Positive Inotropic Stimulation Research Articles

P2508Physical exercise improves diastolic function and attenuates type III collagen myocardial accumulation in aged rats

Abstract Background Interstitial collagen matrix increase and left ventricular (LV) diastolic dysfunction are the most frequent cardiac alterations during aging. Whether changes are part of the aging process or induced by a sedentary life style is not clear. Purpose To evaluate the effects of aerobic exercise on functional capacity, cardiac and myocardial function, and interstitial collagen matrix of aging rats. Methods Male Wistar rats were assigned into three groups: 1) sedentary six-month-old rats (W6, n=24); 2) sedentary 21-month-old rats (W21-Sed, n=25); and 3) exercised 21-month-old rats (W21-Ex, n=20). Physical exercise was by treadmill for 12 weeks. In vivo cardiac evaluation was performed by Doppler echocardiography. Myocardial function was assessed in LV papillary muscle preparation. Total and soluble myocardial collagen concentrations were evaluated by spectrophotometry. Protein expression was analyzed by Western blot. Statistical analysis: ANOVA and Bonferroni or Kruskal-Wallis and Dunn. Results Body weight was greater in W21-Sed and W21-Ex than W6. Before exercise, functional capacity did not differ between aged groups. After training, W21-Ex group ran farther and longer in treadmill than W21-Sed e W6, and W21-Sed presented worse physical capacity than W6. LV diastolic posterior wall, interventricular septum, and relative wall thicknesses were greater in W21-Sed and W21-Ex than W6, and did not differ between aged groups. E wave was lower in both aged groups than W6. E/E' ratio was lower in W21-Ex than W21-Sed. Isolated papillary muscle developed tension was higher in W21-Sed than W6; W21-Ex values did not differ from both W6 and W21-Sed groups. Time to peak tension was higher in W21-Sed and W21-Ex than W6 and did not differ between aged groups. The same results were observed after positive inotropic stimulation. Total collagen concentration was higher in W21-Sed and W21-Ex than W6 and did not differ between aged groups. Soluble collagen did not differ between groups. Type III collagen expression was higher in W21-Sed than W6; the W21-Ex group presented intermediary values that did not differ from W21-Sed or W6 groups. Type I collagen was similar between groups. Conclusion Regular physical aerobic training improves functional capacity and left ventricular diastolic function and attenuates type III collagen myocardial accumulation in aged rats. Acknowledgement/Funding Fapesp, CNPq, Capes, and UNESP

Influence of apocynin on cardiac remodeling in rats with streptozotocin-induced diabetes mellitus

BackgroundIncreased reactive oxygen species (ROS) generation in diabetes mellitus (DM) is an important mechanism leading to diabetic cardiomyopathy. Apocynin, a drug isolated from the herb Picrorhiza kurroa, is considered an antioxidant agent by inhibiting NADPH oxidase activity and improving ROS scavenging. This study analyzed the influence of apocynin on cardiac remodeling in diabetic rats.MethodsSix-month-old male Wistar rats were assigned into 4 groups: control (CTL, n = 15), control + apocynin (CTL + APO, n = 20), diabetes (DM, n = 20), and diabetes + apocynin (DM + APO, n = 20). DM was induced by streptozotocin. Seven days later, apocynin (16 mg/kg/day) or vehicle was initiated and maintained for 8 weeks. Left ventricular (LV) histological sections were used to analyze interstitial collagen fraction. NADPH oxidase activity was evaluated in LV samples. Comparisons between groups were performed by ANOVA for a 2 × 2 factorial design followed by the Bonferroni post hoc test.ResultsBody weight (BW) was lower and glycemia higher in diabetic animals. Echocardiogram showed increased left atrial diameter, LV diastolic diameter, and LV mass indexed by BW in both diabetic groups; apocynin did not affect these indices. LV systolic function was impaired in DM groups and unchanged by apocynin. Isovolumic relaxation time was increased in DM groups; transmitral E/A ratio was higher in DM + APO compared to DM. Myocardial functional evaluation through papillary muscle preparations showed impaired contractile and relaxation function in both DM groups at baseline conditions. After positive inotropic stimulation, developed tension (DT) was lower in DM than CTL. In DM + APO, DT had values between those in DM and CTL + APO and did not significantly differ from either group. Myocardial interstitial collagen fraction was higher in DM than CTL and did not differ between DM + APO and CTL + APO. Serum activity of antioxidant enzymes glutathione peroxidase, superoxide dismutase (SOD), and catalase was lower in DM than CTL; apocynin restored catalase and SOD levels in DM + APO. Myocardial NADPH oxidase activity did not differ between groups.ConclusionApocynin restores serum antioxidant enzyme activity despite unchanged myocardial NADPH oxidase activity in diabetic rats.

