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

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.

2021 ◽  
Vol 116 (1) ◽  
Author(s):  
Gábor Á. Fülöp ◽  
Attila Oláh ◽  
Tamas Csipo ◽  
Árpád Kovács ◽  
Róbert Pórszász ◽  
...  

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.


2006 ◽  
Vol 290 (3) ◽  
pp. H1064-H1070 ◽  
Author(s):  
Shinsuke Kido ◽  
Naoyuki Hasebe ◽  
Yoshinao Ishii ◽  
Kenjiro Kikuchi

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.


2001 ◽  
Vol 280 (4) ◽  
pp. H1513-H1518 ◽  
Author(s):  
Li Lu ◽  
Ya Xu ◽  
Peili Zhu ◽  
Clifford Greyson ◽  
Gregory G. Schwartz

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.


2001 ◽  
Vol 91 (1) ◽  
pp. 154-162 ◽  
Author(s):  
Jennifer B. Lisauskas ◽  
Jasvindar Singh ◽  
Andrew W. Bowman ◽  
Sándor J. Kovács

A chamber stiffness ( KLV)-transmitral flow (E-wave) deceleration time relation has been invasively validated in dogs with the use of average stiffness [(ΔP/ΔV)avg]. KLVis equivalent to kE, the (E-wave) stiffness of the parameterized diastolic filling model. Prediction and validation of 1) (ΔP/ΔV)avgin terms of kE, 2) early rapid-filling stiffness [(ΔP/ΔV)E] in terms of kE, and 3) passive (postdiastasis) chamber stiffness [(ΔP/ΔV)PD] from A waves in terms of the stiffness parameter for the Doppler A wave ( kA) have not been achieved. Simultaneous micromanometric left ventricular (LV) pressure (LVP) and transmitral flow from 131 subjects were analyzed. (ΔP)avgand (ΔV)avgutilized the minimum LVP-LV end-diastolic pressure interval. (ΔP/ΔV)Eutilized ΔP and ΔV from minimum LVP to E-wave termination. (ΔP/ΔV)PDutilized atrial systolic ΔP and ΔV. E- and A-wave analysis generated kEand kA. For all subjects, noninvasive-invasive relations yielded the following equations: kE= 1,401 · (ΔP/ΔV)avg+ 59.2 ( r = 0.84) and kE= 229.0 · (ΔP/ΔV)E+ 112 ( r= 0.80). For subjects with diastasis ( n = 113), kA= 1,640 · (ΔP/ΔV)PD− 8.40 ( r = 0.89). As predicted, kAshowed excellent correlation with (ΔP/ΔV)PD; kEcorrelated highly with (ΔP/ΔV)avg. In vivo validation of average, early, and passive chamber stiffness facilitates quantitative, noninvasive diastolic function assessment from transmitral flow.


2005 ◽  
Vol 288 (6) ◽  
pp. H2603-H2610 ◽  
Author(s):  
Hiroshi Ashikaga ◽  
James W. Covell ◽  
Jeffrey H. Omens

Diastolic dysfunction in volume-overload hypertrophy by aortocaval fistula is characterized by increased passive stiffness of the left ventricle (LV). We hypothesized that changes in passive properties are associated with abnormal myolaminar sheet mechanics during diastolic filling. We determined three-dimensional finite deformation of myofiber and myolaminar sheets in the LV free wall of six dogs with cineradiography of implanted markers during development of volume-overload hypertrophy by aortocaval fistula. After 9 ± 2 wk of volume overload, all dogs developed edema of extremities, pulmonary congestion, elevated LV end-diastolic pressure (5 ± 2 vs. 21 ± 4 mmHg, P < 0.05), and increased LV volume. There was no significant change in systolic function [dP/d tmax: 2,476 ± 203 vs. 2,330 ± 216 mmHg/s, P = not significant (NS)]. Diastolic relaxation was significantly reduced (dP/d tmin: −2,466 ± 190 vs. −2,076 ± 166 mmHg/s, P < 0.05; time constant of LV pressure decline: 32 ± 2 vs. 43 ± 1 ms, P < 0.05), whereas duration of diastolic filling was unchanged (304 ± 33 vs. 244 ± 42 ms, P = NS). Fiber stretch and sheet shear occur predominantly in the first third of diastolic filling, and chronic volume overload induced remodeling in lengthening of the fiber and reorientation of the laminar sheet architecture. Sheet shear was significantly increased and delayed at the subendocardial layer ( P < 0.05), whereas magnitude of fiber stretch was not altered in volume overload ( P = NS). These findings indicate that enhanced filling in volume-overload hypertrophy is achieved by enhanced sheet shear early in diastole. These results provide the first evidence that changes in motion of radially oriented laminar sheets may play an important functional role in pathology of diastolic dysfunction in this model.


