Effect of PDE5 inhibition on coronary hemodynamics in pacing-induced heart failure

2003 ◽  
Vol 284 (5) ◽  
pp. H1513-H1520 ◽  
Author(s):  
YingJie Chen ◽  
Jay H. Traverse ◽  
Mingxiao Hou ◽  
Yunfang Li ◽  
Ruisheng Du ◽  
...  
Keyword(s):  
Heart Failure ◽  
Diastolic Pressure ◽  
Time Derivative ◽  
Systolic Pressure ◽  
Coronary Vessels ◽  
Aortic Pressure ◽  
Left Ventricular ◽  
Pde5 Inhibition ◽  
Rapid Ventricular Pacing ◽  
Phosphodiesterase Type

Inhibition of phosphodiesterase type 5 (PDE5) can relax systemic and coronary vessels by causing accumulation of cGMP. Both the endothelial dysfunction with decreased nitric oxide production and increased natriuretic peptide levels in congestive heart failure (CHF) have the potential to alter cGMP production, thereby influencing the response to PDE5 inhibition. Consequently, this study examined the effects of PDE5 inhibition with sildenafil in dogs with CHF produced by rapid ventricular pacing. CHF resulted in decreases of left ventricular (LV) systolic pressure, coronary blood flow, and the maximal first time derivative of LV pressure (LV dP/d t max) at rest and during treadmill exercise compared with normal, whereas resting LV end-diastolic pressure increased from 10 ± 1.4 to 23 ± 1.4 mmHg. Sildenafil (2 and 10 mg/kg per os) caused a 5- to 6-mmHg decrease of aortic pressure ( P < 0.05), with no change of heart rate, LV systolic pressure, or LV dP/d t max. Sildenafil caused no change in coronary flow or myocardial oxygen consumption in animals with CHF at rest or during exercise. In contrast to findings in normal animals, sildenafil did not augment endothelium-dependent coronary vasodilation in response to acetylcholine in animals with CHF. Furthermore, Western blotting showed decreased PDE5 protein expression in myocardium from failing hearts. These findings demonstrate that PDE5 contributes little to regulation of coronary hemodynamics in CHF.

Inhibition of NO production increases myocardial blood flow and oxygen consumption in congestive heart failure

2002 ◽  
Vol 282 (6) ◽  
pp. H2278-H2283 ◽  
Author(s):  
Jay H. Traverse ◽  
Yingjie Chen ◽  
Mingxiao Hou ◽  
Robert J. Bache
Keyword(s):  
Heart Failure ◽  
Congestive Heart Failure ◽  
Blood Flow ◽  
Oxygen Consumption ◽  
Diastolic Pressure ◽  
Systolic Pressure ◽  
Left Ventricular ◽  
No Production ◽  
Before And After ◽  
Rapid Ventricular Pacing

Coronary blood flow (CBF) and myocardial oxygen consumption (MV˙o 2) are reduced in dogs with pacing-induced congestive heart failure (CHF), which suggests that energy metabolism is downregulated. Because nitric oxide (NO) can inhibit mitochondrial respiration, we examined the effects of NO inhibition on CBF and MV˙o 2 in dogs with CHF. CBF and MV˙o 2 were measured at rest and during treadmill exercise in 10 dogs with CHF produced by rapid ventricular pacing before and after inhibition of NO production with N G-nitro-l-arginine (l-NNA, 10 mg/kg iv). The development of CHF was accompanied by decreases in aortic and left ventricular (LV) systolic pressure and an increase in LV end-diastolic pressure (25 ± 2 mmHg). l-NNA increased MV˙o 2 at rest (from 3.07 ± 0.61 to 4.15 ± 0.80 ml/min) and during exercise; this was accompanied by an increase in CBF at rest (from 31 ± 2 to 40 ± 4 ml/min) and during exercise (both P < 0.05). Althoughl-NNA significantly increased LV systolic pressure, similar increases in pressure produced by phenylephrine did not increase MV˙o 2. The findings suggest that NO exerts tonic inhibition on respiration in the failing heart.

