Increase In Ventricular Contractility Research Articles

Exercise-dependent changes in ventricular-arterial coupling and aortopulmonary collateral flow in Fontan patients: a real-time CMR study.

Inefficient ventricular-arterial (V-A) coupling has been described in Fontan patients and may result in adverse haemodynamics. A varying amount of aortopulmonary collateral (APC) flow is also frequently present that increases volume load of the single ventricle. The aim of the study was to assess changes in V-A coupling and APC flow during exercise CMR. Eighteen Fontan patients (age 24 ± 3 years) and 14 controls (age 23 ± 4 years) underwent exercise CMR using a cycle ergometer. Ventricular volumetry and flow measurements in the ascending aorta (AAO), inferior (IVC), and superior (SVC) vena cava were assessed using real-time sequences during stepwise increases in work load. Measures of systemic arterial elastance Ea, ventricular elastance Ees, and V-A coupling (Ea/Ees) were assessed. APC flow was quantified as AAO - (SVC + IVC). Ea remained unchanged during all levels of exercise in both groups (P = 0.39 and P = 0.11). Ees increased in both groups (P = 0.001 and P < 0.001) with exercise but was lower in the Fontan group (P = 0.04). V-A coupling was impaired in Fontan patients at baseline (P = 0.04). Despite improvement during exercise (P = 0.002) V-A coupling remained impaired compared with controls (P = 0.001). Absolute APC flow in Fontan patients did not change during exercise even at maximum work load (P = 0.98). Inefficient V-A coupling was already present at rest in Fontan patients and aggravated during exercise due to a limited increase in ventricular contractility which demonstrates the importance of a limited functional reserve of the single ventricle. APC flow remained unchanged suggesting no further increase in volume load during exercise.

Muscle Metaboreflex Control of Left Ventricular Filling Pressure

When oxygen delivery to active skeletal muscle is limited, afferent signals from the muscle elicit reflex increases in cardiac output (CO) and mean arterial pressure (MAP) in order to increase perfusion to the ischemic muscle ‐ termed the muscle metaboreflex (MMR). Previous studies have shown that in normal subjects, CO is increased predominantly through increases in heart rate (HR) while maintaining stroke volume (SV) essentially constant. However, increases in HR alone have limited ability to raise CO because as HR increases, SV falls due to decreased filling time. Increases in ventricular contractility can limit the falls in SV, however with sustained increases in CO, blood is translocated from the venous to the arterial circulation and ventricular filling pressure falls which limits the ability to maintain elevated CO. To sustain increases in CO, central blood volume mobilization must also occur to maintain ventricular filling pressure. We previously showed that MMR activation does increase central venous pressure (Sheriff, Augustyniak and O'Leary, Am. J. Physiol., 1998), but whether this translates into increases in left ventricular end‐diastolic pressure (LVEDP) is unknown. MMR was activated via reductions in hindlimb blood flow during mild treadmill exercise in chronically instrumented canines before and after induction of heart failure (HF, rapid ventricular pacing, 220–240 bpm, ~30 days). In normal animals, MMR activation induced a rise in LVEDP from 14.4 ± 1.8 to 18.2 ± 1.8 mmHg (p&lt;0.05) despite substantial increases in HR (Δ 26 ± 4 bpm), CO (Δ 1.45 ± 0.16 l/min) and MAP (Δ 42.3 ± 2.6 mmHg). After induction of HF, MMA activation increased LVEDP from 28.6 ± 2.5 to 38.7 ± 2.6 mmHg (p&lt;0.05) which was a significantly larger rise than observed in normal animals. In HF, the attenuated rise in CO (Δ 0.20 ± 0.08 l/min) with MMR activation likely contributes to the exaggerated increase in LVEDP. We conclude that MMR activation elicits significant blood volume mobilization which increases cardiac filling pressure which thereby likely helps sustain SV despite shortened filling time. In HF, the limited ability to raise CO is not due to reduced filling pressures.Support or Funding InformationNIH RO1 Grants HL055473 and HL126706This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Cardiohemodynamic and electrophysiological effects of a selective EP4 receptor agonist ONO­-AE1­-329 in the halothane-anesthetized dogs