Estresse crônico melhora a função miocárdica sem alterar a atividade do canal-L para Ca+2 em ratos

Chronic stress is associated with cardiac remodeling; however the mechanisms have yet to be clarified. The purpose of this study was test the hypothesis that chronic stress promotes cardiac dysfunction associated to L-type calcium Ca2+ channel activity depression. Thirty-day-old male Wistar rats (70 - 100 g) were distributed into two groups: control (C) and chronic stress (St). The stress was consistently maintained at immobilization during 15 weeks, 5 times per week, 1h per day. The cardiac function was evaluated by left ventricular performance through echocardiography and by ventricular isolated papillary muscle. The myocardial papillary muscle activity was assessed at baseline conditions and with inotropic maneuvers such as: post-rest contraction and increases in extracellular Ca2+ concentration, in presence or absence of specific blockers L-type calcium channels. The stress was characterized for adrenal glands hypertrophy, increase of systemic corticosterone level and arterial hypertension. The chronic stress provided left ventricular hypertrophy. The left ventricular and baseline myocardial function did not change with chronic stress. However, it improved the response of the papillary muscle in relation to positive inotropic stimulation. This function improvement was not associated with the L-type Ca2+ channel. Chronic stress produced cardiac hypertrophy; however, in the study of papillary muscle, the positive inotropic maneuvers potentiated cardiac function in stressed rats, without involvement of L-type Ca2+ channel. Thus, the responsible mechanisms remain unclear with respect to Ca2+ influx alterations.

Subcellular calcium dynamics in a whole-cell model of an atrial myocyte

In this study, we present an innovative mathematical modeling approach that allows detailed characterization of Ca(2+) movement within the three-dimensional volume of an atrial myocyte. Essential aspects of the model are the geometrically realistic representation of Ca(2+) release sites and physiological Ca(2+) flux parameters, coupled with a computationally inexpensive framework. By translating nonlinear Ca(2+) excitability into threshold dynamics, we avoid the computationally demanding time stepping of the partial differential equations that are often used to model Ca(2+) transport. Our approach successfully reproduces key features of atrial myocyte Ca(2+) signaling observed using confocal imaging. In particular, the model displays the centripetal Ca(2+) waves that occur within atrial myocytes during excitation-contraction coupling, and the effect of positive inotropic stimulation on the spatial profile of the Ca(2+) signals. Beyond this validation of the model, our simulation reveals unexpected observations about the spread of Ca(2+) within an atrial myocyte. In particular, the model describes the movement of Ca(2+) between ryanodine receptor clusters within a specific z disk of an atrial myocyte. Furthermore, we demonstrate that altering the strength of Ca(2+) release, ryanodine receptor refractoriness, the magnitude of initiating stimulus, or the introduction of stochastic Ca(2+) channel activity can cause the nucleation of proarrhythmic traveling Ca(2+) waves. The model provides clinically relevant insights into the initiation and propagation of subcellular Ca(2+) signals that are currently beyond the scope of imaging technology.