Effect of sildenafil on coronary active and reactive hyperemia

2000 ◽  
Vol 279 (5) ◽  
pp. H2319-H2325 ◽  
Author(s):  
Yingjie Chen ◽  
Ruisheng Du ◽  
Jay H. Traverse ◽  
Robert J. Bache
Keyword(s):  
Blood Flow ◽  
Myocardial Blood Flow ◽  
Coronary Flow ◽  
Reactive Hyperemia ◽  
Time Derivative ◽  
Systolic Pressure ◽  
Aortic Pressure ◽  
Left Ventricular ◽  
Resistance Vessel ◽  
Phosphodiesterase Type

Sildenafil, a selective inhibitor of phosphodiesterase type 5, produces relaxation of isolated epicardial coronary artery segments by causing accumulation of cGMP. Because shear-induced nitric oxide-dependent vasodilation is mediated by cGMP, this study was performed to determine whether sildenafil would augment the coronary resistance vessel dilation that occurs during the high-flow states of exercise or reactive hyperemia. In chronically instrumented dogs, sildenafil (2 mg/kg per os) augmented the vasodilator response to acetylcholine, with a leftward shift of the dose-response curve relating coronary flow to acetylcholine dose. Sildenafil caused a 6.7 ± 2.1 mmHg decrease of mean aortic pressure, which was similar at rest and during treadmill exercise ( P < 0.05), with no change of heart rate, left ventricular (LV) systolic pressure, or LV maximal first time derivative of LV pressure. Sildenafil tended to increase myocardial blood flow at rest and during exercise (mean increase = 14 ± 3%; P < 0.05 by ANOVA), but this was associated with a significant decrease in hemoglobin, so that the relationship between myocardial oxygen consumption and oxygen delivery to the myocardium (myocardial blood flow × arterial O2 content) was unchanged. Furthermore, sildenafil did not alter coronary venous Po 2, indicating that the coupling between myocardial blood flow and myocardial oxygen demands was not altered. In addition, sildenafil did not alter the peak coronary flow rate, debt repayment, or duration of reactive hyperemia that followed a 10-s coronary occlusion. The findings suggest that cGMP-mediated resistance vessel dilation contributes little to the increase in myocardial flow that occurs during exercise or reactive hyperemia.

Nitric oxide modulates epicardial coronary basal vasomotor tone in awake dogs

1990 ◽  
Vol 258 (4) ◽  
pp. H1250-H1254 ◽  
Author(s):  
A. Chu ◽  
D. E. Chambers ◽  
C. C. Lin ◽  
W. D. Kuehl ◽  
F. R. Cobb
Keyword(s):  
Nitric Oxide ◽  
Coronary Flow ◽  
Diastolic Pressure ◽  
Coronary Vessels ◽  
Aortic Pressure ◽  
Left Ventricular ◽  
Vasomotor Tone ◽  
Coronary Vasomotor Tone ◽  
Endogenous Nitric Oxide

This study evaluates the role of endogenous nitric oxide in the modulation of basal coronary vasomotor tone by studying the effects of NG-monomethyl-L-arginine (L-NMMA), an inhibitor of nitric oxide formation from L-arginine, on resting epicardial coronary diameter and coronary flow. L-NMMA (5 mg/kg) was infused in seven awake dogs chronically instrumented with coronary dimension crystals for measurement of epicardial coronary diameter, and Doppler flow probes for quantitation of phasic coronary flow (vasomotion of distal regulatory resistance coronary vessels). Epicardial coronary diameter decreased 5.5% from 3.47 +/- 0.17 to 3.28 +/- 0.15 mm (mean +/- SE). The diameter change was gradual, reaching a maximum at 13 +/- 2 min after infusion, and persistent, lasting greater than 90 min. Phasic coronary flow did not change. Mean aortic pressure significantly increased from 99 +/- 3 to 111 +/- 3 mmHg and heart rate decreased from 56 +/- 4 to 46 +/- 3 beats/min. Left ventricular end-diastolic pressure and contractility were not significantly altered. L-Arginine (66 mg/kg) but not D-arginine reversed all hemodynamic parameters. These data support an important role of nitric oxide in modulating basal epicardial coronary vasomotor tone and systemic vascular resistance.

