Index Of Myocardial Contractility Research Articles

Улучшение функции сердца у кроликов с хронической сердечной недостаточностью под действием метилина

To study effects of intravenous infusion of a cardioprotective drug metilin, developed at the "National Medical Research Center of Cardiology" on indices of cardiac function in rabbits in vivo after prolonged administration of doxorubicin. Animals of the experimental group were intravenously injected with doxorubicin (2 mg / kg once a week) for 8 weeks, animals of the control group received the same volume of saline. Myocardial damage was characterized by an increase in concentration of malondialdehyde (MDA), troponin (TnI) and MB-fraction of creatine kinase (CK-MB) in venous blood and by disturbances in the left ventricle (LV) structure at morphological examination. Metilin effects on cardiac function were assessed by echocardiography and LV catheterization by the Millar catheter tip pressure transducer. Doxorubicin administration led to a decrease of the body mass of animals, an increase of the plasma concentration of cardiac markers CK-MB and TnI, lipid peroxidation (LPO) product MDA in venous blood, and pronounced disturbances in the structure of LV fibers and microvessels. At the same time, a significant decrease of myocardial contractility indices was observed. Manifestations of this decrease were increase of the end-diastolic and end-systolic dimensions (EDD and ESD, respectively), and decreases in the shortening fraction and ejection fraction (SF and EF, respectively) compared to baseline values. These changes indicated development of chronic heart failure (CHF) in animals of the experimental group. Against this background, intravenous infusion of metilin significantly increased SF and EF, but did not affect the heart rate. Beneficial effects of metilin on the indices of cardiac contractility and relaxation were maintained after the infusion was stopped. Noteworthy, metilin exerted greater influence on cardiac function of rabbits with CHF compared to control animals that did not receive doxorubicin. The obtained results indicate the potential of metilin to reduce LV dysfunction during chemotherapy with doxorubicin.

The Prevalence, Correlates, and Impact on Cardiac Mortality of Right Ventricular Dysfunction in Nonischemic Cardiomyopathy

ObjectivesThis study sought to determine the prevalence, correlates, and impact on cardiac mortality of right ventricular (RV) dysfunction in nonischemic cardiomyopathy. BackgroundCurrent heart failure guidelines place little emphasis on RV assessment due to limited available data on determinants of RV function, mechanisms leading to its failure, and relation to outcomes. MethodsWe prospectively studied 423 patients with cardiac magnetic resonance (CMR). The pre-specified study endpoint was cardiac mortality. In 100 patients, right heart catheterization was performed as clinically indicated. ResultsDuring a median follow-up time of 6.2 years (interquartile range: 2.9 to 7.6 years), 101 patients (24%) died of cardiac causes. CMR right ventricular ejection fraction (RVEF) was a strong independent predictor of cardiac mortality after adjustment for age, heart failure–functional class, blood pressure, heart rate, serum sodium, serum creatinine, myocardial scar, and left ventricular ejection fraction (LVEF). Patients with the lowest quintile of RVEF had a nearly 5-fold higher cardiac mortality risk than did patients with the highest quintile (hazard ratio: 4.68; 95% confidence interval [CI]: 2.43 to 9.02; p < 0.0001). RVEF was positively correlated with LVEF (r = 0.60; p < 0.0001), and inversely correlated with right atrial pressure (r = −0.32; p = 0.001), pulmonary artery pressure (r = −0.34; p = 0.0005), transpulmonary gradient (r = −0.28; p = 0.006) but not with pulmonary wedge pressure (r = −0.15; p = 0.13). In multivariable logistic regression analysis of CMR, clinical, and hemodynamic data the strongest predictors of right ventricular dysfunction were LVEF (odds ratio [OR]: 0.85; 95% CI: 0.78 to 0.92; p < 0.0001), transpulmonary gradient (OR: 1.20; 95% CI: 1.09 to 1.32; p = 0.0003), and systolic blood pressure (OR: 0.97; 95% CI: 0.94 to 0.99; p = 0.02). ConclusionsCMR assessment of RVEF provides important prognostic information independent of established risk factors and LVEF in heart failure patients with nonischemic cardiomyopathy. Right ventricular dysfunction is strongly associated with both indices of intrinsic myocardial contractility and increased afterload from pulmonary vascular dysfunction.