Cardiovascular effects of a highly selective prostaglandin E2 type 4 (EP4) receptor agonist ONO-AE1-329 were assessed with the halothane-anesthetized dogs (n=6). ONO-AE1-329 was intravenously infused in three escalating doses of 0.3, 1 and 3ng/kg/min for 10min with a pause of 20min between the doses. The low dose of 0.3ng/kg/min significantly increased maximum upstroke velocity of left ventricular pressure by 18% at 20min, indicating increase of ventricular contractility. The middle dose of 1ng/kg/min significantly decreased total peripheral resistance by 24% and left ventricular end-diastolic pressure by 32% at 10min, indicating dilation of arteriolar resistance vessels and venous capacitance ones, respectively; and increased cardiac output by 25% at 10min in addition to the change induced by the low dose. The high dose of 3ng/kg/min increased heart rate by 34% at 10min; decreased mean blood pressure by 14% at 10min and atrioventricular nodal conduction time by 13% at 5min; and shortened left ventricular systolic period by 8% at 10min and electromechanical coupling defined as an interval from completion of repolarization to the start of ventricular diastole by 39% at 10min in addition to the changes induced by the middle dose. No significant change was detected in a ventricular repolarization period. These results indicate that ONO-AE1-329 may possess a similar cardiovascular profile to typical phosphodiesterase 3 inhibitors as an inodilator, and suggest that EP4 receptor stimulation can become an alternative strategy for the treatment of congestive heart failure.

The muscle metaboreflex: reining in the heart?

the muscle metaboreflex, also known as the muscle chemoreflex, is one of the principal mediators of the cardiovascular exercise response. This reflex is thought to be triggered by metabolic by-products of ischemia that stimulate afferent nerve endings in skeletal muscle and leads to an increase in

Muscle metaboreflex-induced coronary vasoconstriction functionally limits increases in ventricular contractility

Muscle metaboreflex activation during dynamic exercise induces a substantial increase in cardiac work and oxygen demand via a significant increase in heart rate, ventricular contractility, and afterload. This increase in cardiac work should cause coronary metabolic vasodilation. However, little if any coronary vasodilation is observed due to concomitant sympathetically induced coronary vasoconstriction. The purpose of the present study is to determine whether the restraint of coronary vasodilation functionally limits increases in left ventricular contractility. Using chronically instrumented, conscious dogs (n = 9), we measured mean arterial pressure, cardiac output, and circumflex blood flow and calculated coronary vascular conductance, maximal derivative of ventricular pressure (dp/dt(max)), and preload recruitable stroke work (PRSW) at rest and during mild exercise (2 mph) before and during activation of the muscle metaboreflex. Experiments were repeated after systemic alpha(1)-adrenergic blockade ( approximately 50 microg/kg prazosin). During prazosin administration, we observed significantly greater increases in coronary vascular conductance (0.64 + or - 0.06 vs. 0.46 + or - 0.03 ml x min(-1) x mmHg(-1); P < 0.05), circumflex blood flow (77.9 + or - 6.6 vs. 63.0 + or - 4.5 ml/min; P < 0.05), cardiac output (7.38 + or - 0.52 vs. 6.02 + or - 0.42 l/min; P < 0.05), dP/dt(max) (5,449 + or - 339 vs. 3,888 + or - 243 mmHg/s; P < 0.05), and PRSW (160.1 + or - 10.3 vs. 183.8 + or - 9.2 erg.10(3)/ml; P < 0.05) with metaboreflex activation vs. those seen in control experiments. We conclude that the sympathetic restraint of coronary vasodilation functionally limits further reflex increases in left ventricular contractility.