Congestive Heart Failure in Copper-Deficient Mice

2003 ◽  
Vol 228 (7) ◽  
pp. 811-817 ◽  
Author(s):  
Laila Elsherif ◽  
Raymond V. Ortines ◽  
Jack T. Saari ◽  
Y. James Kang
Keyword(s):  
Heart Failure ◽  
Congestive Heart Failure ◽  
Left Ventricle ◽  
Diastolic Pressure ◽  
Systolic Pressure ◽  
Pressure Rise ◽  
Experimental Models ◽  
Left Ventricular ◽  
Mouse Heart ◽  
Total Period

Copper Deficiency (CuD) leads to hypertrophic cardiomyopathy in various experimental models. The morphological, electrophysiological, and molecular aspects of this hypertrophy have been under investigation for a long time. However the transition from compensated hypertrophy to decompensated heart failure has not been investigated in the study of CuD. We set out to investigate the contractile and hemodynamic parameters of the CuD mouse heart and to determine whether heart failure follows hypertrophy in the CuD heart. Dams of FVB mice were fed CuD or copper-adequate (CuA) diet starting from the third day post delivery and the weanling pups were fed the same diet for a total period of 5 weeks (pre- and postweanling). At week 4, the functional parameters of the heart were analyzed using a surgical technique for catheterizing the left ventricle. A significant decrease in left ventricle systolic pressure was observed with no significant change in heart rate, and more importantly contractility as measured by the maximal rate of left ventricular pressure rise (+dP/dt) and decline (−dP/dt) were significantly depressed in the CuD mice. However, left ventricle end diastolic pressure was elevated, and relaxation was impaired in the CuD animals; the duration of relaxation was prolonged. In addition to significant changes in the basal level of cardiac function, CuD hearts had a blunted response to the stimulation of the β-adrenergic agonist isoproterenol. Furthermore, morphological analysis revealed increased collagen accumulation in the CuD hearts along with lipid deposition. This study shows that CuD leads to systolic and diastolic dysfunction in association with histopathological changes, which are indices commonly used to diagnose congestive heart failure.

scholarly journals Ginsenoside Re Improves Isoproterenol-Induced Myocardial Fibrosis and Heart Failure in Rats

2019 ◽  
Vol 2019 ◽  
pp. 1-9 ◽  
Author(s):  
Quan-wei Wang ◽  
Xiao-feng Yu ◽  
Hua-li Xu ◽  
Xue-zhong Zhao ◽  
Da-yuan Sui
Keyword(s):  
Heart Failure ◽  
Myocardial Fibrosis ◽  
Group Treatment ◽  
Transforming Growth Factor ◽  
Diastolic Pressure ◽  
Systolic Pressure ◽  
Left Ventricular ◽  
Heart Weight ◽  
Hydroxyproline Content ◽  
Ginsenoside Re

Objective. Panax ginseng is used widely for treatment of cardiovascular disorders in China. Ginsenoside Re is the main chemical component of P. ginseng. We aimed to investigate the protective effect of ginsenoside Re on isoproterenol-induced myocardial fibrosis and heart failure in rats. Methods. A model of myocardial fibrosis and heart failure was established by once-daily subcutaneous injection of isoproterenol (5 mg/kg/day) to rats for 7 days. Simultaneously, rats were orally administrated ginsenoside Re (5 or 20 mg/kg) or vehicle daily for 4 weeks. Results. Isoproterenol enhanced the heart weight, myocardial fibrosis, and hydroxyproline content in rat hearts. Ginsenoside Re inhibited (at least in part) the isoproterenol-induced increase in heart weight, myocardial fibrosis, and hydroxyproline content. Compared with the isoproterenol group, treatment with ginsenoside Re ameliorated changes in left ventricular systolic pressure, left ventricular end diastolic pressure, and the positive and negative maximal values of the first derivative of left ventricular pressure. Ginsenoside Re administration also resulted in decreased expression of transforming growth factor (TGF)-β1 in serum and decreased expression of Smad3 and collagen I in heart tissue. Conclusion. Ginsenoside Re can improve isoproterenol-induced myocardial fibrosis and heart failure by regulation of the TGF-β1/Smad3 pathway.