EFFECT OF OXACOM ON THE RIGHT VENTRICULAR PRESSURE IN RATS WITH MONOСROTALIN-INDUCED PULMONARY ARTERIAL HYPERTENSION

Background. Pulmonary arterial hypertension (PAH) is a relatively rare disease, but its therapy is expensive and effectiveness is moderate. One of important mechanisms of PAH pathogenesis is reduced formation of nitric oxide in pulmonary vascular endotheliocytes. Objective . To study the effect of oxacom (dinitrosyle iron complex with ligand glutathione), which already demonstrated long-term decline in blood pressure (BP) in systemic circulation, on pressure in pulmonary circulation. Design and method . To induce PAH, the standard monocrotalin rat model was used. Three weeks after monocrotalin introduction (60 mg/kg), a catheterization of the right ventricle was performed in anesthetized rats (100 mg/kg ketamine) through jugular vein and pressure was measured. Simultaneously, BP in femoral artery and ECG were recorded. Results . Systolic pressure in the right ventricle (SPRV) in rats after monocrotalin introduction doubled compared with the control group, from 35 to 70 mmHg, but myocardial contractility index fell by 28 %, also duration of QRS complex and the height of T-wave increased. Intravenous oxacom (40 mg/kg) quickly reduced SPRV by average of 12 ± 3 mmHg, and this level was maintained for an hour. This effect was absent in control rats. Similar BP changes in systemic circulation were observed in both groups. Inhalation of nitric oxide led to BP decrease only in animals with high level of SPRV. Inhalation of oxacom was ineffective. Conclusion . Oxacom is a promising substance for sustained pressure decline in the pulmonary circulation in PAH, but further investigations are needed for the development of a more suitable prolonged-action form of the drug.

A Non-Contact Method to Assess Contractility on the Langendorff’s Model Based on CCD Imaging

Cardiac performance measurements of the isolated beating heart are essential for the evaluation of new pharmaceutical heart treatments. In the small animal, the means for these measurements usually are direct pressure changes in the left ventricle. Although volume equations are also used, they usually are indirect correlates of the pressure changes as opposed to true anatomical or dimensional measurements. In order to acquire detailed cardiac physiological data echocardiographic studies have been used in alive small animals. However, these are experimental techniques that demand a high level of expertise and expensive equipment. A new easy to use and fast charge-coupled device (CCD) analysis tool has been developed by our team for the isolated beating heart, based on morphometric changes of the projected heart‘s surface. It uses a commercially available fast CCD camera technology, home-made software and an image acquisition-analysis method to extract true dimensional changes. Its significance relies on acquisition and assessment of the cardiac anatomical parameters, using non-contact methods. A high definition CCD camera is used to acquire images from the isolated beating heart. Subsequently, image analysis software is used to eliminate noise and provide morphometric data (heart chamber dimensional changes) which are transformed to myocardial contractility indices and heart rate measurements. In conclusion, the new method presented in this paper is contactless, unbiased, cost effective, simple and can be used to evaluate the cardiac function in an ex vivo working model.

Can detect the left ventricular contraction performance from pep using ecg r wave?

The onset of ventricular depolarization defines the start of the pre-ejection period (PEP), which is commonly used as an index of myocardial contractility. Although the fiducial point for this onset has traditionally been the onset of the Q wave of the electrocardiogram (qPEP), the Q wave is not visible in some patients. Therefore, other measurement points have also been used in the literature, including the peak of the R wave (rPEP). However, there has been little systematic examination of measurement issues associated with the selection of the fiducial point for ventricular activation.