Direct-Acting Vasodilators

KEY POINTS AND PRACTICAL RECOMMENDATIONS: • Hydralazine and minoxidil act by dilating resistance arterioles, thus reducing peripheral resistance, with no dilating effect on the venous side of the circulation. • There is a baroreflex-mediated venoconstriction, resulting in an increase in venous return to the heart, along with a direct catecholamine-mediated positive inotropic and chronotropic stimulation of the heart. • Hydralazine therapy is usually combined with a sympathetic inhibitor to prevent expression of this reflex, as well as with a diuretic agent to prevent sodium retention caused by reduction in renal perfusion pressure. • Hydralazine is indicated in the long-term therapy of essential hypertension, in the short-term therapy of pregnancy-induced hypertension and eclampsia, and in the therapy of hypertensive crisis. • Adverse effects include the anticipated tachycardia, fluid retention, and headache, caused by the vasodilation, especially in the early days of therapy, but may frequently be prevented by the concomitant use of a β-blocker. • As with other drugs that are N-acetylated, there is a low risk of lupus-like syndrome with high doses and long-term use. • Because of the severity of adverse effects with minoxidil, its usage is limited to persons with severe hypertension unresponsive to other treatments. • Hirsutism, a common side effect of minoxidil, is particularly bothersome in women and reverses in a few months after discontinuation. • Sodium nitroprusside is used in the intensive care setting to lower pressure in hypertensive crisis or to treat severe left ventricular failure, particularly valuable when elevated pressure or severe left ventricular failure threatens the patient's survival. • Although nitrates have not achieved widespread use as antihypertensive agents, they are effective in producing sustained blood pressure (BP) reductions when added to other antihypertensive regimens.

High energy phosphates in postischemic myocardium with reduced or normalized function

Mitochondrial damage and decreased levels of high energy phosphates are well-known findings in reversibly injured postischemic myocardium (=stunning). Using an isovolumetrically beating isolated rat heart preparation (Langendorff perfusion apparatus) we investigated the effect of postischemic positive inotropic stimulation on the myocardial high energy phosphate content. During postischemic functional steady state with moderately reduced left ventricular developed pressure (118.7 mmHg after 30 minutes of ischemia vs 136.1 mmHg preischemic), dopamine in a dose to reestablish preischemic function was administered for a 20-minute period. Data were compared with postischemic hearts without positive inotropic stimulation: ATP was 2.5 vs 2.5 (μmol/g ww; phosphocreatine was 5.5 vs 6.7 μmol/g ww. These findings indicate that reversibly injured postischemic myocardium can be stimulated for a prolonged period without loss of high-energy phosphates. Therefore, a failure of the energy-generating apparatus is not the reason for the reversible postischemic dysfunction.

Influence of pyruvate on economy of contraction in isolated rabbit myocardium

Treatment of acute heart failure frequently requires positive-inotropic stimulation. However, there is still no inotropic agent available, which combines a favourable haemodynamic profile with low expenditure for energy metabolism. Pyruvate exhibits positive inotropic effects in vitro and in patients with heart failure. The effect on myocardial energy metabolism however remains unclear, but is meaningful in light of a clinical application. We investigated the influence of pyruvate on contractility and oxygen consumption in isolated isometric contracting rabbit myocardium compared to beta-adrenergic stimulation with isoproterenol. Pyruvate (30 mM) increased developed force from 18.7+/-4.1 to 50.8+/-12.1 mN/mm2 (n=10, p<0.01). Force-time integral (FTI) increased by 329%, oxygen consumption assessed by diffusion-microelectrode technique increased from 2.86+/-0.30 mlO2/min*100 g to 6.28+/-1.28 mlO2/min*100 g (n=7, p<0.05). Economy of myocardial contraction calculated as the ratio of total FTI to oxygen consumption remained unchanged. In contrast, while isoproterenol (10 microM) produced a comparable increase in developed force from 21.4+/-8.3 to 67.3+/-15 mN/mm2 (n=7, p<0.01), FTI increased only by 260% and MVO2 increased from 2.96+/-0.43 to 6.12+/-1.01 mlO2/min*100 g (n=7, p<0.01); thus, economy decreased by 23% (n=7, p<0.05). Pyruvate does not impair economy of myocardial contraction while isoproterenol decreases economy. Regarding energy expenditure, pyruvate appears superior to isoproterenol for the purpose of positive inotropic stimulation.

