Left Ventricular Minimal Pressure Research Articles

Novel clinical method: left ventricular diastolic pressure curve by echocardiography

Abstract Background A non-invasive clinical method for construction of the systolic part of the left ventricular (LV) pressure curve was recently introduced. There is, however, no clinical method available to construct the LV diastolic pressure curve. Purpose The aim of this study was construction of patient-specific LV diastolic pressure curves from echocardiographic data and have initial validation against simultaneously acquired pressure curves by high-fidelity LV pressure catheters (micromanometers). Methods The study included 108 patients referred for diagnostic left heart catheterization due to suspected coronary artery disease. 81 patients were used as a training cohort. The construction of a diastolic pressure curve is based on a reference unitless pressure trace and seven key pressure-time diastolic events estimated in each patient. The reference diastolic pressure trace was generated from a group of 8 patients with LV pressures recorded by micromanometer. Each individual pressure trace from the reference cohort was first annotated with the occurrence of the key diastolic events: mitral valve (MV) opening, minimum LV pressure, peak of early-diastolic mitral flow velocity (E) and start and peak of atrial contraction-induced velocity (A), and MV closure. Then the temporal intervals between these events were normalized before calculating an averaged pressure curve (Figure 1, panels A-C). A patient-specific LV diastolic pressure curve was constructed by adjusting the standard curve according to estimated LV pressure at the key diastolic events (shown in Figure 1D). The estimation of the pressure-time instants is based on the LV volume temporal transient, used to estimate filling flow rate (Q=dV/dt) and flow acceleration and deceleration (dQ/dt=d2V/dt2), as well as a set of biomarkers including left atrial reservoir strain, peak systolic LV pressure, and body mass index. LV volume temporal traces were generated by combining global 2D volumes with global longitudinal strain. The ability to generate patient-specific diastolic LV pressure curves was validated in a second cohort of 7 patients studied with micromanometer-tipped catheters. Echocardiography and LV pressure were recorded from the same series of beats and recordings were done during breath-hold at end-expiration. The agreement was accessed qualitatively and considering the mean diastolic LV pressure. Results There was good agreement between measured and estimated LV diastolic pressure curves, qualitatively and quantitatively, via mean diastolic PLV: Bias 0.2 mmHg, limits of agreement <3.2 mmHg (Figure 1D-F). Conclusions The results suggest that the LV diastolic pressure curve can be estimated by echocardiography. The method needs validation in larger populations.Non-invasive diastolic LV pressure curve

Cardiac effects of 5F-Cumyl-PEGACLONE

Synthetic cannabinoids become increasingly popular as a supposedly safe and legal alternative to cannabis. In order to circumvent the German New Psychoactive Substances Law, producers of so-called herbal mixtures rapidly design new substances with structural alterations that are not covered by the law. Acting as full agonists not only at the cannabinoid receptors 1 and 2, synthetic cannabinoids might have not only desired mental but also serious physical adverse effects. However, knowledge of adverse effects of specific substances is sparse and incomplete. This also accounts for 5F-Cumyl-PEGACLONE, a synthetic cannabinoid, which has been detected regularly in Germany in recent years. By using an animal model, the isolated perfused Langendorff heart, the study at hand aimed on finding out more about possible cardiovascular adverse effects of 5F-Cumyl-PEGACLONE. Hearts of male Wistar rats, which were excised postmortem, were exposed to two different concentrations of 5F-Cumyl-PEGACLONE: 13 hearts were exposed to 50 ng/ml and 12 hearts were exposed to 100 ng/ml. Thirteen control hearts were merely exposed to an additional amount of buffer solution. Functional parameters heart rate, minimal and maximum left ventricular pressure and coronary flow were documented at pre-defined time points during and after the administration of 5F-Cumyl-PEGACLONE/additional buffer solution. Electrocardiograms (ECGs) were documented throughout the experiments and evaluated afterwards. Kruskal–Wallis analysis was performed for each functional parameter as well as for the duration of the QRS complexes and the duration of RR intervals as derived from the ECGs. Furthermore, a multivariate analysis, comprising all functional and ECG parameters, was performed. Kruskal–Wallis analysis revealed only single significant p-values for QRS duration and minimum left ventricular pressure that did not pass a Bonferroni test. The results of the multivariate approach were also comparably homogeneous, but still the model correctly recognized hearts exposed to 100 ng/ml of 5F-Cumyl-PEGACLONE more often than hearts exposed to the low concentration of 5F-Cumyl-PEGACLONE or additional buffer solution. Evaluation of the ECGs presented single cases of ST depression and QT prolongation. Though certainly not unambiguous, these findings support the assumption that 5F-Cumyl-PEGACLONE can cause severe, if not lethal, cardiac adverse effects like arrhythmias or myocardial infarctions especially if it is consumed in combination with other drugs like alcohol or if the consumer suffers from pre-existing heart diseases.