CHANGE OF CARDIAC INO- AND CHRONOTROPIC FUNCTIONS IN STRESSED ANIMALS WITH BLOCKADE OF DIFFERENT NO-SYNTHASES

Aim: to investigate the effect of long-term immobilization-painful stress on ino- and chronotropic functions of the heart with inhibition of various NO-synthases. Materials and methods: 30 female albino rats were taken. Blockers of NO-system were: aminoguanidine (50 mg/kg), 7-Nitroindazole (50 mg/kg) and NG-nitro-L-arginine methyl ester (10 mg/kg). Stress was modeled by suspending the animals for cervical dorsal skin fold for 24 hours. The functional reserves of the heart were studied using adrenoreactivity and isometric load tests. Results: experiments showed that immobilization-painful stress leads to a decrease of cardiac ino- and chronotropic functions which is observed in the reduction of increment dp/dt+, dp/dt-, LVP and HR during load tests in comparison to control group of intact animals. Selective blockade of nNOS with 7-Nitroindazole causes even greater decrease an increment indices of myocardial contractility and LVP in stressed animals during load tests. The most pronounced inhibition of inotropic function of the stressed animal’s heart observed in the non-selective inhibition of NO-synthases by L-NAME. Administration of aminoguanidine to animals (inducible NOS blocker)before and after stress causes an increase of inotropic reserve of the heart, resulting in increased increment of myocardial contractility and relaxation findings, left ventricular pressure and heart rate during load tests. Conclusions: NO-ergic system plays a significant role in limiting of the negative stress effects on the contractile function of the heart.

Центральная и периферическая гемодинамика при ожирении (литературный обзор проблемы и собственные исследования)

Diagnosis and treatment of hemodynamic disorders and especially hypertension in obese patients is a medico-social problem. Dynamic monitoring and control of the treatment with a non-invasive method of examination is required for these patients with labile psycho-emotional status. Dynamics control is necessary during a certain period of time and with a computer program evaluating the obtained results. The authors examined the patients with obesity on the complex Simon III, allowing to carrying out a comprehensive survey of non-invasive dynamic within a few minutes of observation with the software of the survey process. From a study of the literature suggests that overweight reduces contractility and diastolic function. The examination of 14 men (who do not have acute and chronic diseases, without bad habits, aged (29-52 years) revealed an inverse relationship between increasing body mass index and the index of myocardial contractility (r = -0.62, p &amp;#60;98 %) and the feedback correlation inotropy condition index (r = - 0,75, p &amp;#60;99%)., stroke index and left ventricular work fell well within the normal range of values. Such a detailed interpretation of hemodynamics makes it possible to more reasonable therapy of hypertension and prediction of outcomes in patients with obesity.

The Action of Apelin-12 and Its Analog on Hemodynamics and Cardiac Contractile Function of Rats With Isoproterenol-Induced Myocardial Lesion

Introduction of isoproterenol (beta-adrenoreceptor agonist) into rats is one of the widespread experimental models of heart failure. It is caused by diffuse ischemic damage of cardiomyocytes, followed by development of substitutive fibrosis. Apelin is a natural regulator of the myocardial contractility. The effects of apelin molecule fragment, apelin-12 and its more stable synthetic analogue, apelin-12-2 on cardiac contractile function of rats with isoproterenol-induced myocardial lesion (IML) and control animals has been studied in this work using invasive (catheterization of the left ventricle) and non-invasive (echocardiography and impedansometry) methods. Infusion of both peptides was made by sequentially increasing rate from 0.5 to 50 µg/kg/min. In the control group, efficacy of apelin-12 was low while apelin-12-2 moderately but significantly increased indices of myocardial contractility and relaxability. These changes were more pronounced in rats with IML and, in addition, the heart rate and LV systolic pressure increased in this group. These results correlate well with echocardiographic studies which showed increases of LV end diastolic volume, stroke volume and ejection fraction by 17-38%. These alterations are probably due to improved Ca2+ transport in cardiomyocytes, as in experiments on isolated cardiomyocytes both apelins have facilitated and improved Ca2+ removal from myoplasma. The results allow to conclude that apelin-12-2 seems to be a promising candidate for further development as a therapeutic agent in heart failure.

Effects of early hemodynamic resuscitation on left ventricular performance and microcirculatory function during endotoxic shock.