Active myocyte shortening during the ‘isovolumetric relaxation’ phase of diastole is responsible for ventricular suction; ‘systolic ventricular filling’

To study the 'isovolumetric relaxation' phase of rapid ventricular filling by analysis of the shortening of cardiac muscle in the endocardial and epicardial segments of the left ventricle in the dual helical model of the ventricular band, described by Torrent-Guasp. In 10 pigs (27-82 kg), temporal shortening by sonomicrometer crystals was recorded while recording ECG, and measuring intraventricular pressure and dP/dt with Millar pressure transducers. The following sequence was observed; shortening began in descending or endocardial segment, and 82+/-23 ms later it was initiated in the epicardial or ascending segment of the band. The descending segment stops shortening during the rapid filling phase of fast descent of ventricular pressure, but the ascending segment shortening continues for 92+/-33 ms, so that active shortening continues during the period of isovolumetric relaxation. During the rapid filling phase, dopamine decreased the interval between completion of endocardial and termination of epicardial contraction from 92+/-20 to 33+/-8 ms. Conversely propranolol delayed the start of epicardial shortening from 82+/-23 to 121+/-20 ms, and prolonged the duration of endocardial contraction, causing a closer (21+/-5 ms vs 92+/-20 ms) interval between termination of contraction of endocardial and epicardial fibers. The resultant slope of the rapid descent of the left ventricular pressure curve became prolonged. These time sequences show that ongoing unopposed ascending segment shortening occurs during the phase of rapid fall of ventricular pressure. These active shortening phases respond to positive and negative inotropic stimulation, and indicate the classic concept of 'isovolumetric relaxation', IVR, must be reconsidered, and the new term 'isovolumetric contraction', IVC, or systolic ventricular filing may be used.

Differential positive inotropic effects of the I Kr-blocker dofetilide and the I TO/I Kur-blocker AVE0118 in canine atrial myocytes

Background: Patients undergoing cardioversion of atrial tachyarrhythmias might benefit from positive inotropic stimulation of the atria. The shape of the atrial action potential (AP) is a major determinant of atrial contractility. Newly developed Ito/IKur-blockers prolong early repolarisation and increase the ’plateau potential’ of the atrial AP while IKr-blockers (e.g. dofetilide) prolong final repolarisation without affecting the plateau phase. We compared the inotropic effects of dofetilide and the Ito/IKur-blocker AVE0118 on isolated atrial myocytes. Methods: Shortening transients (edge detection) and transmembrane APs of isolated canine atrial myocytes were recorded under current clamp conditions using the perforated patch technique (37°C). The ’plateau potential’ was defined as the average potential between 10 and 50ms after the upstroke of the AP. The effect of changes of: 1) plateau duration, 2) plateau potential, and 3) the time required for final repolarisation (prolongation of APD90 without change in APD30) on cellular shortening of atrial myocytes was studied in voltage-clamp experiments. Results: Dofetilide (1 M) prolonged APD90 from 318 25ms to 435 35ms but did not significantly change the plateau potential or the shortening of atrial myocytes (7 cells, 4 dogs). In contrast, AVE0118 increased the plateau potential from -5 6mV to 21 8mV and enhanced myocyte shortening from 4.0 1.0% to 9.8 1.3% (9 cells, 5 dogs). APD90 was unchanged. In voltage clamp experiments, prolongation of the plateau increased myocyte shortening from 1.9 0.4% at 50ms to 16.6 1.2% at 600ms. Increasing the plateau potential enhanced shortening from 0.7 0.1% at -20mV to 17.8 1.2% at 60mV. In contrast, prolongation of APD90 by 200ms without changes of plateau potential or duration did not enhance shortening (9 cells, 5 dogs). Conclusion: AVE0118 enhances atrial contractility by increasing the plateau potential due to prolongation of the early repolarisation. Dofetilide does not affect the plateau phase of the AP and therefore does not enhance atrial contractility.