Impaired Diastolic Function Predicts Improved Ischemic Myocardial Flow by Mechanical Left Ventricular Unloading in a Swine Model of Ischemic Heart Failure.

Background: Impact of mechanical left ventricular (LV) unloading on myocardial tissue perfusion and its regulating factors remain unclear. This study was conducted to elucidate the predictors of regional blood flow (RBF) improvement by mechanical LV unloading.Materials and Methods: One to four weeks after percutaneous induction of myocardial infarction (MI), Yorkshire pigs (n = 15) underwent mechanical LV unloading using Impella CP. Hemodynamic parameters were collected prior to LV unloading. RBF in infarct, border and remote myocardium were measured by fluorescent microsphere injections before and 120 min after LV unloading.Results: RBF showed variable responses to mechanical LV unloading. While infarct RBF improved in general (0.33 ± 0.13 to 0.42 ± 0.19 mL/min/g, p = 0.06), there were a few pigs that showed little improvement. Meanwhile, there were no clear trends in the border (1.07 ± 0.47 to 1.02 ± 0.65 mL/min/g, p = 0.73) and remote myocardial RBF (1.25 ± 0.52 to 1.23 ± 0.68 mL/min/g, p = 0.85). In the simple linear regression analysis, cardiac output, mean pulmonary arterial wedge pressure, mean left atrial pressure, minimum LV pressure, end-diastolic LV pressure, maximum dP/dt, slope of end-diastolic pressure-volume relationship (EDPVR) and end-diastolic wall stress were significantly associated with % change of infarct RBF. In the multiple regression model, slope of EDPVR and maximum dP/dt remained as independent predictors of infarct RBF change.Conclusion: Steeper EDPVR and lower maximum dP/dt were associated with increased blood perfusion in the infarct area after LV unloading. Our data suggests mechanical LV unloading is more beneficial in post-MI patients with high diastolic pressure associated with increased LV stiffness and in those with worse cardiac contractility.

Cardiac, biochemical and histopathological analysis reveals impaired heart function in hypertensive rats with apical periodontitis.

To investigate the association between experimentally induced apical periodontitis (AP) and heart function in hypertensive rats. Forty-eight normotensive Wistar albino and spontaneously hypertensive (SHR) rats were divided into four equal groups: control (C), normotensive with AP (AP), SHR and SHR with AP (SHR+AP). AP was induced on the first right mandibular molars by exposing the pulp chambers to the oral environment for four weeks and confirmed radiographically. Thereafter, the animals were sacrificed by cervical dislocation, whilst hearts were isolated and perfused according to the Langendorff technique gradually increasing coronary perfusion pressures 40-120cmH2 O. The hemimandibles were analysed radiographically (mm2 and pixels) to verify the presence of AP. Biomarkers of cardiac oxidative stress (OS) were determined in coronary venous effluent and cardiac tissue homogenate. Cardiac tissue was analysed histopathologically for signs of heart damage (oedema, fibrosis and necrosis). All data were analysed by Kruskal-Wallis and one-way anova tests (p<.05). The levels of the maximum left ventricular pressure development rate of the SHR+AP group were significantly increased compared to the AP and C groups, and of the SHR group compared with the C group (p<.05). The levels of the minimum left ventricular pressure development rate of the SHR+AP group were significantly decreased compared to the AP, SHR and C groups, and of the SHR group compared to the C group (p<.05). The radiographic AP area was significantly larger in the SHR+AP group than in the AP group (p<.01). The levels of superoxide anion were significantly higher in the SHR+AP group than in the AP, SHR and C groups (p<.05). The activities of superoxide dismutase in cardiac tissue homogenate were significantly lower in the SHR+AP and AP groups compared with the SHR and C groups (p<.05). In rats, AP was associated with impaired cardiodynamics, disturbed cardiac OS, antioxidant defence and cardiac pathologic changes in hypertensive conditions. Hypertension was associated with an increase in the AP radiographic area. Further studies should confirm whether root canal treatment can have a cardioprotective effect and reduce cardiac OS in hypertensive conditions.