BackgroundMicrocirculation and macrohemodynamics are severely compromised during septic shock. However, the relationship between these two compartments needs to be further investigated. We hypothesized that early resuscitation restores left ventricular (LV) performance and microcirculatory function but fails to prevent metabolic disorders. We studied the effects of an early resuscitation protocol (ERP) on LV pressure/volume loops-derived parameters, sublingual microcirculation, and metabolic alterations during endotoxic shock.MethodsTwenty-five pigs were randomized into three groups: LPS group: Escherichia coli lipopolysaccharide (LPS); ERP group: LPS + ERP based on volume expansion, dobutamine, and noradrenaline infusion; Sham group. LV pressure/volume-derived parameters, systemic hemodynamics, sublingual microcirculation, and metabolic profile were assessed at baseline and after completing the resuscitation protocol.ResultsLPS significantly decreased LV end-diastolic volume, myocardial contractility, stroke work, and cardiac index (CI). Early resuscitation preserved preload, and myocardial contractility, increased CI and heart rate (p < .05). LPS severely diminished sublingual microvascular flow index (MFI), perfused vascular density (PVD), and the proportion of perfused vessels (PPV), while increased the heterogeneity flow index (HFI) (p < .05). Despite MFI was relatively preserved, MVD, PVD, and HFI were significantly impaired after resuscitation (p < .05). The macro- and microcirculatory changes were associated with increased lactic acidosis and mixed venous O2 saturation when compared to baseline values (p < .05). The scatter plot between mean arterial pressure (MAP) and MFI showed a biphasic relationship, suggesting that the values were within the limits of microvascular autoregulation when MAP was above 71 ± 6 mm Hg (R2 = 0.63).ConclusionsEarly hemodynamic resuscitation was effective to restore macrohemodynamia and myocardial contractility. Despite MAP and MFI were relatively preserved, the persistent microvascular dysfunction could explain metabolic disorders. The relationship between micro- and systemic hemodynamia and their impact on cellular function and metabolism needs to be further studied during endotoxic shock.Electronic supplementary materialThe online version of this article (doi:10.1186/s40635-015-0049-y) contains supplementary material, which is available to authorized users.

Determination of the effects of pulmonary arterial hypertension and therapy on the cardiovascular system of rats by impedance cardiography.

AimTo evaluate the effects of bosentan, sildenafil, and combined therapy on the cardiovascular system using impedance cardiography (ICG) in rats with monocrotaline (MCT)-induced pulmonary arterial hypertension (PAH).MethodsSeventy male Wistar-albino rats were randomized into five groups. A single dose of MCT was given to all rats, except to the control group. After 4 weeks, bosentan, sildenafil, and combined treatment was started and lasted for 3 weeks. The last group that developed PAH did not receive any medication. Echocardiographic evaluation was performed to determine the PAH development. Thoracic fluid content index (TFCI), stroke volume index (SI), heart rate (HR), cardiac index (CI), and myocardial contractility index (IC) were determined. All procedures were performed at the baseline and after 4 and 7 weeks.ResultsEchocardiographic parameters showed that the all MCT-injected rats developed PAH. There were no significant inter- and intra-group differences in TFCI, SI, and IC (P > 0.05), but at the 7th week, CI value in the sildenafil-treated PAH rats was significantly higher than in other groups and HR of PAH rats with combined therapy was significantly lower than in other groups.ConclusionPAH did not have an effect on LV function of rats, or if it did, the effect was compensated by physiological processes. Also, sildenafil treatment deteriorated the LV cardiac index.

Endothelial and neuronal nitric oxide synthases variably modulate the oestrogen-mediated control of blood pressure and cardiovascular autonomic control

1. We have shown previously that long-term oestrogen (E2) replacement lowers blood pressure (BP) and improves cardiovascular autonomic control in ovariectomized (OVX) rats. In the present study, we investigated whether constitutive and/or inducible (i) nitric oxide synthase (NOS) modulate these E2 effects. 2. We evaluated changes in BP, myocardial contractility index (dP/dtmax ) and power spectral indices of haemodynamic variability following selective inhibition of endothelial (e) NOS with N(5)-(1-iminoethyl)-L-ornithine (L-NIO), neuronal (n) NOS with N(ω)-propyl-L-arginine (NPLA) or iNOS with 1400W in telemetered OVX rats treated for 16 weeks with (OVXE2) or without (control; OVXC) E2. 3. The OVXE2 rats exhibited: (i) reduced BP and increased dP/dtmax ; (ii) cardiac parasympathetic dominance, as reflected by the reduced low-frequency (LF; 0.25-0.75 Hz)/high-frequency (HF; 0.75-3 Hz) ratio of interbeat intervals (IBI(LF/HF)); and (iii) reduced LF oscillations of systolic BP, suggesting a reduced vasomotor sympathetic tone. Inhibition of eNOS (L-NIO; 20 mg/kg, i.p.) elicited a shorter-lived pressor response in OVXE2 than OVXC, rats along with reductions in dP/dtmax and increases in the spectral index of spontaneous baroreflex sensitivity (index α). Treatment with 1 mg/kg, i.p., NPLA reduced BP and increased the IBI(LF/HF) ratio in OVXE2 but not OVXC rats. The iNOS inhibitor 1400W (5 mg/kg, i.p.) caused no haemodynamic changes in OVXC or OVXE2 rats. 4. Overall, constitutive NOS isoforms exert restraining tonic modulatory BP effects that encompass eNOS-mediated reductions and nNOS-mediated elevations in BP in OVXE2 rats. Baroreflex facilitation and dP/dtmax reductions may account for the shorter pressor action of L-NIO in E2-treated, compared with untreated, OVX rats.