Autonomic modulation and cardiac contractility in vasovagal syncope

BackgroundPrevious studies proposed as one of the main mechanisms involved in neurally mediated syncope, the stimulation of ventricular mechanoreceptors as the final trigger for vagal discharge. ObjectivesThis study aimed to verify the presence of a sympathetic driven increase of cardiac contractility before vasovagal syncope. MethodsWe studied 23 patients with recurrent syncope. All underwent a 60° tilt with pharmacologic challenge (sublingual spray nitrate). Two conditions were used to assess autonomic activity by heart rate variability analysis: in a supine position after 5 min of rest and after 15 min of tilt. Simultaneously, cardiac contractility was quantified by tissue-Doppler echocardiography at the base of the free walls of left ventricle. The peak myocardial velocities during systole (Sw) and late diastole (Aw) were considered. ResultsPassive tilt induced a significant increase of the low frequency component (LF) as well as a decrease of the high frequency component (HF) in positive patients (LF: from 49±18 to 65±18 nu, p<0.05; HF: from 41±21 to 26±16 nu, p<0.05). Tissue-Doppler showed a similar increase in Sw in both positive and negative patients but showed a significant decrease of Aw in syncopal subjects (p<0.005). ConclusionsOur results do not show an increase in ventricular contractility before tilt-induced syncope, or in presence of a valuable increase of sympathetic activity. Instead, we observe a reduction of atrial contractility, which may be a contributory component in the pathogenesis of vasovagal syncope.

Effects of Initiation of Continuous Renal Replacement Therapy on Hemodynamics in a Pediatric Animal Model

There are no studies analyzing the initial hemodynamic impact of continuous renal replacement therapy (CRRT) in children. We have performed a prospective observational study in 34 immature Maryland pigs to analyze the initial hemodynamic changes during venovenous CRRT. The heart rate, blood pressure, central venous pressure (CVP), pulmonary arterial occlusion pressure (PAOP), pulmonary capillary wedge pressure, temperature, and cardiac output (CO), simultaneously by pulmonary arterial thermodilution and femoral arterial thermodilution, were measured at 30-min intervals during 2 h. Venovenous CRRT induced an initial significant diminution of volemic hemodynamic parameters (intrathoracic blood volume, global end-diastolic volume, stroke volume index, PAOP, and CVP). Simultaneously, a significant increase in systemic vascular resistance index and left ventricular contractility, and a decrease in CO, was observed. We conclude that CRRT in a pediatric animal model induces initial hypovolemia, and a systemic cardiovascular response with vasoconstriction and increase in ventricular contractility.

Muscle metaboreflex control of ventricular contractility during dynamic exercise

When oxygen delivery to active skeletal muscle is insufficient for the metabolic demands, afferent nerves within muscles are activated, which elicit reflex increases in heart rate (HR), cardiac output (CO), and arterial pressure (AP), termed the muscle metaboreflex (MMR). To what extent the increases in CO are the result of increased ventricular contractility is unclear. A widely accepted index of contractility is maximal left ventricular elastance (Emax), the slope of the end-systolic pressure-volume relationship, such as during rapidly imposed reductions in preload. The objective of the present study was to determine whether MMR activation elicits increases in Emax. Experiments were performed using conscious dogs chronically instrumented to measure left ventricular pressure and volume at rest and during mild or moderate treadmill exercise with and without partial hindlimb ischemia to elicit MMR responses. At both workloads, MMR activation significantly increased CO, HR, AP, and maximum rate of change of left ventricular pressure. During both mild and moderate exercise, MMR activation increased Emax to 159.6 +/- 8.83 and 155.8 +/- 6.32% of the exercise value under free-flow conditions, respectively. We conclude that the increase of ventricular elastance associated with MMR activation indicates that a substantial increase in ventricular contractility contributes to the rise in CO during dynamic exercise.

Acupuncture in the treatment of heart failure.