Repetitive Preload Elevation and Stretch‐Induced Stiffening of Non‐Ischemic Myocardium in a Porcine Model of Multi‐Vessel Coronary Artery Disease

Objective We have recently shown that a transient elevation in left ventricular (LV) preload causes stretch-induced myocyte injury, with repetitive episodes resulting in interstitial fibrosis and reduced diastolic compliance. The present study was designed to test the hypothesis that this phenomenon contributes to stiffening of remote, non-ischemic myocardium that is subjected to repetitive preload elevation secondary to demand-induced ischemia in the setting of chronic multi-vessel coronary artery disease (CAD). Methods Swine (n=12) were instrumented with fixed 1.5 mm constrictors on the proximal left anterior descending (LAD) and left circumflex (LCx) coronary arteries. One month later, continuous ECG and LV pressure monitoring was initiated via implantable telemetry (PhysioTel Digital, DSI) to assess the frequency of preload elevation (LV end-diastolic pressure (EDP) > 30 mmHg) and tachycardia (heart rate > 170 beats/min). Serial physiological studies were performed for 3 months to assess stenosis severity (angiography), coronary flow reserve (fluorescent microspheres at rest and during adenosine vasodilation), and LV function (echocardiography). Circumferential diastolic stiffness was derived from stress-strain relationships obtained via speckle tracking echocardiography and invasive measurements of LV minimum pressure and EDP. Myocardial tissue samples were subsequently collected from the LAD (ischemic) and right coronary artery (RCA; non-ischemic) perfusion territories for post-mortem quantification of collagen content (hydroxyproline assay) and comparison to normal controls (n=8). Results By the end of the 3 month study period, animals exhibited severe LAD (93 ± 2 %) and LCx (91 ± 3 %) stenoses and significant reductions in subendocardial flow reserve (LAD: 1.4 ± 0.2; LCx: 1.3 ± 0.2) relative to the RCA territory (3.8 ± 0.6). Although LV EDP was only mildly elevated at rest (18 ± 2 mmHg), transient preload elevation occurred frequently (63 ± 10 episodes/day) and resulted in a total of 199 ± 45 min/day during which LV EDP exceeded 30 mmHg. Spontaneous tachycardia was also common (26 ± 5 episodes/day) and associated with transient elevations in LV EDP (28 ± 2 mmHg; p<0.05 vs. rest). Although LV ejection fraction was preserved (58 ± 3 %), radial and circumferential strain was depressed in ischemic and non-ischemic segments of the LV compared with controls (Table). Non-ischemic segments also exhibited increased diastolic stiffness, which coincided with a significant ~40% elevation in collagen content (0.31 ± 0.03 mg/g) vs. normal controls (0.22 ± 0.03 mg/g) that was comparable to that observed in the ischemic area of the LV (0.29 ± 0.02 mg/g). Conclusions Transient elevations in preload are common in swine with multi-vessel CAD and associated with interstitial fibrosis and myocardial stiffening in normally-perfused segments of the LV. Repetitive stretch-induced stiffening of remote myocardium may contribute to diastolic dysfunction and could explain the high prevalence of angiographically-significant CAD in patients with heart failure with preserved ejection fraction (HFpEF).

The influence of folic acid-induced acute kidney injury on cardiac function and redox status in rats.

The aim of this study was to evaluate the influence of acute kidney injury caused by high doses of folic acid on cardiac function and markers of oxidative stress in serum and isolated rat heart. Isolated hearts of Wistar albino rats (divided into two groups: control and folic acid group) were perfused according to Langendorff technique at basal coronary perfusion pressure CPP of 70cm H2O. After a stabilization period, CPP was lowered to 60cm H2O and then gradually increased to 80, 100, 120 and finally decreased to 40cm H2O in order to establish coronary autoregulation. For each perfusion pressure value, the left ventricular function parameters were determined. Samples of coronary venous effluent were collected for determination of coronary flow and biomarkers of oxidative stress. The blood samples were collected in order to examine the values of serum urea, creatinine, Na, K, and parameters of oxidative stress and antioxidant defense system. Heart and kidney tissue samples were collected for histopathological examination. Folic acid group showed reduction of systolic and diastolic left ventricular pressure and increase of coronary flow and minimum left ventricular pressure development rate. In coronary flow, folic acid group showed increased levels of TBARS and reduction of H2O2 and NO2-. Serum ROS concentrations were lower in rats treated with folic acid, particularly levels of TBARS and NO2- in which values were significantly lower. The parameters of systemic antioxidative stress were at significantly high levels especially SOD and GSH. This study is the experimental confirmation of cardio-renal syndrome type 3, which represents the acute kidney injury that causes a damage of a heart function. The data suggest that negative effects of acute kidney injury on myocardium do not necessarily involve oxidative stress, which may lead to future investigations which will be based on inflammation as a one of the important factors in the organ crosstalk.

C-Type Natriuretic Peptide Improves Left Ventricular Functional Performance at Rest and Restores Normal Exercise Responses after Heart Failure.