Adenosine triphosphate–dependent potassium channel modulation and cardioplegia-induced protection of human atrial muscle in an in vitro model of myocardial stunning

Objectives: Although adenosine triphosphate–dependent potassium channel openers have been shown to enhance cardioplegic protection in animal myocardium, there is a lack of data on human cardiac tissues. We aimed at determining, on human atrial muscle, whether adenosine triphosphate– dependent potassium channels are involved in protection caused by high-potassium cardioplegia and whether adenosine triphosphate–dependent potassium channel activation might improve cardioplegic protection in an in vitro model of myocardial stunning. Methods: Human atrial trabeculae were obtained from adult patients undergoing cardiac operations. In an organ bath at 37°C, the preparations were subjected to 60 minutes of hypoxia at a high stimulation rate either in Tyrode solution (control, n = 17) or in St Thomas’ Hospital solution without additives (n = 6) or associated with 100 nmol/L bimakalim (n = 7) or 1 μmol/L glibenclamide (n = 7), followed by 60 minutes of reoxygenation and 15 minutes of positive inotropic stimulation with 1 μmol/L dobutamine. Results: Atrial developed tension was reduced by hypoxia to 27% ± 5% of baseline and incompletely recovered after reoxygenation to 38% ± 7%, whereas dobutamine restored contractility to 74% ± 7% of basal values. St Thomas’ Hospital solution with or without bimakalim improved developed tension after reoxygenation and dobutamine ( P < .0001 vs control), whereas glibenclamide inhibited these protective effects of cardioplegic arrest ( P = .001 vs St Thomas’ Hospital solution). After reoxygenation, the protective effect of bimakalim disappeared at a high pacing rate (400- and 300-ms cycle length) but recovered during dobutamine superfusion. Conclusions: Adenosine triphosphate–dependent potassium channels are likely involved in the cardioprotective effects of cardioplegia in human atrial trabeculae and adenosine triphosphate–dependent potassium channel activation with bimakalim used as an additive to cardioplegia enhanced protection. (J Thorac Cardiovasc Surg 2000;119:842-8)

Beta-adrenergic blocking agents: past, present, and future perspectives.

The 'proof of concept' of beta-blockade for heart failure (i.e. that the pharmacologic actions of beta-blockers are beneficial) is now firmly established, as the treatment of heart failure has progressed from using positive inotropic stimulation, via drugs with no direct effect on cardiac function, to beta-blockers with negative intropic effects. This review addresses some remaining issues regarding beta-blockade in heart failure. The mechanism of action of beta-blockers in heart failure is more likely to be improved intrinsic cardiac myocyte function and prevention or reversal of remodeling, than restoration of beta-adrenergic signal transduction. The role of the differentiating characteristics of beta-blockers is not clear at this time, and there is no compelling evidence to select one agent over another on the basis of individual drug properties. Recent reports suggest that beta-blockers reduce the combined risk of all-cause mortality and hospitalizations by about 30-35%. These results are heavily influenced by experience with carvedilol, but other agents tested include metoprolol, bucindolol, bisoprolol, and nebivolol. Responsiveness to beta-blockers is not related to patients' age, sex, or race, or to the etiology or severity of heart failure. Beta-blockers are currently recommended as adjunctive treatment in patients who remain mildly to moderately symptomatic while receiving added digitalis, diuretics, and angiotensin-converting enzyme inhibitors. Existing gaps in our knowledge must be filled in order to achieve optimal clinical application of beta-blockers. Ongoing studies will provide much of the information required. The role of beta-blockers will probably expand as we improve our understanding of the pathophysiology of heart failure, and especially of the remodeling process.