Few clinical studies evaluating the efficacy of acupuncture in heart failure have been performed. These studies have focused on the acupoint Neiguan (P6) in patients experiencing heart failure and have variably reported either an acute increase in ventricular contractility and/or relaxation or no effect on ventricular contractility and/or relaxation. To date, clinical studies have been hampered by small enrollment, inadequate controls, and unblinded design. Recent scientific studies of animal models of acupuncture support the concept that acupuncture produces release of endogenous opioids in the central nervous system, which in turn could inhibit central sympathetic outflow. Patients experiencing heart failure have markedly elevated sympathetic activity, and those with the greatest sympathetic activation have the worst survival. Preliminary data from our laboratory suggests that acupuncture could be sympatholytic in heart failure. We found that sympathetic activation during acute mental stress was virtually eliminated after acupuncture. More studies defining the efficacy of acupuncture, and its mechanisms, in the treatment of heart failure are warranted.

Muscle metaboreflex increases ventricular performance in conscious dogs.

Ischemia of active skeletal muscle stimulates neuronal afferents within the muscle, which elicits a reflex increase in systemic arterial pressure (SAP), heart rate (HR), and cardiac output (CO) termed the muscle metaboreflex. We investigated whether activation of the muscle metaboreflex elicits increases in ventricular performance using conscious, chronically instrumented dogs trained to run on a treadmill (3.2 km/h, 0% grade). The muscle metaboreflex was activated via progressive partial vascular occlusion of the terminal aorta during control experiments and with HR maintained constant via a pacemaker connected to ventricular electrodes (225 beats/min). In control experiments, hindlimb ischemia elicited substantial increases in SAP, HR, and CO (+53.9 +/- 4.3 mmHg, +32.4 +/- 4.5 beats/min, and +1.57 +/- 0.22 l/min, respectively; all changes P < 0.05), whereas stroke volume (SV) remained unchanged with reflex activation (control 45.9 +/- 2.3 vs. 46.1 +/- 2.4 ml, P > 0.05). During metaboreflex activation at constant HR, SV significantly increased such that the increases in CO and SAP were not significantly different from control experiments (+1.77 +/- 0.56 l/min and +57.4 +/- 3.8 mmHg, P > 0.05 vs. control experiments). No significant change in central venous pressure occurred in either experiment, indicating no Frank-Starling effect on SV. We conclude that muscle metaboreflex-induced increases in ventricular contractility act to sustain SV despite decreases in ventricular filling time due to the tachycardia such that the sustained SV coupled with the tachycardia elicits substantial increases in CO that contribute importantly to the reflex increase in SAP.

Effect of exercise on left ventricular mechanical efficiency in conscious dogs.

We studied the effect of exercise (7.2 to 8.0 km/h) on the efficiency of the conversion of metabolic energy to external work or stroke work (SW) by the left ventricle (LV). Energy use was calculated from LV myocardial oxygen consumption per beat (MVO2). LV volume was calculated from orthogonal dimensions and coronary flow measured with ultrasonic flow probes. The total mechanical energy of the LV was calculated as the pressure-volume area (PVA). At rest, the MVO2-PVA point fell on the MVO2-PVA relation determined by steady-state changes in arterial pressure produced by graded infusions of phenylephrine. Exercise increased the slope (Ees) of LV end-systolic pressure-volume (PV) relation by 29%. During exercise, the MVO2-PVA point shifted to the right only slightly above the control MVO2-PVA relation by 0.007 +/- 0.005 mL O2.beat-1.100 g LV-1. Despite the increase in ventricular contractility with exercise, the PVA/MVO2 ratio was unchanged because of the marked increase in PVA. During exercise, the transmission of total mechanical energy to external work (SW/PVA) increased from 65 +/- 5% to 72 +/- 4% (P < .01) as the ratio of the arterial end-systolic elastance to Ees decreased from 1.1 +/- 0.2 to 0.8 +/- 0.1 (P < .05). Thus, LV mechanical efficiency (SW/MVO2 = SW/PVA.PVA/MVO2) improved from 12.9 +/- 1.5% to 14.3 +/- 1.1% (P < .05) during exercise. Exercise increases the efficiency of conversion of metabolic energy to external work by the LV due to alteration in LV arterial coupling resulting in increased production of mechanical energy and enhanced transmission of mechanical energy to external work, which more than offsets any increased metabolic cost of the enhanced contractility.