In heart failure (HF), the impaired left ventricular (LV) arterial coupling and diastolic dysfunction present at rest are exacerbated during exercise. C-type natriuretic peptide (CNP) is elevated in HF; however, its functional effects are unclear. We tested the hypotheses that CNP with vasodilating, natriuretic, and positive inotropic and lusitropic actions may prevent this abnormal exercise response after HF. We determined the effects of CNP (2 μg/kg plus 0.4 μg/kg per minute, i.v., 20 minutes) on plasma levels of cGMP before and after HF and assessed LV dynamics during exercise in 10 chronically instrumented dogs with pacing-induced HF. Compared with the levels before HF, CNP infusion caused significantly greater increases in cGMP levels after HF. After HF, at rest, CNP administration significantly reduced LV end-systolic pressure (PES), arterial elastance (EA), and end-diastolic pressure. The peak mitral flow (dV/dtmax) was also increased owing to decreased minimum LVP (LVPmin) and the time constant of LV relaxation (τ) (P < 0.05). In addition, LV contractility (EES) was increased. The LV-arterial coupling (EES/EA) was improved. The beneficial effects persisted during exercise. Compared with exercise in HF preparation, treatment with CNP caused significantly less important increases in PES but significantly decreased τ (34.2 vs. 42.6 ms) and minimum left ventricular pressure with further augmented dV/dtmax Both EES, EES/EA (0.87 vs. 0.32) were increased. LV mechanical efficiency improved from 0.38 to 0.57 (P < 0.05). After HF, exogenous CNP produces arterial vasodilatation and augments LV contraction, relaxation, diastolic filling, and LV arterial coupling, thus improving LV performance at rest and restoring normal exercise responses after HF.

Magnetic resonance-compatible model of isolated working heart from large animal for multimodal assessment of cardiac function, electrophysiology, and metabolism.

To provide a model close to the human heart, and to study intrinsic cardiac function at the same time as electromechanical coupling, we developed a magnetic resonance (MR)-compatible setup of isolated working perfused pig hearts. Hearts from pigs (40 kg, n = 20) and sheep (n = 1) were blood perfused ex vivo in the working mode with and without loaded right ventricle (RV), for 80 min. Cardiac function was assessed by measuring left intraventricular pressure and left ventricular (LV) ejection fraction (LVEF), aortic and mitral valve dynamics, and native T1 mapping with MR imaging (1.5 Tesla). Potential myocardial alterations were assessed at the end of ex vivo perfusion from late-Gadolinium enhancement T1 mapping. The ex vivo cardiac function was stable across the 80 min of perfusion. Aortic flow and LV-dP/dtmin were significantly higher (P < 0.05) in hearts perfused with loaded RV, without differences for heart rate, maximal and minimal LV pressure, LV-dP/dtmax, LVEF, and kinetics of aortic and mitral valves. T1 mapping analysis showed a spatially homogeneous distribution over the LV. Simultaneous recording of hemodynamics, LVEF, and local cardiac electrophysiological signals were then successfully performed at baseline and during electrical pacing protocols without inducing alteration of MR images. Finally, (31)P nuclear MR spectroscopy (9.4 T) was also performed in two pig hearts, showing phosphocreatine-to-ATP ratio in accordance with data previously reported in vivo. We demonstrate the feasibility to perfuse isolated pig hearts in the working mode, inside an MR environment, allowing simultaneous assessment of cardiac structure, mechanics, and electrophysiology, illustrating examples of potential applications.

The Cathepsin-L Inhibitor CAA0225 Improves Cardiac Function During Ischaemia-Reperfusion

Cathepsins are lysosomal cysteine proteases involved in molecular signaling and protein degradation. Importantly, these proteases can also be secreted into the extracellular space. Cathepsin-L is elevated in the serum of patients with ischaemic heart disease and correlates with disease severity. Our data demonstrate that cathepsin-L levels are increased in the coronary effluent of ex vivo rat hearts after a period of 30 min ischaemia, however the contribution of cathepsin-L to cardiac contractile function remains unknown. Using a cathepsin-L inhibitor (CAA0225), we investigated the hypothesis that cathepsin-L contributes to contractile dysfunction post ischaemia. Langendorff perfused ex vivo adult rat hearts under went 30 min whole heart ischaemia followed by 90 min reperfusion. Left ventricular (LV) function was assessed using a solid-state pressure catheter within a balloon in the LV cavity. In separate cohorts of hearts, CAA0225 or DMSO (control) was applied for 25 min prior to ischaemia. CAA0225 had no effect on LV developed pressure prior to ischaemia. However, during reperfusion post-ischaemia CAA0225 led to a sustained increase of LV developed pressure to 177% of control levels at 90 min reperfusion (25.1 vs. 44.5 % developed LV pressure of pre-ischaemia level; DSMO [n=15] vs. CAA0225 [n=6]; P<0.05). The maximum rate of rise and fall in developed LV pressure were also elevated by CAA0225 by 169% and 151% respectively. Whilst there was no significant difference in the minimum LV pressure during the ischaemic period, this parameter was reduced during reperfusion which after 90 min was 68% of control levels (78.0 vs. 53.0 mmHg; DSMO [n=15] vs. CAA0225 [n=6]; P<0.05). These data demonstrate for the first time that the cathepsin-L inhibitor CAA0225 improves both systolic and diastolic cardiac functional parameters during ischaemia-reperfusion in ex vivo adult rat hearts.