scholarly journals Novel Neuromodulation Approach to Improve Left Ventricular Contractility in Heart Failure

2020 ◽  
Vol 13 (11) ◽  
Author(s):  
Vivek Y. Reddy ◽  
Jan Petrů ◽  
Filip Málek ◽  
Lee Stylos ◽  
Steve Goedeke ◽  
...  
Keyword(s):  
Heart Failure ◽  
Pulmonary Artery ◽  
Diastolic Pressure ◽  
Acute Decompensated Heart Failure ◽  
Systolic Pressure ◽  
Decompensated Heart Failure ◽  
Left Ventricular ◽  
Ventricular Contractility ◽  
Right Pulmonary Artery ◽  
The Right

Background: Morbidity and mortality outcomes for patients admitted for acute decompensated heart failure are poor and have not significantly changed in decades. Current therapies are focused on symptom relief by addressing signs and symptoms of congestion. The objective of this study was to test a novel neuromodulation therapy of stimulation of epicardial cardiac nerves passing along the posterior surface of the right pulmonary artery. Methods: Fifteen subjects admitted for defibrillator implantation and ejection fraction ≤35% on standard heart failure medications were enrolled. Through femoral arterial access, high fidelity pressure catheters were placed in the left ventricle and aortic root. After electro anatomic rendering of the pulmonary artery and branches, either a circular or basket electrophysiology catheter was placed in the right pulmonary artery to allow electrical intravascular stimulation at 20 Hz, 4 ms pulse width, and ≤20 mA. Changes in maximum positive dP/dt (dP/dt Max ) indicated changes in ventricular contractility. Results: Of 15 enrolled subjects, 5 were not studied due to equipment failure or abnormal pulmonary arterial anatomy. In the remaining subjects, dP/dt Max increased significantly by 22.6%. There was also a significant increase in maximum negative dP/dt (dP/dt Min ), mean arterial pressure, systolic pressure, diastolic pressure, and left ventricular systolic pressure. There was no significant change in heart rate or left ventricular diastolic pressure. Conclusions: In this first-in-human study, we demonstrated that in humans with stable heart failure, left ventricular contractility could be accentuated without an increase in heart rate or left ventricular filling pressures. This benign increase in contractility may benefit patients admitted for acute decompensated heart failure.

Vascular β-adrenergic receptor system is dysfunctional after myocardial infarction

2001 ◽  
Vol 280 (3) ◽  
pp. H1129-H1135 ◽  
Author(s):  
Mohamed A. Gaballa ◽  
Andrea Eckhart ◽  
Walter J. Koch ◽  
Steven Goldman
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Carotid Artery ◽  
Membrane Protein ◽  
Adrenergic Receptor ◽  
Vascular Reactivity ◽  
Diastolic Pressure ◽  
Systolic Pressure ◽  
Left Ventricular ◽  
Receptor System

We identified abnormalities in the vascular β-adrenergic receptor (β-AR) signaling pathway in heart failure after myocardial infarction (MI). To examine these abnormalities, we measured β-AR-mediated hemodynamics, vascular reactivity, and the vascular β-AR molecular signaling components in rats with heart failure after MI. Six weeks after MI, these rats had an increased left ventricular (LV) end-diastolic pressure, decreased LV systolic pressure, and decreased rate of LV pressure change (dP/d t). LV dP/d t responses to isoproterenol were shifted downward, although the responses for systemic vascular resistance were shifted upward in heart failure rats ( P < 0.05). Isoproterenol- and IBMX-induced vasorelaxations were blunted in heart failure rats ( P< 0.05) with no change in the forskolin-mediated vasorelaxation. These changes were associated with the following alterations in β-AR signaling ( P < 0.05): decreases in β-AR density (aorta: 58.7 ± 6.0 vs. 35.7 ± 1.9 fmol/mg membrane protein; carotid: 29.6 ± 5.6 vs. 18.0 ± 3.9 fmol/mg membrane protein, n = 5), increases in G protein-coupled receptor kinase activity levels (relative phosphorimage counts of 191 ± 39 vs. 259 ± 26 in the aorta and 115 ± 30 vs. 202 ± 7 in the carotid artery, n = 5), and decreases in cGMP and cAMP in the carotid artery (0.85 ± 0.10 vs. 0.31 ± 0.06 pmol/mg protein and 2.3 ± 0.3 vs. 1.2 ± 0.1 pmol/mg protein, n = 5) with no change in Gαs or Gαi in the aorta. Thus in heart failure there are abnormalities in the vascular β-AR system that are similar to those seen in the myocardium. This suggests a common neurohormonal mechanism and raises the possibility that treatment in heart failure focused on the myocardium may also affect the vasculature.