Complex study of the rat heart at isoproterenol damage

Introduction of isoproterenol (an agonist of beta-adrenoreceptors) to rats is one of the widespread experimental models of cardiac failure. It is caused by damage of cardiomyocytes with the subsequent development of substitutive fibrosis. The purpose of the given work was the complex characteristic of cardiac function by means of invasive and noninvasive (echocardiography and impedansometry) methods of research. Isoproterenol was injected twice with a daily interval in dozes 85, 120, 150 or 180 mg/kg. Echocardiographic study of the heart in 2 weeks revealed obvious attributes of cardiac failure (left ventricular dilatation, lowered ejection fraction) in the groups which have received high cumulative dozes of isoproterenol (300-360 mg/kg). The catheterization of the left ventricle in these groups has shown raised enddiastolic pressure, decreased maximal rate of pressure development and fall, and also lowered indices of myocardial contractility and relaxability. In the groups which have received smaller isoproterenol dozes, apparent decrease in relaxability parameters (constants of isovolumic and auxovolumic relaxation) has been revealed at only slightly changed parameters of contractility. A strong correlation between echocardiographic and invasive parameters of myocardial contractility has been found. The phase analysis of the cardiac cycle has shown a lengthening of isometric phases of contraction and relaxation, as well as duration of ejection due to shortening duration of filling of both ventricles. Cardiomyocytes isolated from hearts with obvious cardiac failure responded to electrostimulation by arrhythmic contractions and also by much slowed and incomplete removal of free Ca++ from the myoplasm. Results allow to conclude that relatively smaller extent of myocardial damage is accompanied by decreased relaxability at slightly changed contractility, while at greater degree of damage both processes fail, but delay of relaxation still prevails.

Myocardial contractility indices based on strain imaging

Background The principal determinants of chronic left ventricular (LV) dysfunction are reduced myocardial contractility and afterload excess due to adverse LV remodeling. To determine the relative contribution of each to a given instance of LV dysfunction, reliable quantitative indices of both myocardial contractility and afterload are needed. At the LV chamber level, ventricular volume and LV pressure can be used in a ventricular elastance model. But at the myocardial level, afterload must be normalized per unit of myocardium, conventionally done using wall stress (WS) calculations, while myocardial function is best characterized as systolic myocardial deformation, or strain (ST). Prior experimental model studies have suggested that the ratio of strain to afterload may be an effective contractility index. However, this has not been evaluated in human disease. We have recently shown that a nongeometric LV end-systolic afterload index (NGI, = (end-systolic LV pressure(P) × volume (V))/LV mass(M), or PV/M), may be superior to conventional circumferential WS (CWS) as a quantitative measure of afterload at the myocardial level, and correlates more closely than CWS with circumferential ST(CST), Therefore, we evaluated the ratios CST/CWS and CST/PV/ M, as candidate contractility indices in normals(NL) and in patients with nonischemic dilated cardiomyopathy(CM).