β3-Adrenergic receptor antagonist improves exercise performance in pacing-induced heart failure.

In heart failure (HF), the impaired left ventricular (LV) arterial coupling and diastolic dysfunction present at rest are exacerbated during exercise. We have previously shown that in HF at rest stimulation of β3-adrenergic receptors by endogenous catecholamine depresses LV contraction and relaxation. β3-Adrenergic receptors are activated at higher concentrations of catecholamine. Thus exercise may cause increased stimulation of cardiac β3-adrenergic receptors and contribute to this abnormal response. We assessed the effect of L-748,337 (50 μg/kg iv), a selective β3-adrenergic receptor antagonist (β3-ANT), on LV dynamics during exercise in 12 chronically instrumented dogs with pacing-induced HF. Compared with HF at rest, exercise increased LV end-systolic pressure (PES), minimum LV pressure (LVPmin), and the time constant of LV relaxation (τ) with an upward shift of early diastolic portion of LV pressure-volume loop. LV contractility decreased and arterial elastance (EA) increased. LV arterial coupling (EES/EA) (0.40 vs. 0.51) was impaired. Compared with exercise in HF preparation, exercise after β3-ANT caused similar increases in heart rate and PES but significantly decreased τ (34.9 vs. 38.3 ms) and LVPmin with a downward shift of the early diastolic portion of LV pressure-volume loop and further augmented dV/dtmax. Both EES and EES/EA (0.68 vs. 0.40) were increased. LV mechanical efficiency improved from 0.39 to 0.53. In conclusion, after HF, β3-ANT improves LV diastolic filling; increases LV contractility, LV arterial coupling, and mechanical efficiency; and improves exercise performance.

Clinical Significance of Abnormal Relaxation Pattern of the Transmitral Flow Velocity Waveform in Older Patients With Preserved Left Ventricular Ejection Fraction

The pathophysiology of abnormal relaxation pattern in the transmitral flow (TMF) velocity waveform has not been fully elucidated. A total of 173 patients who underwent comprehensive Doppler echocardiography and diagnostic cardiac catheterization for coronary artery disease were enrolled in the study. Peak early and late diastolic TMF velocities (E and A, respectively) were measured. Minimum left ventricular (LV) pressure; LV pre-A wave pressure (surrogate of mean left atrial [LA] pressure); time constant (τ) of LV pressure decay; and LV ejection fraction (LVEF) were calculated. Patients with E/A ratio <1.0 and LVEF ≥ 50% were enrolled. Patients with τ ≥ 48 ms and those with τ <48 ms were compared. The 2 groups had no significant differences in E or E/A. Minimum LV pressure (6.9 ± 2.2 mmHg vs. 3.6 ± 2.9 mmHg, P<0.0001) and LV pre-A wave pressure (9.5 ± 2.4 mmHg vs. 6.1 ± 3.0 mmHg, P<0.0001) were significantly higher in patients with τ ≥ 48 ms compared to those with τ <48 ms, but the difference between the LV pre-A and minimum LV pressures was similar between the groups (2.6 ± 1.4 mmHg vs. 2.5 ± 1.5 mmHg, P=0.89). Proportional elevations in minimum LV and pre-A pressures, due to deteriorated LV relaxation, resulted in no changes in the pressure gradient between the LA and LV in early diastole, E, or E/A.

On the In Vivo Deformation of the Mitral Valve Anterior Leaflet: Effects of Annular Geometry and Referential Configuration

Alteration of the native mitral valve (MV) shape has been hypothesized to have a profound effect on the local tissue stress distribution, and is potentially linked to limitations in repair durability. The present study was undertaken to elucidate the relation between MV annular shape and central mitral valve anterior leaflet (MVAL) strain history, using flat annuloplasty in an ovine model. In addition, we report for the first time the presence of residual in vivo leaflet strains. In vivo leaflet deformations were measured using sonocrystal transducers sutured to the MVAL (n = 10), with the 3D positions acquired over the full cardiac cycle. In six animals a flat ring was sutured to the annulus and the transducer positions recorded, while in the remaining four the MV was excised from the exsanguinated heart and the stress-free transducer positions obtained. In the central region of the MVAL the peak stretch values, referenced to the minimum left ventricular pressure (LVP), were 1.10 ± 0.01 and 1.31 ± 0.03 (mean ± standard error) in the circumferential and radial directions, respectively. Following flat ring annuloplasty, the central MVAL contracted 28% circumferentially and elongated 16% radially at minimum LVP, and the circumferential direction was under a negative strain state during the entire cardiac cycle. After valve excision from the exsanguinated heart, the MVAL contracted significantly (18 and 30% in the circumferential and radial directions, respectively), indicating the presence of substantial in vivo residual strains. While the physiological function of the residual strains (and their associated stresses) are at present unknown, accounting for their presence is clearly necessary for accurate computational simulations of MV function. Moreover, we demonstrated that changes in annular geometry dramatically alter valvular functional strains in vivo. As levels of homeostatic strains are related to tissue remodeling and homeostasis, our results suggest that surgically introduced alterations in MV shape could lead to the long term MV mechanobiological and microstructural alterations that could ultimately affect MV repair durability.