Effect of dopamine and atrial pacing on stunned myocardium1

Post-ischaemic stunned myocardium shows an impaired function at restored coronary blood flow, but performance can be normalized by positive inotropic stimulation. The power of stunned myocardium, however, is not augmented with increasing heart rate by atrial pacing, which is in contrast to intact areas. This pathological response is mitigated by inhibiting the degradation of cyclic AMP. The present experiments studied the effect of stimulating cyclic AMP formation by dopamine on the response of stunned myocardium to atrial pacing. In anaesthetized (piritramide) open chest pigs, heart rate, left ventricular and aortic pressure, left descending (LAD) and circumflex (LCX) coronary artery and aortic blood flow, myocardial systolic shortening in the LAD and LCX area were monitored, and myocardial power was calculated. The LAD region was subjected to ischaemia and reperfused for 2 h. Subsequently, heart rate was raised by right atrial pacing before and during intravenous infusion of dopamine (10 microg/kg per min). The ischaemic/reperfused area was sliced post mortem and stained by triphenyl tetrazolium chloride to exclude myocardial infarction. Data from 11 experiments are presented. After 2 h LAD reperfusion, LAD blood flow and power were 100% and 36% of pre-ischaemic control, respectively, indicating myocardial stunning. The power of the intact area was not changed significantly (111% of control). Increasing heart rate by +36 and +70 from 94 beats/min increased the power of the intact area to 161% and 183% of control; the power of the stunned myocardium decreased to 34% and 19% of pre-stunning control. Dopamine increased the power of the stunned region to 143% of the pre-stunning level and the power of the intact area to 206% of control. Increasing heart rate by +34 and +70 from 113 beats/min during dopamine, increased the power of the intact myocardium to 288% and 344% of control and the power of the stunned region to 177% and 174% of the pre-stunning level. The data confirm the pathological response of stunned myocardium to atrial pacing and the recruitment of a functional reserve by catecholamines. The adverse effect of pacing on the function of stunned myocardium is abolished by positive inotropic stimulation. Possibly, the cyclic AMP system is involved in the normal response to pacing and this pathway is disturbed in stunned myocardium; other defects are not excluded or supported, however. Physiologically increased heart rate by an increased activity of the sympathetic nervous system, is probably not accompanied by a reduced power of stunned myocardium, due to the associated positive inotropic stimulation.

Inotropic response of stunned hypertrophied myocardium: responsiveness of hypertrophied and normal postischemic isolated rat hearts to calcium and dopamine stimulation.

Severely hypertrophied myocardium was described to have a reduced tolerance towards ischemia. For non-hypertrophied hearts inconclusive findings on the Ca(2+)-responsiveness are reported. Information sensitivity to reversible ischemia and on postischemic Ca(2+)-responsiveness of hearts with clinically common moderate hypertrophy is lacking. Thus, the responsiveness of hypertrophied and normal postischemic myocardium to positive inotropic stimulation should be investigated in the present study. Hearts from spontaneously hypertensive rats (SHR, 4 months old) with significant LV-hypertrophy (+ 50%) and hearts from normotensive 4 months old Wistar rats were investigated using an isovolumic beating isolated heart model (8 hearts/each of the 8 groups). Functional recovery after 30 min of no-flow ischemia was 78 +/- 1% and 77 +/- 3% of preischemic control data in hypertrophied and non-hypertrophied hearts assessed as developed left ventricular pressure (non-ischemic controls: 95 +/- 2% in hypertrophied and 93 +/- 3% in non-hypertrophied controls). Maximum short-term stimulation with Ca2+ revealed a decreased peak left ventricular pressure of 124 +/- 4% in hypertrophied and 120 +/- 5% in non-hypertrophied postischemic hearts, as compared with non-ischemic controls 138 +/- 3% and 157 +/- 5%, respectively ( p < 0.01). A maximum dose of dopamine stimulated hypertrophied and non-hypertrophied postischemic hearts comparable to Ca2+. Analysing the dose-response curve for Ca(2+)-stimulation, the sensitivity expressed as fraction of the maximum was identical in non-ischemic and postischemic myocardium of hypertrophied and non-hypertrophied ventricles in spite of the reduced peak values. The findings demonstrate that after moderate reversible ischemia the steady-state function is similarly decreased in hypertrophied and non-hypertrophied postischemic myocardium. The maximum response to Ca2+ is significantly reduced in both types of myocardium, while the Ca2+ sensitivity is unchanged. Identical results after maximum dopamine stimulation as after Ca2+ indicate that the releasibility of Ca2+ and the beta-adrenoceptors are not the critical causes for the postischemic dysfunction in hypertrophied or non-hypertrophied myocardium.

Effects of positive inotropic stimulation on postischemic myocardium with graded dysfunction.