Change of cardiac ino- and chronotropic functions in stressed animals with blockade of different NO-synthases

To investigate the effect of long-term immobilization-painful stress on ino- and chronotropic functions of the heart with inhibition of various NO-synthases. 30 female albino rats were taken. Blockers of NO-system were: aminoguanidine (50 mg/kg), (50 mg/kg) and NG-nitro-L-arginine methyl ester (10 mg/kg). Stress was modeled by suspending the animals for cervical dorsal skin fold for 24 hours. The functional reserves of the heart were studied using adrenoreactivity and isometric load tests. experiments showed that painful stress leads to a decrease of cardiac ino- and chronotropic functions which is observed in the reduction of increment dp/dt+, dp/dt-, LVP and HR during load tests in comparison to control group of intact animals. Selective blockade of nNOS with 7-Nitroindazole causes even greater decrease an increment indices of myocardial contractility and LVP in stressed animals during load tests. The most pronounced inhibition of inotropic function of the stressed animal's heart observed in the non-selective inhibition of NO-synthases by L-NAME. Administration of aminoguanidine to animals (inducible NOS blocker) before and after stress causes an increase of inotropic reserve of the heart, resulting in increased increment of myocardial contractility and relaxation findings, left ventricular pressure and heart rate during load tests, NO-ergic system plays a significant role in limiting of the negative stress effects on the contractile function of the heart.

Abstract 125: Genetic Deletion Of Telomerase Promotes Premature Cardiac Aging

Telomeropathies are a group of human diseases characterized by mutations in the telomerase gene, accelerated telomere attrition, and premature organ aging. Manifestations of telomere disease include bone marrow failure, liver cirrhosis, and lung fibrosis. It remains, however, to be documented whether loss of telomerase activity is coupled with alterations in cardiac structure and function. To address this issue, the heart of mice carrying a deletion of the RNA component of telomerase (Terc -/- mice) was studied at 3-13 months of age. This allowed us to define whether defects in telomerase function in cardiac stem cells (CSCs) and their progeny promote ventricular dysfunction independently from chronological age, which is typically associated with significant telomere erosion. For this purpose, the characteristics of the aging cardiomyopathy were defined first in 30-month-old wild-type mice (WT). Deteriorations in systolic and diastolic indices of myocardial contractility were detected in senescent mice by echo-Doppler, MRI, and invasive hemodynamics. Importantly, 6-month-old Terc -/- mice showed severe ventricular dysfunction comparable to that seen in 30 month-old WT. Telomere length in Terc -/- mouse CSCs was ~50% shorter than in age-matched WT cells but was comparable to that found in 30 month-old WT cells. The number of CSCs was 60% lower in Terc -/- than age-matched WT mice, and the fraction of BrdU-positive CSCs decreased 1.4-fold, from 25% to 14%. The absence of Terc led to a 50% reduction in myocyte turnover, which was coupled with myocyte hypertrophy and myocyte loss. BrdU labeling was reduced 60% in Terc -/- myocytes. Old CSCs formed a senescent progeny composed of cardiomyocytes, which carried markedly shortened telomeres and showed a severe depression in cell shortening and re-lengthening. Moreover, the renewal of endothelial cells was 75% lower in Terc -/- mice mimicking the rarefaction in capillary typically seen in the old myocardium. Our findings document that loss of telomerase activity is a critical determinant of cardiac aging with reduced cardiomyogenesis and vasculogenesis. These maladaptive responses may be operative in patients carrying mutations of telomerase.

Extent of load-independence of pressure-normalized stress in swine

A load-independent index of myocardial contractility provides a measure of cardiac function. Previous contractility indices have been shown to be either load-dependent or invasive. We sought to determine the extent of load (preload and afterload)-independence of dσ*/dtmax (σ* is pressure-normalized stress) in comparison with other well-established indices. Six anaesthetized pigs underwent left ventricular pressure-volume measurements under various load conditions. The average preload was decreased by 70.0 ± 15.0% (from 39.2 ± 6.4 mL to 11.7 ± 7.7 mL) and increased by 49.3 ± 5.9% (from 35.1 ± 7.4 mL to 51.7 ± 8.9 mL). The average afterload was increased by 74.3 ± 43.5% (from 3.3 ± 0.6 mmHg/mL to 5.7 ± 1.7 mmHg/mL). When preload was reduced within an average of 21.7% (39.2 ± 6.4 mL to 30.7 ± 6.2 mL) using occlusion of the inferior vena cava, dσ*/dt max did not change significantly (6.50 ± 1.10 s⁻¹ vs 6.60 ± 0.90 s⁻¹, P = non-significant [NS]). When preload was increased within an average of 29.3% (35.1 ± 7.4 mL to 45.4 ± 7.3 mL) from infusion of normal saline, dσ*/dt max did not change significantly (7.04 ± 1.00 s⁻¹ vs 7.29 ± 1.10 s⁻¹, P = NS). When afterload was increased within an average of 42.4% (3.3 ± 0.6 mmHg/mL to 4.7 ± 1.0 mmHg/mL) using intra-aortic balloon occlusion, dσ*/dtmax did not change significantly (6.72 ± 1.18 s⁻¹ vs 6.89 ± 1.28 s⁻¹, P = NS). As expected, dσ*/dtmax was significantly increased with dobutamine. A linear regression showed no correlation between dσ*/dtmax and preload (r² = 0.02, P = 0.17) within a maximum range of -30% to +50% of preload change, or between dσ*/dtmax and afterload (r² = 0.03, P = 0.36) within maximum range of 0-100% of afterload increase, respectively. In conclusion, dσ*/dtmax is independent of loading conditions within an average of 21.7% of preload decrease, 29.3% of preload increase, 42.4% of afterload increase, and sensitive to dobutamine infusion.