Removal of the N-terminal Extension of Cardiac Troponin I as a Functional Compensation for Impaired Myocardial β-Adrenergic Signaling

Although beta-adrenergic stimuli are essential for myocardial contractility, beta-blockers have a proven beneficial effect on the treatment of heart failure, but the mechanism is not fully understood. The stimulatory G protein alpha-subunit (Gsalpha) couples the beta-adrenoreceptor to adenylyl cyclase and the intracellular cAMP response. In a mouse model of conditional Gsalpha deficiency in the cardiac muscle (Gsalpha-DF), we demonstrated heart failure phenotypes accompanied by increases in the level of a truncated cardiac troponin I (cTnI-ND) from restricted removal of the cTnI-specific N-terminal extension. To investigate the functional significance of the increase of cTnI-ND in Gsalpha-DF cardiac muscle, we generated double transgenic mice to overexpress cTnI-ND in Gsalpha-DF hearts. The overexpression of cTnI-ND in Gsalpha-DF failing hearts increased relaxation velocity and left ventricular end diastolic volume to produce higher left ventricle maximum pressure and stroke volume. Supporting the hypothesis that up-regulation of cTnI-ND is a compensatory rather than a destructive myocardial response to impaired beta-adrenergic signaling, the aberrant expression of beta-myosin heavy chain in adult Gsalpha-DF but not control mouse hearts was reversed by cTnI overexpression. These data indicate that the up-regulation of cTnI-ND may partially compensate for the cardiac inefficiency in impaired beta-adrenergic signaling.

Recommendations for the Evaluation of Left Ventricular Diastolic Function by Echocardiography

The assessment of left ventricular (LV) diastolic function should be an integral part of a routine examination, particularly in patients presenting with dyspnea or heart failure. About half of patients with new diagnoses of heart failure have normal or near normal global ejection fractions (EFs). These patients are diagnosed with “diastolic heart failure” or “heart failure with preserved EF.”1 The assessment of LV diastolic function and filling pressures is of paramount clinical importance to distinguish this syndrome from other diseases such as pulmonary disease resulting in dyspnea, to assess prognosis, and to identify underlying cardiac disease and its best treatment. LV filling pressures as measured invasively include mean pulmonary wedge pressure or mean left atrial (LA) pressure (both in the absence of mitral stenosis), LV end-diastolic pressure (LVEDP; the pressure at the onset of the QRS complex or after A-wave pressure), and pre-A LV diastolic pressure (Figure 1).Although these pressures are different in absolute terms, they are closely related, and they change in a predictable progression with myocardial disease, such that LVEDP increases prior to the rise in mean LA pressure. Figure 1 The 4 phases of diastole are marked in relation to high-fidelity pressure recordings from the left atrium (LA) and left ventricle (LV) in anesthetized dogs. The first pressure crossover corresponds to the end of isovolumic relaxation and mitral valve opening. In the first phase, left atrial pressure exceeds left ventricular pressure, accelerating mitral flow. Peak mitral E roughly corresponds to the second crossover. Thereafter, left ventricular pressure exceeds left atrial pressure, decelerating mitral flow. These two phases correspond to rapid filling. This is followed by slow filling, with almost no pressure differences. During atrial contraction, left atrial pressure again exceeds left ventricular pressure. The solid arrow points to left ventricular minimal pressure, the dotted arrow to left ventricular …

The Effect of Acute Hypertension on Left Ventricular Diastolic Pressures in a Canine Model of Left Ventricular Dysfunction with a Preserved Ejection Fraction and Elevated Left Ventricular Filling Pressures