Acute Effects of Nifedipine on Systolic and Diastolic Ventricular Function in Patients With Chronic Obstructive Pulmonary Disease

To evaluate how nifedipine influences systolic and diastolic ventricular function, the effects of 20 mg sublingual nifedipine were studied in 13 stable COPD patients. Nifedipine induced no change in mean pulmonary arterial pressure, decreased mean arterial pressure, pulmonary and systemic vascular resistance index, and increased heart rate and cardiac index. It also caused an increase in right and left ventricular ejection fractions. The end-diastolic volume index of both ventricles remained unchanged, whereas the end-systolic volume index tended to decrease without reaching a significant level, and the right ventricular contractility increased. After nifedipine administration, right and left ventricular compliance increased. This study suggests that short-term administration of nifedipine improves the systolic function by a decrease in ventricular afterload and an increase in ventricular contractility and increases the ventricular compliance by a reflex sympathetic stimulation and an afterload reduction.

Chemistry and positive inotropic effect of pelrinone and related derivatives. A novel class of 2-methylpyrimidones as inotropic agents.

A novel series of pyrimidine derivatives was synthesized and evaluated for positive inotropic activity. Inotropic and chronotropic effects were determined in vitro in cat papillary muscle and right atrium, respectively. Selected compounds were then evaluated in vivo in a dog heart failure model. Changes in ventricular dP/dt, heart rate, and blood pressure were monitored. Several of these agents produced relatively minor changes in heart rate. This class of agents demonstrated a varying degree of vasodilator effects concomitant with increases in ventricular contractility. The most potent analogues, 9, 48, and 49, were evaluated orally in conscious dogs with implanted Konisberg pressure transducers, and their effect on left ventricular dP/dt was compared with that of milrinone. Mechanistically, the agents of this novel class appear not to mediate their effect via beta-receptors or inhibition of Na+/K+-ATPase. A major component of their inotropic effect is mediated by the inhibition of cardiac phosphodiesterase (PDE)-Fr. III. This was clearly demonstrated by 9, 48, and 49. Compound 48 was found to be the most potent inhibitor of PDE-Fr. III from among the compounds tested in this assay.

Effect of captopril on left ventricular end-systolic pressure-volume and stress-shortening relations in severe cardiac failure.

The effects of captopril on cardiovascular dynamics and left ventricular (LV) contractility were studied in 11 patients with severe congestive heart failure and very poor global LV function. Pressures were measured using a flow-guided catheter, cardiac output by thermodilution, and LV contraction and ejection fraction by simultaneous radionuclide angiography. Ventricular loading conditions were altered by sublingual isosorbide dinitrate to facilitate construction of LV pressure-volume and stress-shortening curves. Captopril decreased mean arterial pressure (p less than 0.02) and systemic vascular resistance, while stroke and cardiac index increased in most patients. Left ventricular ejection fraction increased from 18 +/- 5 to 22 +/- 7% (p less than 0.05), but contractility, assessed from end-systolic pressure-volume and end-systolic pressure-shortening relations, was unchanged or decreased slightly. Heart rate and double product also tended to decrease. In contrast, arteriovenous oxygen difference widened and calculated total oxygen consumption increased during captopril therapy (p less than 0.05). The study showed that captopril improved forward blood flow, total oxygen extraction, and LV ejection fraction following the decrease impedance to LV emptying but not at the expense of an increase in ventricular contractility. This makes captopril an attractive drug for patients with end-stage cardiac failure and a severely damaged myocardium.

Neuropeptide Y and sympathetic control of heart contractility and coronary vascular tone.