Ethanol‐evoked reduction in myocardial contractility and autonomic dysregulation in freely moving female rats

Acute ethanol reduces blood pressure (BP) in proestrus female rats via reduction in cardiac output, which reflected reduced cardiac contractility based on indirectly measured dP/dtmax (maximal rise of ventricular pressure over time). In this study we directly measured cardiac contractility indices [left ventricular developed pressure (LVDP), dP/dtmax and the ventricular isovolumic relaxation time constant (Tau)] in conscious freely moving female rats via fluid filled catheter. We validated this technique using isoproterenol, which produced the expected dose‐related increases in dP/dtmax. To test whether ethanol cardiac depressant effect precedes the hypotensive response in freely moving female rats, we directly measured cardiac function along with BP, HR, in two animal groups received either intragastric ethanol (1 g/kg) or water (control). Further, we conducted offline analysis of sympathovagal activity (spectral analysis) to elucidate ethanol effect on autonomic balance. Acute ethanol, compared to water, caused slowly developing reduction in BP that was significant at 40 min, reached its nadir at 70 min, and lasted till the experiment ended at 90 min. However, significant reductions in myocardial contractility indices (LVDP and dP/dtmax) started 10 min after ethanol, which preceded the hypotensive response. The high‐frequency (HFα) component of spectral analysis of RRI (cardiac vagal control) increased by intragastric ethanol starting at 20 min and continued throughout the experiment. However, the spectral measure of sympathetic activity, low‐frequency (LFα) component of RRI, was not affected by ethanol resulting in net decreases in the sympathovagal, LFRRI/HFRRI, ratio. Collectively, our findings directly implicate the reduction in cardiac contractility and enhancement of cardiac vagal control, at least partly, in acute ethanol‐evoked hypotensive effect in proestrus female rats.Supported by NIAAA Grant 2R01 AA14441–06

The Estrogen‐Mediated Control Of Blood Pressure And Cardiovascular Autonomic Control Are Differentially Modulated By Endothelial And Neuronal Nitric Oxide Synthases

Estrogen (E2) replacement lowers blood pressure (BP) and improves the cardiovascular autonomic control in ovariectomized (OVX) rats. We investigated whether constitutive and/or inducible nitric oxide synthase (NOS) modulate these E2 effects. We evaluated changes in BP, myocardial contractility (dP/dtmax), and power spectral indices of hemodynamic variability following inhibition of eNOS (L‐NIO), nNOS (NPLA), or iNOS (1400W) in telemetered OVX rats treated for 16 weeks with (OVXE2) or without (control, OVXC) E2. OVXE2 rats exhibited (i) reduced BP, and increased dP/dtmax, (ii) enhanced cardiac parasympathetic influence as reflected by decreases in low‐frequency/high‐frequency ratio of interbeat intervals (IBILF/HF), and (iii) reduced LF oscillations of systolic BP, suggesting a reduced vasomotor sympathetic tone. L‐NIO elicited a shorter‐lived pressor response in OVXE2, than in OVXC, rats along with reductions in dP/dtmax and increases in the spectral index of spontaneous baroreflex sensitivity (index α). NPLA reduced BP and increased IBILF/HF ratio in OVXE2 but not in OVXC rats. No hemodynamic changes were caused by 1400W. Overall, eNOS and nNOS exert contrasting tonic modulatory BP effects, which comprise induction of hypotension and hypertension, respectively, in OVXE2 rats. Baroreflex facilitation and dP/dtmax reductions might explain the shorter pressor action of L‐NIO in OVXE2 rats.