Decompensated heart failure with preserved left ventricular (LV) ejection fraction (EF) is often accompanied by hypertensive episodes. We hypothesized that acute increase in arterial pressure results in elevated early and late diastolic LV pressures as a result of further impaired LV relaxation. To test this hypothesis, we used a chronic canine model of LV systolic dysfunction with preserved LV function (LVDPEF) (EF > 50%) and elevated LV end-diastolic pressure using coronary microsphere embolization. At baseline and with LVDPEF, each dog was paced 10 beats above their baseline heart rate and high-fidelity LV pressures, echocardiographic LV volumes, and transmitral Doppler were obtained before and after methoxamine pressure loading. With normal LV function, LV pressures at peak negative dP/dt (+18 mm Hg, P < .05) and at LV pressure minimum (+3.6 mm Hg, P < .01) increased. Both tau (P < .05) and LV end-diastolic pressure increased (5 +/- 3 vs 13 +/- 4 mm Hg, P < .01). EF was unchanged, although LV end-diastolic volume increased (P < .01). Pressure loading with LVDPEF resulted in a timing delay (P < .05) and a greater increase in LV pressures at peak negative dP/dt (+45 mm Hg) and LV minimal pressure (+7.5 mm Hg) as compared with normal LV function (P < .01). LV end-diastolic pressure increased (9 +/- 2-23 +/- 5 mm Hg, P < .001), diastolic filling period shortened (288 +/- 51-204 +/- 54 milliseconds, P < .01), and tau increased (P < .001). EF declined from 54 +/- 9% to 43 +/- 9% (P < .05) and LV size increased (P < .01). Pressure loading with normal LV function and with LVDPEF results in increased LV diastolic pressures, which are further exaggerated with LVDPEF as a result of prolonged relaxation and shortened diastolic filling.

Assessment of left ventricular diastolic function by early diastolic mitral annulus peak acceleration rate: experimental studies and clinical application

We sought to examine the hemodynamic determinants and clinical application of the peak acceleration rate of early (Ea) diastolic velocity of the mitral annulus by tissue Doppler. Simultaneous left atrial and left ventricular (LV) catheterization and Doppler echocardiography were performed in 10 dogs. Preload was altered using volume infusion and caval occlusion, whereas myocardial lusitropic state was altered with dobutamine and esmolol. The clinical application was examined in 190 consecutive patients (55 control, 41 impaired relaxation, 46 pseudonormal, and 48 restrictive LV filling). In addition, in 60 consecutive patients, we examined the relation between it and mean wedge pressure with simultaneous Doppler echocardiography and right heart catheterization. In canine studies, a significant positive relation was present between peak acceleration rate of Ea and transmitral pressure gradient only in the stages with normal or enhanced LV relaxation, but with no relation in the stages where the time constant of LV relaxation (tau) was > or =50 ms. Its hemodynamic determinants were tau, LV minimal pressure, and transmitral pressure gradient. In clinical studies, peak acceleration rate of Ea was significantly lower in patients with impaired LV relaxation irrespective of filling pressures (P < 0.001) and with similar accuracy to peak Ea velocity (area under the curve for septal and lateral peak acceleration rates: both 0.78) in identifying these patients. No significant relation was observed between peak acceleration rate and mean wedge pressure. Peak acceleration rate of Ea appears to be a useful index of LV relaxation but not of filling pressures and can be applied to identify patients with impaired LV relaxation irrespective of their filling pressures.

Levosimendan improves LV systolic and diastolic performance at rest and during exercise after heart failure.

The new myofilament Ca2+ sensitizer levosimendan (LSM) is a positive inotropic and vasodilatory agent. Its beneficial effects have been demonstrated at rest in congestive heart failure (CHF). However, its effect during exercise (Ex) in CHF is unknown. We assessed the effects of LSM on left ventricular (LV) dynamics at rest and during Ex in eight conscious, instrumented dogs with pacing-induced CHF. After CHF, with dogs at rest, LSM decreased arterial elastance (Ea) and increased LV contractile performance as assessed by the slope of LV pressure-volume (P-V) relation. LSM caused a >60% increase in the peak rate of mitral flow (dV/dtmax) due to decreases in minimal LV pressure and the time constant of LV relaxation (tau). LV arterial coupling, quantified as the ratio of end-systolic elastance (Ees) to Ea, was increased from 0.47 to 0.85%. LV mechanical efficiency, determined as the ratio of stroke work to total P-V area, was improved from 0.54 +/- 0.09 to 0.61 +/- 0.07. These beneficial effects persisted during Ex after CHF. Compared with CHF Ex dogs, treatment with LSM prevented Ex-induced abnormal increases in mean left atrial pressure and end-diastolic pressure and decreased Ees/Ea. With LSM treatment during CHF Ex, the early diastolic portion of the LV P-V loop was shifted downward with decreased minimal LV pressure and tau values and a further augmented dV/dtmax. Ees/Ea improved, and mechanical efficiency further increased from 0.61 +/- 0.07 to 0.67 +/- 0.07, which was close to the value reached during normal Ex. After CHF, LSM produced arterial vasodilatation; improved LV relaxation and diastolic filling; increased contractility, LV arterial coupling, and mechanical efficiency; and normalized the response to Ex.

Relation between exercise capacity and left ventricular systolic versus diastolic function during exercise in patients after myocardial infarction.

