Mechanisms of desensitization to a PDE inhibitor (milrinone) in conscious dogs with heart failure

1999 ◽  
Vol 276 (5) ◽  
pp. H1699-H1705 ◽  
Author(s):  
Naoki Sato ◽  
Kuniya Asai ◽  
Satoshi Okumura ◽  
Gen Takagi ◽  
Richard P. Shannon ◽  
...  
Keyword(s):  
Heart Failure ◽  
Wall Stress ◽  
Major Effect ◽  
Left Ventricular ◽  
Conscious Dogs ◽  
Internal Diameter ◽  
Compensatory Mechanism ◽  
Before And After ◽  
Rapid Ventricular Pacing ◽  
Camp Levels

The goal of this study was to determine the extent to which the effects of milrinone were desensitized in heart failure (HF) and to determine the mechanisms, i.e., whether these effects could be ascribed to changes in cAMP or phosphodiesterase (PDE) activity in HF. Accordingly, we examined the effects of milrinone in seven conscious dogs before and after HF was induced by rapid ventricular pacing at 240 beats/min. The dogs were chronically instrumented for measurements of left ventricular (LV) pressure and first derivative of LV pressure (dP/d t), arterial pressure, LV internal diameter, and wall thickness. Milrinone (10 μg ⋅ kg−1 ⋅ min−1iv) increased LV dP/d t by 1,854 ± 157 from 2,701 ± 105 mmHg/s ( P < 0.05) before HF. After HF the increase in LV dP/d t in response to milrinone was attenuated significantly ( P < 0.05); it increased by 615 ± 67 from 1,550 ± 107 mmHg/s, indicating marked desensitization. In the presence of ganglionic blockade the increases in LV dP/d t (+445 ± 65 mmHg/s) in response to milrinone were markedly less ( P < 0.01), and milrinone increased LV dP/d t even less in HF (+240 ± 65 mmHg/s). cAMP and PDE activity were measured in endocardial and epicardial layers in normal and failing myocardium. cAMP was decreased significantly ( P < 0.05) in LV endocardium (−26%) but not significantly in LV epicardium (−14%). PDE activity was also decreased significantly ( P < 0.05) in LV endocardium (−18%) but not in LV epicardium (−4%). Thus significant desensitization to milrinone was observed in conscious dogs with HF. The major effect was autonomically mediated. The biochemical mechanism appears to be due in part to the modest reductions in PDE activity in failing myocardium, which, in turn, may be a compensatory mechanism to maintain cAMP levels in HF. Reductions in cAMP and PDE levels were restricted to the subendocardium, suggesting that the increased wall stress and reduced coronary reserve play a role in mediating these changes.

Sodium channel enhancer restores baroreflex sensitivity in conscious dogs with heart failure

2005 ◽  
Vol 288 (4) ◽  
pp. H1508-H1514 ◽  
Author(s):  
Weiqun Shen ◽  
Robert M. Gill ◽  
Jian-Ping Zhang ◽  
Bonita D. Jones ◽  
Angela K. Corbly ◽  
...  
Keyword(s):  
Heart Failure ◽  
Arterial Pressure ◽  
Baroreflex Sensitivity ◽  
Vena Cava ◽  
Left Ventricular ◽  
Conscious Dogs ◽  
Inotropic Effect ◽  
Pulse Interval ◽  
Adrenergic Blockade ◽  
Before And After

We compared the cardiac inotropic, lusitropic, and chronotropic responses to the Na+ channel enhancer LY-368052 in conscious dogs before and after development of congestive heart failure (CHF). We also examined the effect of LY-368052 on baroreflex sensitivity and the efferent neural mechanisms of the bradycardic response in heart failure. Dogs were chronically instrumented, and heart failure was induced by right ventricular pacing at 240 beats/min for 3–4 wk. LY-368052 dose-dependently increased left ventricular contractile performance before and after the development of CHF to a similar extent. The inotropic effect of LY-368052 in heart failure was not altered by either ganglionic or β-adrenergic receptor blockade. LY-368052 improved cardiac relaxation and induced bradycardia in dogs with heart failure but not in normal dogs. The negative chronotropic effect of LY-368052 was eliminated by ganglionic blockade but not β-adrenergic blockade, suggesting that the bradycardia was mediated by the autonomic nervous system via enhanced parasympathetic tone. Baroreflex sensitivity was assessed as the pulse interval-mean arterial pressure slope in response to temporary pharmacological (nitroglycerin or phenylephrine) and mechanical (brief occlusion of inferior vena cava) alterations of arterial pressure in conscious dogs before and after development of heart failure. Baroreflex sensitivity was significantly depressed in heart failure and restored completely by acute treatment with LY-368052. Thus the Na+ channel enhancer LY-368052 maintains its β-receptor-independent inotropic effect in chronic CHF and specifically improves ventricular relaxation and depressed baroreflex function.

