1b-type Na+-channel blocker that decreases intracellular Na+, could affect the diastolic pressure-volume relationship because of indirect effects on intracellular Ca2+. Lidocaine is a drug widely used to treat arrhythmias in patients with myocardial ischemia. We studied the effects of lidocaine on diastolic dysfunction associated with demand ischemia. We compared diastolic (as represented by the shift in the diastolic pressure-volume relationship) and systolic function during demand ischemia before and after lidocaine injection. We created demand ischemia in pigs before and after administering lidocaine (5 mg/kg) in eight open-pericardium anesthetized pigs. Demand ischemia was induced by constricting the left anterior descending coronary artery and then pacing at 1.5–1.8 times the baseline heart rate for 1.5–3 min. Hemodynamics were recorded during baseline, demand ischemia, baseline after lidocaine injection, and demand ischemia after lidocaine. Lidocaine did not affect systolic function or the time constant of isovolumic relaxation, but it increased the upward shift of the diastolic pressure-volume curve during demand ischemia compared with the increase that occurred before lidocaine was administered. This result suggests that lidocaine could aggravate diastolic dysfunction in patients with ischemic heart disease.

Cardiac diastolic dysfunction in conscious dogs with heart failure induced by chronic coronary microembolization

2006 ◽  
Vol 291 (6) ◽  
pp. H3154-H3158 ◽  
Author(s):  
Robert M. Gill ◽  
Bonita D. Jones ◽  
Angela K. Corbly ◽  
Juan Wang ◽  
Julian C. Braz ◽  
...  
Keyword(s):  
Heart Failure ◽  
Diastolic Dysfunction ◽  
Diastolic Pressure ◽  
Systolic Function ◽  
Canine Model ◽  
Left Ventricular ◽  
Plasminogen Activator Inhibitor 1 ◽  
Stiffness Constant ◽  
Coronary Embolization ◽  
Pai 1

Left ventricular (LV) diastolic dysfunction is a fundamental impairment in congestive heart failure (CHF). This study examined LV diastolic function in the canine model of CHF induced by chronic coronary embolization (CCE). Dogs were implanted with coronary catheters (both left anterior descending and circumflex arteries) for CCE and instrumented for measurement of LV pressure and dimension. Heart failure was elicited by daily intracoronary injections of microspheres (1.2 million, 90- to 120-μm diameter) for 24 ± 4 days, resulting in significant depression of cardiac systolic function. After CCE, LV maximum negative change of pressure with time (dP/d tmin) decreased by 25 ± 2% ( P < 0.05) and LV isovolumic relaxation constant and duration increased by 19 ± 5% and 25 ± 6%, respectively (both P < 0.05), indicating an impairment of LV active relaxation, which was cardiac preload independent. LV passive viscoelastic properties were evaluated from the LV end-diastolic pressure (EDP)-volume (EDV) relationship (EDP = beα*EDV) during brief inferior vena caval occlusion and acute volume loading, while the chamber stiffness coefficient (α) increased by 62 ± 10% ( P < 0.05) and the stiffness constant ( k) increased by 66 ± 13% after CCE. The regional myocardial diastolic stiffness in LV anterior and posterior walls was increased by 70 ± 25% and 63 ± 24% (both P < 0.05), respectively, after CCE, associated with marked fibrosis, increase in collagen I and III, and enhancement of plasminogen activator inhibitor-1 (PAI-1) protein expression. Thus along with depressed LV systolic function there is significant impairment of LV diastolic relaxation and increase in chamber stiffness, with development of myocardial fibrosis and activation of PAI-1, in the canine model of CHF induced by CCE.

Abstract 3430: Left Ventricular Hypertrophy and Diastolic Dysfunction in Mice Lacking All Nitric Oxide Synthase Isoforms

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Masato Tsutsui ◽  
Kiyoko Shibata ◽  
Hiroaki Shimokawa ◽  
Yasuko Yatera ◽  
Yumi Furuno ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Diastolic Dysfunction ◽  
Cardiac Fibrosis ◽  
Systolic Function ◽  
Left Ventricular ◽  
Functional Changes ◽  
Arterial Blood ◽  
Oxide Synthase

We have recently succeeded in developing mice in which all three nitric oxide synthase isoforms (nNOS, iNOS, and eNOS) are completely disrupted ( PNAS 2005). In this study, we examined cardiac morphology and function in those mice. Cardiac echocardiography and left ventricular (LV) hemodynamic measurement were performed in male wild-type (WT), singly nNOS −/− , iNOS −/− , eNOS −/− , and triply n/i/eNOS −/− mice at 2 and 5 months of age (n=5–8). At 2 months of age, no significant cardiac morphological or functional changes were detected in any strains studied. However, at 5 months of age, significant LV hypertrophy (wall thickness, mm) were noted in the triply n/i/eNOS −/− mice (1.3±0.1, P <0.01) and to a lesser extent in the singly eNOS −/− mice (1.1±0.1, P <0.05), but not in the singly nNOS −/− (0.8±0.1) or iNOS −/− mice (1.0±0.1), as compared with the WT mice (1.0±0.2). Furthermore, significant LV diastolic dysfunction (as evaluated by echocardiographic E/A ratio and by hemodynamic peak negative dP/dt), with preserved LV systolic function (as assessed by echocardiographic ejection fraction and by hemodynamic peak positive dP/dt), was noted only in the 5-month-old triply n/i/eNOS −/− mice (2.7±0.1 and 2505±60, both P <0.05), but not in any singly nNOS −/− (2.1±0.2 and 3833±402), iNOS −/− (2.0±0.1 and 3773±747), or eNOS −/− mice (2.0±0.3 and 2934±122), as compared with the WT mice (1.9±0.1 and 4038±344). In addition, significant cardiac fibrosis (fibrosis area, %, Masson-trichrome staining) was also detected only in the 5-month-old triply n/i/eNOS −/− mice (1.4±0.2, P <0.05) compared with the WT mice (0.3±0.1). Importantly, arterial blood pressure (mmHg, tail-cuff method) was significantly elevated in the triply n/i/eNOS −/− (143±3.1, P <0.05) than in the WT mice (104±7.3), but the hypertensive level was comparable to that in the singly eNOS −/− mice (140±8.5). Thus, mechanism(s) other than hypertension appears to be involved in the cardiac abnormalities of the triply n/i/eNOS −/− mice. These results provide the first evidence that genetic disruption of all NOSs results in LV hypertrophy and diastolic dysfunction in mice in vivo, suggesting a pivotal role of the NOS system in maintaining cardiac homeostasis.

Estimation of Left Ventricular Wall Stiffness by Analysis of Late Diastolic Pressure Components

2011 ◽  
Author(s):  
Casandra L. Niebel ◽  
Kelley C. Stewart ◽  
Takahiro Ohara ◽  
John J. Charonko ◽  
Pavlos P. Vlachos ◽  
...  
Keyword(s):  
Heart Failure ◽  
Left Ventricle ◽  
Diastolic Dysfunction ◽  
Diastolic Pressure ◽  
Left Ventricular Diastolic Dysfunction ◽  
Left Ventricular ◽  
Ventricular Wall ◽  
Ventricular Relaxation ◽  
Wall Stiffness ◽  
Ventricular Diastolic Dysfunction

Left ventricular diastolic dysfunction (LVDD) is any abnormality in the filling of the left ventricle and is conventionally evaluated by analysis of the relaxation driven phase, or early diastole. LVDD has been shown to be a precursor to heart failure and the diagnosis and treatment for diastolic failure is less understood than for systolic failure. Diastole consists of two filling waves, early and late and is primarily dependent on ventricular relaxation and wall stiffness.

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