Cardiovascular Autonomic Activity Modulation By Nitric Oxide Synthases Mediates The Augmented Enalapril‐Evoked Hypotension In Ethanol‐Fed Female Rats

Chronic ethanol enhances the hypotensive action of enalapril in female rats. Here, we investigated whether cardiovascular auto‐nomic modulation by nitric oxide synthases (NOS) contributes to such enhancement. We investigated the effect of inhibition of eNOS [N5‐(1‐iminoethyl)‐L‐ornithine; L‐NIO], nNOS (Nω‐propyl‐L‐arginine; NPLA), or iNOS (1400W) on blood pressure (BP), myocardial contractility (dP/dtmax), and power spectral indices of hemodynamic variability in telemetered female rats fed with ethanol (5% w/v, 8 weeks) or control liquid diet in absence or presence of enalapril. In control rats, enalapril‐evoked hypotension was abolished by L‐NIO, but not by NPLA or 1400W, suggesting a preferential role for eNOS in this response. In ethanol‐fed, the greater enalapril hypotension was associated with reductions in (i) dP/dtmax, (ii) low‐frequency/high‐frequency ratio of interbeat intervals, suggesting cardiac parasympathetic dominance, and (iii) low‐frequency band of systolic BP, a marker of vasomotor sympathetic tone. While all NOS inhibitors attenuated the hemodynamic and autonomic responses of enalapril in ethanol‐fed rats, L‐NIO was the most efficacious in rectifying enalapril‐evoked autonomic responses. These findings implicate NOS isoforms, particularly eNOS, in autonomic imbalances that leads to the augmented enalapril hypotension in ethanol‐fed rats.

Increased 99mTc-Sestamibi Washout Reflects Impaired Myocardial Contractile and Relaxation Reserve During Dobutamine Stress Due to Mitochondrial Dysfunction in Dilated Cardiomyopathy Patients

This study investigated whether the technitium-99m sestamibi (MIBI) washout rate (WR) would predict mitochondrial damage and myocardial dysfunction in patients with dilated cardiomyopathy (DCM). Myocardial mitochondrial damage reduces adenosine triphosphate production, resulting in myocardial dysfunction. Increased myocardial (99m)Tc-MIBI washout is reportedly caused by mitochondrial dysfunction. Twenty DCM patients (New York Heart Association functional class I-III) underwent myocardial (99m)Tc-MIBI scintigraphy and cardiac catheterization. Myocardial MIBI uptake was quantified as an early and delayed heart-to-mediastinum ratio, and WR was calculated. Maximum first derivative of left ventricular (LV) pressure (LV dP/dtmax) (an index of myocardial contractility) and LV pressure half-time (T1/2) (an index of myocardial relaxation) were calculated by the left ventricular pressure curve at baseline and during dobutamine infusion (15 μg/kg/min at maximum). Endomyocardial biopsy specimens were obtained for quantitative mRNA analysis and electron microscopy. The patients were divided into two groups as follows: 1) group A of 10 patients showing a WR ≤ 24.3% (median value) and 2) group B of 10 patients showing a WR >24.3%. WR was significantly correlated with the percentage changes in LV dP/dtmax (%LV dP/dtmax) (r: -0.59; p = 0.01) and T1/2 (r: -0.57; p = 0.03) from baseline to peak dobutamine stress. The %LV dP/dtmax was significantly greater in group B than in group A. The abundance of mRNAs for mitochondrial electron transport-related enzymes was more significantly reduced in group B than in group A. Electron microscopy revealed significant correlations between WR and the severity of mitochondrial damage (r: 0.88; p = 0.048) and glycogen accumulation (r: 0.90; p = 0.044). Increased (99m)Tc-MIBI washout may predict mitochondrial dysfunction and the impairment of myocardial contractile and relaxation reserves during dobutamine stress in DCM patients.