Nonsympathetic increased inotropic state early after aortic insufficiency

1982 ◽  
Vol 242 (6) ◽  
pp. H973-H979
Author(s):  
B. Crozatier ◽  
D. Caillet ◽  
J. L. Chevrier ◽  
P. Y. Hatt
Keyword(s):  
Volume Overload ◽  
Wall Stress ◽  
Aortic Insufficiency ◽  
Left Ventricular ◽  
Beta Blockade ◽  
Internal Diameter ◽  
Inotropic State ◽  
Chronic Volume Overload ◽  
Before And After ◽  
Ventricular Response

The very early left ventricular response to chronic volume overload induced by aortic insufficiency (AI) was examined in conscious dogs previously instrumented with a left ventricular micromanometer and ultrasonic crystals measuring internal diameter, segmental length, and parietal wall thickness. Acute volume loading with dextran (AVL) was compared with that 24 and 48 h after AI induced by a perforation of the aortic valve. beta-Blockade was also produced before and after AI. For a similar increase in preload in AVL and after AI, the percent change in systolic shortening of diameters and segments (% delta L) increased from 30.4 to 34.1% after AI (P less than 0.01). For matched calculated wall stress during AVL and AI, % delta L and peak velocity of shortening were significantly increased after AI, and the same results were reproduced after beta-blockade. We conclude that, at the early phase of chronic volume overload before hypertrophy appears, left ventricular hyperfunction is mainly due to a nonsympathetic increased contractility and that, in the conscious dog, the inotropic state appears to be modified by a sustained increased preload.

Trabecular cutting: a novel surgical therapy to increase diastolic compliance

2019 ◽  
Vol 127 (2) ◽  
pp. 457-463
Author(s):  
Meagan Oglesby ◽  
Danny Escobedo ◽  
Gladys Patricia Escobar ◽  
Fatemeh Fatemifar ◽  
Edward Y. Sako ◽  
...  
Keyword(s):  
Heart Failure ◽  
Left Ventricle ◽  
Diastolic Pressure ◽  
Ex Vivo ◽  
Systolic Function ◽  
Wall Stress ◽  
Rabbit Heart ◽  
Left Ventricular ◽  
Before And After ◽  
Diastolic Compliance

Heart failure with preserved ejection fraction (HFpEF) is a common cause of hospital admission in patients over 65 yr old and has high mortality. HFpEF is characterized by left ventricular (LV) hypertrophy that reduces compliance. Current HFpEF therapies control symptoms, but no existing medications or therapies can sustainably increase LV compliance. LV trabeculae develop hypertrophy and fibrosis that contribute to reduced LV compliance. This study expands our previous results in ex vivo human hearts to show that severing LV trabeculae increases diastolic compliance in an ex vivo working rabbit heart model. Trabecular cutting was performed in ex vivo rabbit hearts set up in a working heart perfusion system perfused with oxygenated Krebs-Henseleit buffer. A hook was inserted in the LV to cut trabeculae. End-systolic and end-diastolic pressure-volume relationships during transient preload reduction were recorded using an admittance catheter in the following three groups: control (no cutting; n = 9), mild cutting (15 cuts; n = 5), and aggressive cutting (30 cuts; n = 5). In a second experiment, each heart served as its own control. Hemodynamic data were recorded before and after trabecular cutting ( n = 10) or sham cutting ( n = 5) within the same heart. In the first experiments, trabecular cutting did not affect systolic function ( P > 0.05) but significantly increased overall diastolic compliance ( P = 0.009). Greater compliance was seen as trabecular cutting increased ( P = 0.002, r2 = 0.435). In the second experiment, significant increases in systolic function ( P = 0.048) and diastolic compliance ( P = 0.002) were seen after trabecular cutting compared with baseline. In conclusion, trabecular cutting significantly increases diastolic compliance without reducing systolic function. NEW & NOTEWORTHY We postulate that, in mammalian hearts, free-running trabeculae carneae exist to provide tensile support to the left ventricle and minimize diastolic wall stress. Because of hypertrophy and fibrosis of trabeculae in patients with left ventricular hypertrophy, this supportive role can become pathologic, worsening diastolic compliance. We demonstrate a novel operation involving cutting trabeculae as a method to acutely increase diastolic compliance in patients presenting with heart failure and diastolic dysfunction to improve their left ventricle compliance.

scholarly journals Altered LV inotropic reserve and mechanoenergetics early in the development of heart failure

2000 ◽  
Vol 278 (3) ◽  
pp. H698-H705 ◽  
Author(s):  
Sumanth D. Prabhu ◽  
Gregory L. Freeman
Keyword(s):  
Heart Failure ◽  
Systolic Pressure ◽  
Left Ventricular ◽  
Stroke Work ◽  
Short Term ◽  
Before And After ◽  
Autonomic Blockade ◽  
Anesthetized Dogs ◽  
Rapid Ventricular Pacing ◽  
Volume Relation