2020 ◽  
Vol 12 (525) ◽  
pp. eaay7205 ◽  
Author(s):  
Markus Wallner ◽  
Deborah M. Eaton ◽  
Remus M. Berretta ◽  
Laura Liesinger ◽  
Matthias Schittmayer ◽  
...  

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.


2002 ◽  
Vol 283 (6) ◽  
pp. H2567-H2574 ◽  
Author(s):  
Jacob Joseph ◽  
Abeer Washington ◽  
Lija Joseph ◽  
Laura Koehler ◽  
Louis M. Fink ◽  
...  

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.


1998 ◽  
Vol 274 (6) ◽  
pp. H2100-H2109 ◽  
Author(s):  
Masao Tayama ◽  
Steven B. Solomon ◽  
Stanton A. Glantz

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.


2008 ◽  
Vol 65 (2) ◽  
pp. 113-118
Author(s):  
Radomir Matunovic ◽  
Zdravko Mijailovic ◽  
Dragan Tavciovski ◽  
Zoran Cosic ◽  
Zoran Stajic

Background/Aim. It is well known that patients with coronary artery disease and viable tissue as a guarantee of contractile recovery (CR), despite of decreasing ejection fraction (EF) and systolic dysfunction, could have benefit from surgical revascularization. Therefore, relationship between diastolic filling type and early postoperative recovery and complications need to be established. The aim of this study was to investigate the relation between different left ventricular (LV) diastolic filling types and CR in patients after surgical revascularization with differently preserved systolic function. Methods. We investigated 60 patients. All of them had CR estimated by stress echocardiography regardless the extent of recovery of the heart systolic function. Echocardiographic evidence of diastolic dysfunction was estimated by Doppler examination of transmitral diastolic flow. According to the derived different diastolic filling types the patients were divided into three groups: I ? patients with disorder of LV relaxation, II ? with pseudovascularisation, and III ? with restrictive filling type, and according to the value of systolic function into two subgroups: 1) relatively recovered systolic function ? EF > 40% and 2) pronounced LV dysfunction ? EF < 40%. Echocardiographic evaluation was performed before and two week after surgical revascularization. In the preoperative period the medication therapy was optimized. We estimated CR by echocardiografic paremeters but also by detection of cardiovascular events. Results. After CABG the mean value of WMSI LV tended to decrease in any groups: in the group I (n = 12) from 1.64?0.22 to 1.34?0.22; in the group II (n = 22) from 1.85?0.16 to 1.53?0.42, and in the group III (n = 26) from 1.92?0.29 to 1.81?0.52. The lowest improvement of systolic function according to EF value expressed by the number of patients was found in the group of patients with restrictive LV filling type (12; 53.8%) as contrasting to the group with pseudonormalisation (15; 78.9%). In the group of patients with restrictive diastolic filling type also was recorded the highest number of lethal outcomes (6; 23.1%), as well as cardiovascular complications (10; 38.5%). Conclusions. Restrictive LV diastolic filling type was the marker of poor prognosis in the patients with clinical heart failure undergoing surgical revascularization. The patients with heart failure and preserved systolic function were associated with similar prognosis.


2006 ◽  
Vol 291 (6) ◽  
pp. H3154-H3158 ◽  
Author(s):  
Robert M. Gill ◽  
Bonita D. Jones ◽  
Angela K. Corbly ◽  
Juan Wang ◽  
Julian C. Braz ◽  
...  

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.


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