scholarly journals Elevated Swelling-Activated Chloride Current Densities in Hypertrophied Ventricular Myocytes in a Rabbit Heart Failure Model

2019 ◽  
Vol 22 (2) ◽  
pp. E107-E111
Author(s):  
Hongwei Shi ◽  
Zhenming Jiang ◽  
Teng Wang ◽  
Yongting Chen ◽  
Feng Cao
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Protein Expression ◽  
Diastolic Pressure ◽  
Rabbit Model ◽  
Systolic Pressure ◽  
Left Ventricular ◽  
Control Group ◽  
Sham Operation ◽  
Failure Group

Background: The status of the swelling-activated chloride channel (ICl, swell) during heart failure remains unclear. This study aimed to investigate whether the ICl, swell activity is altered during heart failure and to determine how the ICl, swell influences atrial arrhythmias of the failing heart. Methods: We established a heart failure rabbit model and analyzed the hemodynamic indicators 8 weeks after myocardial infarction, which include left ventricular systolic pressure (LVSP) and left ventricular end-diastolic pressure (LVDEP). Five untreated rabbits and 5 receiving a sham operation served as the control group. Left auricular appendage tissues were obtained and CLCN3 mRNA/CLCN3 protein expression levels were examined by using reverse transcription–polymerase chain reaction and Western blot, respectively. Results: Compared to the control group, the heart failure group showed a significantly decreased LVSP (14.2 ± 0.27 versus 16.9 ± 0.86 kPa, P <.05)and elevated LVDEP (2.49 ± 0.30 versus 0.15 ± 0.03 kPa, P <.05), indicating that myocardial infarction leads to progressive heart failure of rabbits in the heart failure group. CLCN3 mRNA and CLCN3 protein expression were both significantly elevated in the heart failure group compared to the control group (P <.05). Conclusion: In sum, we propose that the dynamic nature of ICl, swell upregulation may contribute to the elevated expression of CLCN3 mRNA and CLCN3 protein, resulting in myocardial cell remodeling induced by heart failure. However, further study is needed to investigate the potential functions of ICl, swell, especially the relation between ICl, swell augmentation and arrhythmia after heart failure.

Abstract 2474: Dynamic Change in LV Twist Mechanics in a Canine Model of Pacing-Induced Heart Failure

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Jianwen Wang ◽  
Sherif F Nagueh ◽  
Nilesh Mathuria ◽  
April L Gilbert ◽  
Daryl G Schulz ◽  
...  
Keyword(s):  
Heart Failure ◽  
Diastolic Pressure ◽  
Dynamic Change ◽  
Time Derivative ◽  
Systolic Pressure ◽  
Canine Model ◽  
Systolic Volume ◽  
Relaxation Period ◽  
End Diastolic Volume ◽  
The Difference