To test the hypothesis that alterations in left ventricular (LV) mechanoenergetics and the LV inotropic response to afterload manifest early in the evolution of heart failure, we examined six anesthetized dogs instrumented with LV micromanometers, piezoelectric crystals, and coronary sinus catheters before and after 24 h of rapid ventricular pacing (RVP). After autonomic blockade, the end-systolic pressure-volume relation (ESPVR), myocardial O2 consumption (MV˙o 2), and LV pressure-volume area (PVA) were defined at several different afterloads produced by graded infusions of phenylephrine. Short-term RVP resulted in reduced preload with proportionate reductions in stroke work and the maximum first derivative of LV pressure but with no significant reduction in baseline LV contractile state. In response to increased afterload, the baseline ESPVR shifted to the left with maintained end-systolic elastance ( E es). In contrast, after short-term RVP, in response to comparable increases in afterload, the ESPVR displayed reduced E es ( P < 0.05) and significantly less leftward shift compared with control ( P< 0.05). Compared with the control MV˙o 2-PVA relation, short-term RVP significantly increased the MV˙o 2 intercept ( P< 0.05) with no change in slope. These results indicate that short-term RVP produces attenuation of afterload-induced enhancement of LV performance and increases energy consumption for nonmechanical processes with maintenance of contractile efficiency, suggesting that early in the development of tachycardia heart failure, there is blunting of length-dependent activation and increased O2requirements for excitation-contraction coupling, basal metabolism, or both. Rather than being adaptive mechanisms, these abnormalities may be primary defects involved in the progression of the heart failure phenotype.

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.

Abstract 16018: Impaired Intrinsic Myocardial Shortening in Both Two Directions and Compensatory Mechanism to Maintain Left Ventricular Ejection Fraction in Patients With Hypertensive Heart Disease

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Satoshi Yamada ◽  
Kazunori Okada ◽  
Hisao Nishino ◽  
Hiroyuki Iwano ◽  
Daisuke Murai ◽  
...  
Keyword(s):  
Heart Disease ◽  
Ejection Fraction ◽  
Wall Thickness ◽  
Circumferential Strain ◽  
Hypertensive Heart Disease ◽  
Wall Stress ◽  
Left Ventricular ◽  
Relative Wall Thickness ◽  
Left Ventricular Ejection ◽  
Compensatory Mechanism

Background: Longitudinal myocardial shortening is known to be reduced even if left ventricular (LV) ejection fraction (EF) is preserved in patients with hypertensive heart disease (HHD). However, the compensatory mechanism remains to be elucidated. Thus layer-specific longitudinal and circumferential strain as well as stress-strain relationship was observed in HHD patients. Methods: In 46 HHD patients with preserved EF (>50%) and 29 age-matched control subjects, global longitudinal strain (LS) and layer-specific circumferential strain (CS) were measured from the apical 4-chamber view and mid-ventricular short-axis view, respectively, by using speckle tracking echocardiography. LS was measured at innermost LV wall layer, and CS at innermost, midwall, and outermost layers. Layer-specific end-systolic circumferential wall stress (CWS) according to Mirsky’s formula and endocardial meridional wall stress (MWS) were calculated. Results: Systolic blood pressure (147±20 mm Hg), interventricular septal thickness (13±2 mm), and LV dimension (48±4 mm) were greater in HHD than controls, whereas EF was comparable (66±8 vs 66±5%). LS was smaller in HHD than controls (-13±3 vs -17±3%, p<0.001) in spite of reduced MWS (520±141 vs 637±164 dyn·mm -2 , p<0.01), suggesting impaired longitudinal myocardial function in HHD. Similarly, CS was smaller in HHD than controls at outer layer (-6.8±2.2 vs -8.8±2.2%, p<0.01) and at midwall (-11.3±3.4 vs -13.9±3.2%, p<0.01) in spite of reduced CWS (outer: 238±82 vs 336±110 dyn·mm -2 , p<0.001; mid: 360±107 vs 473±131 dyn·mm -2 , p<0.001). In contrast, at the innermost layer, both CS (-26±5 vs -25±5%, p=0.41) and CWS (979±153 vs 992±139 dyn·mm -2 , p=0.72) were comparable between groups. Furthermore, the difference of CS between inner and outer layers significantly correlated with relative wall thickness (r=-0.33, p<0.01). Finally, CS at inner layer significantly correlated with EF (r=-0.43, p<0.001), whereas LS did not. Conclusions: In patients with HHD, intrinsic myocardial shortening was impaired both longitudinally and circumferentially. Some compensatory mechanism associated with increased relative wall thickness might work to maintain subendocardial CS, resulting in preserved EF.