To investigate the effects of moderate prolonged and of maximum short-term positive inotropic stimulation of postischemic myocardium as a function of the severity of stunning. Stunned isolated rat hearts (n = 116) after 30 min and 45 min of ischemia were stimulated with dopamine to raise systolic function (double product) back to control levels. In the isovolumetrically beating hearts, left ventricular developed pressure, double product, dp/dtmax, coronary flow, and myocardial oxygen consumption were determined during steady-state conditions. After maximum stimulation the contractile reserve was examined. Measurements of adenine nucleotides (n = 47) and electron microscopy (n = 9) were made. 30 min ischemia resulted in moderate postischemic dysfunction (LVP 81 +/- 3%; P < 0.05). After 45 min ischemia, function was more severely reduced (LVP 66 +/- 5%; P < 0.01). Coronary flow tended to be lower after ischemia. Myocardial oxygen consumption was not reduced in parallel with the dysfunction. Adenine nucleotides were gradually reduced after ischemia (ATP: 2.5 +/- 0.2 and 1.2 +/- 0.1 vs. 4.2 +/- 0.2 mumol/gww; P < 0.01). Contractile reserve also decreased in relation to the previous ischemic injury (after 45 min ischemia max. LVP 105 +/- 10% vs. max. LVP 152 +/- 8% in controls, P < 0.01). Prolonged stimulation did not result in further reduction in adenine nucleotides and function. Contractile reserve is decreased in postischemic myocardium in parallel with the previous ischemic burden. Depending on the degree of contractile dysfunction a disturbed function-flow-oxygen consumption relation is present. Prolonged stimulation of stunned myocardium with dopamine back to the control level of function has no harmful short-term effects, indicating sufficient mitochondrial energy generation.

Coronary heart disease: Overview

Coronary heart disease: Overview

Effect of prolonged inotropic stimulation on ventricular remodeling during healing after myocardial infarction in the dog: Mechanistic insights

Objectives. We hypothesized that positive inotropic stimulation during healing after myocardial infarction might increase contractile pull on the infarct segment, increase expansion and promote ventricular dilation.Background. The effect of prolonged inotropic stimulation on left ventricular remodeling during healing after myocardial infarction has not been studied.Methods. The effects of 6 weeks of inotropic stimulation on in vivo changes in left ventricular topography, function and mass (serial two-dimensional echocardiograms), hemodynamic variables, postmortem topography (planimetry) and collagen (hydroxyproline content) were studied in 36 chronically instrumented dogs randomized, 2 days after small anterior infarction, to digoxin (0.125 mg daily) and no digoxin (control group).Results. Heart rate and arterial and left atrial pressures were similar in the two groups, but the first derivative of left ventricular pressure (peak dP/dt), systolic thickening of the noninfarct wall and systolic thinning of the infarct wall were higher in the digoxin group during the 6 weeks. At 6 weeks, infarct scar size and collagen content were similar in both groups, but the digoxin group had more infarct expansion and thinning. Between 2 days and 6 weeks, the digoxin group showed more in vivo diastolic infarct expansion, thinning and bulging; more aneurysm but less global dilation and increase in mass; and no change in ejection fraction. The effects of inotropic stimulation on remodeling were more marked in infarcts with 100% than 85% transmurality.Conclusions. Prolonged inotropic stimulation with digoxin during healing after small anterior infarction increases infarct bulging without decreasing infarct collagen content and preserves global ventricular size, mass and systolic function.

Changes in calcium transient and left ventricular function during positive inotropic stimulation and myocardial ischemia in indo-1-loaded beating guinea pig heart

To elucidate the issues such as excitation-contraction coupling and myocardial ischemia, it is necessary to measure intracellular free Ca 2+ concentration and mechanical function of hearts perfused via the normal arterial circulation. For this purpose, we simultaneously measured Ca 2+-dependent indo-1 fluorescence and left ventricular (LV) pressure on a beat-to-beat basis in Langendorff guinea-pig hearts, and investigated the changes in Ca 2+ transient and LV function during inotropic stimulation and myocardial ischemia. The indo-1 fluoresence ratio and LV developed pressure increased the perfusate [Ca 2+] increased from 1.6 to 3.2 mmol/L, and there was a good correlation between Ca 2+ transient and LV contractility. Digoxin (10 −6 mol/L) and milrinone (10 −5 mol/L) increased LV contractility with a concomitant increase in Ca 2+ transient, and the relative increase of Ca 2+ transient produced by milrinone was much more than that by digoxin. The reduction of coronary perfusion pressure from 80 to 40 mm Hg decreased LV contractility with an increase in indo-1 fluorescence ratio. These results suggest that Ca 2+ responsiveness of contractile apparatus declines during inotropic stimulation by milrinone and during myocardial ischemia. Thus, this experimental technique is useful to investigate the interrelation of Ca 2+ regulation and LV function during a variety of pharmacological and physiologic perturbations.