It is known that left ventricular systolic function at rest does not correlate well with exercise capacity of patients with heart failure. However, the contribution of left ventricular diastolic dysfunction, especially during exercise, to exercise capacity of cardiac patients remains to be determined. To determine the impact of left ventricular systolic and diastolic function during exercise on exercise capacity of patients with left ventricular dysfunction after myocardial infarction. A symptom-limited exercise test was performed with measurements for hemodynamics and uptake of oxygen (Vo2) of 26 men who had previously suffered myocardial infarction. These patients were divided into two groups according to their peak Vo2 (group 1 with peak Vo2 > or = 16 ml/kg per min, n= 13; and group 2 with peak Vo2 < 16 ml/kg per min, n= 13). Pulmonary arterial pressure, left ventricular and systemic arterial pressure, and cardiac output were measured at rest and during exercise. At rest, there was no difference between the two groups in terms of hemodynamic parameters except for minimal dP/dt, minimal left ventricular pressure (LVP) and time constant for decay of left ventricular pressure (tau). During peak exercise, cardiac output, left ventricular end-diastolic pressure (EDP), minimal dP/dt, minimal LVP, and tau for the two groups were significantly different. Furthermore, peak Vo2 was significantly correlated with T, minimal LVP, minimal dP/dt, EDP, and maximal dP/dt during peak exercise for the whole group of patients. Left ventricular diastolic function during exercise, i.e. diastolic reserve, may be an important determinant of exercise capacity of patients with left ventricular dysfunction after myocardial infarction.

The role of ANG II and endothelin-1 in exercise-induced diastolic dysfunction in heart failure.

The diastolic dysfunction present at rest in congestive heart failure (CHF) is exacerbated during exercise (Ex). Increases in circulating ANG II and endothelin-1 (ET-1) during Ex may contribute to this response. We assessed the effect of Ex on circulating plasma levels of ANG II and ET-1 and left ventricular (LV) dynamics before and after pacing-induced CHF at rest and during Ex in nine conscious, instrumented dogs. Before CHF, there were modest increases in circulating levels of ANG II (but not ET-1) during Ex. LV diastolic performance was enhanced during Ex with decreases in the time constant of LV relaxation (tau), LV end-systolic volume (V(ES)), and LV minimum pressure with a downward shift of the LV early diastolic portion of the pressure-volume (P-V) loop. This produced an increase in peak LV filling rate without an increase in mean left atrial (LA) pressure. After CHF, the resting values of ANG II and ET-1 were elevated and increased to very high levels during Ex. After CHF, mean LA pressure, tau, and LV minimum pressure were elevated at rest and increased further during Ex. Treatment with L-754,142, a potent ET-1 antagonist, or losartan, an ANG II AT(1)-receptor blocker, decreased these abnormal Ex responses in CHF more effectively than an equally vasodilatory dose of sodium nitroprusside. Combined treatment with both ANG II- and ET-1-receptor blockers was more effective than either agent alone. We conclude that in CHF, circulating ANG II and ET-1 increase to very high levels during Ex and exacerbate the diastolic dysfunction present at rest.

Hemodynamic determinants of the mitral annulus diastolic velocities by tissue Doppler

OBJECTIVESOur goal was to identify the hemodynamic determinants of the mitral annulus (MA) diastolic velocities by tissue Doppler.BACKGROUNDThe MA diastolic velocities are promising indexes of left ventricular (LV) diastolic function. However, their hemodynamic determinants have not yet been evaluated.METHODSTen adult mongrel dogs underwent left atrial (LA) and LV pressure measurements by Millar catheters while tissue Doppler was applied to record the MA diastolic velocities at the septal and lateral corners. Conventional transmitral flow was also obtained. Left atrial and LV pressures were modified utilizing fluid administration and caval occlusion, whereas dobutamine and esmolol were used to change LV and LA relaxation. Left ventricular filling pressures were altered during different lusitropic states to evaluate for the possible interaction of preload and LV relaxation on the early diastolic velocity (Ea).RESULTSIn the majority of dogs, a positive significant relation was observed between Ea and the transmitral pressure gradient (r = 0.57, p = 0.04). The Ea had strong correlations with tau (r = −0.83, p < 0.001), LV −dP/dt (r = 0.8, p < 0.001) and minimal LV pressure (r = −0.76, p < 0.01). However, there was no relation between Ea and the transmitral pressure gradient in experimental stages where tau >50 ms. Furthermore, the late diastolic velocity at both corners of the MA had significant positive relations with LA dP/dt (r = 0.67, p < 0.01) and LA relaxation (r = 0.73, p < 0.01) but an inverse correlation with LV end-diastolic pressure (r = –0.53, p = 0.01).CONCLUSIONSLeft ventricular relaxation, minimal pressure and preload determine Ea while late diastolic velocity determinants include LA dP/dt, LA relaxation and LV end-diastolic pressure.