Influence of CO2 on cardiovascular response to hypoxia in conscious dogs

1980 ◽  
Vol 239 (4) ◽  
pp. H545-H545 ◽  
Author(s):  
Raymond C. Koehler ◽  
Brian W. McDonald ◽  
John A. Krasney
Keyword(s):  
Cardiovascular Response ◽  
Left Ventricular ◽  
Vagal Afferents ◽  
Conscious Dogs ◽  
Coronary Vasodilation ◽  
Circulatory Response ◽  
Wide Range ◽  
Before And After ◽  
Tension Time ◽  
Arterial Chemoreceptor

The modulating effect of CO2 on the circulatory response to hypoxia in chronically instrumented conscious dogs was examined over a wide range of arterial partial pressure of O2 [PaO2 (from 80 to 25 Torr)] during a 41-min rebreathing period at three CO2 levels: hypocapnia (from PaCO2 of 32 to 18 Torr), eucapnia (32 Torr), and mild hypercapnia (40 Torr). Eucapnic and hypercapnic hypoxic responses were also measured after sinoaortic denervation (SAD) to assess the arterial chemoreceptor and baroreceptor reflex contributions. Elevating PaCO2 attenuated the tachycardia during hypoxia and produced progressively greater systemic, renal, and splanchnic vasoconstriction before but not after SAD. Vagal block converted the rises in renal and splanchnic flows observed during hypocapnic hypoxia to declines. The increase in left ventricular dP/d tmax was not affected by varying PaCO2 either before or after SAD. Coronary flow increased an additional onefold during hypoxia when PaCO2 was elevated both before and after SAD, but the tension-time indices did not differ significantly. These results indicate that: a) cardiopulmonary vagal afferents effectively counteract chemoreflex-induced vasoconstriction during hypocapnic hypoxia; b) chemoreflex vasoconstriction predominates in the renal and splanchnic beds when PaCO2 is elevated; c) the sinoaortic reflexes restrain the heart rate, but not the contractility response to hypoxia when PaCO2 is increased; and d) the augmented coronary vasodilation produced by CO2 is probably mediated by local CO2-hypoxic interactions.

scholarly journals NT-proBNP level and left ventricle diameters before and after transcatheter closure of PDA and VSD

2018 ◽  
Vol 58 (5) ◽  
pp. 213-20
Author(s):  
Devy Kusmira ◽  
Ria Nova ◽  
Achirul Bakri
Keyword(s):  
Left Ventricle ◽  
Transcatheter Closure ◽  
Ductus Arteriosus ◽  
Left Ventricular ◽  
Internal Diameter ◽  
Positive Correlation ◽  
Amino Terminal ◽  
Muscle Stretching ◽  
Before And After ◽  
Moderate Positive Correlation

Background Amino-terminal pro-B-type natriuretic peptide (NT-proBNP) levels before and after transcatheter closure may correlate with changes in left ventricular internal diameter end diastole (LVIDd) and end systole (LVIDs). Patent ductus arteriosus (PDA) and ventricular septal defect (VSD) are structural abnormalities which effects cardiac hypertrophy. Cardiac muscle stretching decreases after closure, followed by reduced left ventricle diameters and decreased NT-proBNP levels. Objective To analyze for possible correlations between NT-proBNP levels and left ventricle diameters before and after transcatheter closure. Methods Subjects were PDA and VSD patients who underwent transcatheter closure in the Pediatrics Department of dr. Moh Hoesin Hospital, Palembang, South Sumatera, from May 2016 to March 2017. Measurement of NT-proBNP levels and echocardiography were performed before closure, as well as one and three months after closure. Results There were 34 subjects (15 girls) with median age of 91.5 months. Median NT-proBNP levels were significantly reduced after closure: before closure 111.7pg/mL, one month after closure 62pg/mL, and three months after closure 39 pg/mL (P<0.05). Median LVIDd and LVIDs were also significantly reduced after closure [LVIDd: 39.5mm before, 34.5mm one mo after, and 32.5mm 3 mo after (P<0.05); LVIDs: 23.9mm before, 20.5mm 1 mo after, and 20.0mm 3 mo after (P<0.05)]. At one month after closure, there was a moderate positive correlation between NT-proBNP levels and LVIDd (r=0.432; P=0.011), but no correlation with LVIDs (r=0.287; P=0.100). At three months after closure, there was a significant moderate positive correlation between changes of NT-proBNP levels and changes of LVIDd (r=0.459; P=0.006), as well as LVIDs (r=0.563; P=0.001). Conclusion In pediatric PDA and VSD patients, NT-proBNP levels have a significant positive correlation with diastolic and systolic left ventricle diameters at three months after closure. Decreased NT-proBNP levels may be considered as a marker of closure effectiveness.

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