Background : LV twist may reflect LV contractility under different conditions. This study investigated LV twist dynamics and its determinants in a canine model of congestive heart failure (CHF). Methods : Pacemakers and percutaneous leads were implanted in 8 adult hound dogs (mean weight, 38 kg), and continuous chronic RV pacing was applied at 230–250 bpm until CHF induction. Subsequently, pacing was turned off to allow the heart to recover. Echocardiography and LV catheterization were performed simultaneously at baseline, during CHF while pacing was temporarily switched off, and during recovery from CHF after pacing was stopped. CHF induction by pacing was repeated in 4 dogs. Apical and basal rotations were measured using 2D speckle tracking, and LV twist was calculated as the difference between apical and basal rotations. Untwisting rate was calculated as the peak diastolic time derivative of LV twist. Results : CHF developed after 2–4 wks of pacing with LV end-diastolic volume (LVEDV), end-systolic volume (LVESV), end-diastolic pressure (LVEDP), and time constant of LV relaxation during isovolumic relaxation period (tau) all increasing significantly compared to baseline (Table ), and recovering to baseline levels 2–4 wks after pacing was stopped. LV twist and untwisting rate decreased with CHF compared to baseline, and improved during recovery from CHF although the change in untwisting rate between CHF and baseline was not significant. In pooled data, LV twist was significantly related to LVEDV (r=-0.60, P<0.001), LVESV (r=-0.59, P=0.001), LVEF (r=0.81, P<0.001), LVEDP (r=0.41, P=0.03) and +dp/dt (r=0.71, P<0.001), but not with end-systolic pressure (r=0.06, P=0.77). In multiple analysis, +dp/dt was the only independent predictor of twist (P < 0.001). Conclusions : LV twist dynamics can reflect the presence of pacing-induced CHF and its recovery. LV contractility appears to be the only determinant of LV twist in CHF.

Abstract 12325: Compensatory Increase of Left Atrial External Work to Left Ventricular Dysfunction During Afterload Increase: Insights Into the Mechanism of Decompensation in Heart Failure With Preserved Ejection Fraction

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Katsuji Inoue ◽  
Toshihiko Asanuma ◽  
Kasumi Masuda ◽  
Daisuke Sakurai ◽  
Masamichi Oka ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ejection Fraction ◽  
Diastolic Pressure ◽  
Systolic Pressure ◽  
Strain Curve ◽  
Left Ventricular ◽  
Preserved Ejection Fraction ◽  
External Work ◽  
Reservoir Function ◽  
Left Pulmonary Vein

Introduction: Afterload mismatch is considered as a cause of acute decompensation in patients with heart failure with preserved ejection fraction (HFPEF). However, behaviors of left atrium (LA) and ventricle (LV) to afterload increase have not been fully elucidated. We investigated how LA and LV acted to acute increase in afterload using speckle tracking echocardiography. Methods: Serial echocardiographic and hemodynamic data were acquired in 10 dogs during banding of the descending aorta (AoB). LA pressure was measured by a micromanometer via left pulmonary vein. As shown in Figure, peak negative strain during LA contraction and strain change during LA relaxation (early reservoir strain) and that during systole (late reservoir strain) were generated by simultaneous acquisition of LA longitudinal strain and volume. Pressure-strain curve showed 2 loops (A-loop, V-loop) and areas in A-loop and V-loop were computed as the work during active contraction and relaxation (A-work) and that during passive filling and emptying (V-work), respectively. Results: AoB increased LV systolic pressure by about 60 mmHg, mean LA pressure (3.8±1.3 vs. 7.1±2.0 mmHg) and LV end-diastolic pressure (4.5±1.7 vs. 10.7±4.0 mmHg, all p < 0.01). LV global circumferential strain decreased (-18.8±3.5 vs. -13.2±3.5%, p < 0.01) but LV stroke volume was maintained (8.4±2.3 vs. 9.6±3.6 ml). LA peak negative strain (-2.9±2.3 vs. -9.8±4.0%, p < 0.01) and early reservoir strain (3.4±1.1 vs. 7.8±2.6%, p < 0.01) increased substantially by AoB, but late reservoir function did not change (9.3±3.5 vs. 6.1±2.0%). A-work significantly increased (3.2±2.0 to 19.2±15.1 mmHg %, p < 0.01), while V-work did not change (13.3±7.1 vs. 13.6±8.0 mmHg %). Conclusions: During aortic banding, LA contraction, early reservoir function and thereby external work during the phase increased as a compensation to LV dysfunction. The failure of this mechanism may lead to decompensation in HFPEF.

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