High energy phosphates in postischemic myocardium with reduced or normalized function

Mitochondrial damage and decreased levels of high energy phosphates are well-known findings in reversibly injured postischemic myocardium (=stunning). Using an isovolumetrically beating isolated rat heart preparation (Langendorff perfusion apparatus) we investigated the effect of postischemic positive inotropic stimulation on the myocardial high energy phosphate content. During postischemic functional steady state with moderately reduced left ventricular developed pressure (118.7 mmHg after 30 minutes of ischemia vs 136.1 mmHg preischemic), dopamine in a dose to reestablish preischemic function was administered for a 20-minute period. Data were compared with postischemic hearts without positive inotropic stimulation: ATP was 2.5 vs 2.5 (μmol/g ww; phosphocreatine was 5.5 vs 6.7 μmol/g ww. These findings indicate that reversibly injured postischemic myocardium can be stimulated for a prolonged period without loss of high-energy phosphates. Therefore, a failure of the energy-generating apparatus is not the reason for the reversible postischemic dysfunction.

Effects of positive inotropic stimulation (post-extrasystolic potentiation) on non-uniformity of left ventricular contraction in patients with coronary artery disease.

In patients with chronic coronary artery disease, post-extrasystolic potentiation (PESP) slightly worsens relaxation, increasing the constant tau of ventricular pressure decay. However, it does not negatively influence left ventricular (LV) diastolic filling. To our knowledge, no data are available on the effects of PESP on segmental relaxation in chronic coronary artery disease. The effects of PESP on the LV pressure-volume (P/V) relationship and on segmental pressure-length loops (P/L) were studied in eight patients with coronary artery disease submitted to LV angiography. P/V loops were constructed by means of frame-to-frame analysis of ventriculograms and simultaneous high-fidelity LV pressure tracings; P/L loops were calculated by the endocardial movement of 45 chords intersecting the LV outline (centreline method). PESP was produced by programmed stimulation during ventriculography. P/V and P/L loops were studied in basal conditions and after PESP.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of isoproterenol on regional myocardial segment work, O2 consumption, and oxygen balance.

We tested the hypothesis that positive inotropic stimulation by isoproterenol alters the relationship between regional segment work and regional myocardial oxygen consumption. Regional parameters were compared with external cardiac work and global LV oxygen consumption. In anesthetized open-chest dogs, regional myocardial segment length (ultrasonic dimension crystals) and force development (miniature force transducer) were measured. The integrated multiples of myocardial shortening by corresponding force during an averaged beat expressed segment work (area under the systolic portion of the length-force loop). External cardiac work was calculated from aortic blood pressure and cardiac output. Global and regional myocardial MVO2 were evaluated at baseline and during intravenous infusion of isoproterenol (0.5 and 1.0 micrograms/kg per min). Regional coronary blood flow was measured with radioactive microspheres, and microspectrophotometry of frozen myocardial biopsies was used to evaluate O2 saturation in small arteries and veins. These parameters were used to calculate regional MVO2. Arterial and coronary sinus O2 saturation was used to calculate global LV O2 consumption. Regional myocardial O2 balance was estimated by measurement of NADH redox level using surface fluorometry. It was found that 0.5 micrograms/kg per min isoproterenol increased regional segment work/minute from 4650 +/- 495 to 6750 +/- 750 mm.g/min. Corresponding regional oxygen consumption was disproportionately increased from 5.43 +/- 0.61 to 15.24 +/- 1.37 ml/min per 100 g. External cardiac work was found to decrease from 728 +/- 13 to 562 +/- 25 mmHg.1/min (due to decreased aortic blood pressure), whereas global myocardial O2 consumption increased. Regional myocardial O2 extraction and NADH fluorescence were elevated, indicating impaired tissue oxygenation. Regional MVO2 was increased by 153 +/- 56%, but regional work by only 45.3 +/- 33% (P < 0.05). These results indicate that regional contraction efficiency was markedly reduced by isoproterenol.