The effects of neuropeptide Y (NPY) on contractility of the spontaneously beating guinea-pig atrium and transmural nerve stimulation (TNS)-induced efflux of tritium-noradrenaline (3H-NA) were studied in vitro. NPY induced a moderate positive chronotropic and inotropic atrial response, which was resistant to metoprolol. TNS at 2 Hz for 2 s caused an increase in rate and contractile force. These effects were significantly reduced by NPY. NPY also reduced the TNS induced (2 Hz for 20 s), fractional [3H]NA release by 40% without affecting the contractile response. The contractile effects of exogenous NA on the guinea-pig atrium were not affected by NPY. NPY caused a long-lasting increase in coronary perfusion pressure, and also, in high doses, an inhibition of ventricular contractility in the isolated, perfused guinea-pig heart. The perfusion pressure increase to NPY, which most likely reflects coronary vasoconstriction, was resistant to alpha- and beta-adrenoceptor blockade but sensitive to the calcium antagonist nifedipine. A 50% reduction of the vascular NPY response occurred at 10(-9) M nifedipine, which did not influence cardiac contractility per se or the contractile effects of NA. NPY did not modify the increase in ventricular contractility induced by NA. Noradrenaline did not influence coronary perfusion pressure after beta-blockade. Since NPY is present together with NA in cardiac nerves, it may be suggested that NPY is involved in the regulation of NA release as well as the sympathetic control of atrial contractility and coronary blood flow.

Antiadrenergic action of adenosine on ventricular myocardium in embryonic chick hearts

Adenosine, a physiological metabolite, is known to exert a negative inotropic effect on atrial muscle [5, 7], to impair atrioventricular conduction [2, 7, 17] and depress pacemaker activity [18]. In addition to such direct actions, adenosine is also known to modulate several of the actions of catecholamines in different tissues [9, 15, 16]. In ventricular muscle, adenosine attenuates the inotropic effect of catecholamines, but has no contractile effect in the absence of catecholamines [1, 6, 15]. Thus, adenosine appears to exert its functions in heart by direct [2, 5, 7, 18] and indirect (anti-adrenergic) [1, 11, 15] mechanisms. The isoproterenol-induced increase in ventricular contractility is associated with an increase in cyclic AMP (cAMP) [19]. Since isoproterenol, cAMP analogs, and cAMP itself (applied internally), increase the Ca 2+-inward current (Isi) and slow action potentials, a causal relationship between cAMP and Isi has been proposed [10]. The ability of isoproterenol to restore excitability to partially depolarized cardiac fibers and/or enhance pre-existing slow action potentials is attributed to increase in cAMP that leads to an increase in the Isi. Adenosine decreased the cAMP levels of catecholamine-treated hearts [1, 6, 15] but unexpectedly adenosine had no inhibitory effect on slow action potentials obtained in elevated K + (27 mM) plus 10 −7 to 10 −6 M isoproterenol solution [12, 13]. In the present study, we wanted to find out whether adenosine would attenuate ventricular slow action potentials enhanced by relatively low concentrations of isoproterenol in normal K + solution. We set out to confirm in parallel experiments that adenosine also reduces the cAMP content of hearts exposed to isoproterenol.

Effects of continuous administration of angiotensin II on ventricular performance

The effects of angiotensin II on circulatory dynamics and coronary blood flow were studied in the cat. With equal single doses of angiotensin II and norepinephrine a greater blood pressure response occurred with angiotensin. With continuous administration of angiotensin II a large initial blood pressure response occurred, but rapidly returned to an intermediate value. During this time the animal was refractory to further single doses. A sustained large increase of ventricular contractility was readily demonstrated with the continuous administration of norepinephrine, but could not be demonstrated with equal amounts of angiotensin II. Acute transient changes of ventricular contractility were observed. Frequently an acute increase of both stroke work at a given filling pressure, and mean rate of ejection occurred. Occasionally, however, marked acute myocardial depression, which rapidly returned to control values, was observed. In about one-third of the preparations prolonged myocardial depression was observed following a period of continuous angiotensin II infusion. This was in sharp contrast to continuous norepinephrine infusion following which myocardial depression was never observed. Measurements of coronary blood flow indicated that when ventricular work was maintained constant, continuous angiotensin II infusion was frequently associated with a transient reduction of coronary flow. This was usually small, but occasionally marked. During this phase concomitant myocardial depression was evident. Continuous norepinephrine infusion produced only an increase of coronary blood flow with an associated increase of myocardial contractility.