Inotropic Stimulation Research Articles

Milrinone and levosimendan during porcine myocardial ischemia – no effects on calcium overload and metabolism

Although inotropic stimulation is considered harmful in the presence of myocardial ischaemia, both calcium sensitisers and phosphodiesterase inhibitors may offer cardioprotection. We hypothesise that these cardioprotective effects are related to an acute alteration of myocardial metabolism. We studied in vivo effects of milrinone and levosimendan on calcium overload and ischaemic markers using left ventricular microdialysis in pigs with acute myocardial ischaemia. Anaesthetised juvenile pigs, average weight 36 kg, were randomised to one of three intravenous treatment groups: milrinone 50 μg/kg bolus plus infusion 0.5 μg/kg/min (n = 7), levosimendan 24 μg/kg plus infusion 0.2 μg/kg/min (n = 7), or placebo (n = 6) for 60 min prior to and during a 45 min acute regional coronary occlusion. Systemic and myocardial haemodynamics were assessed, and microdialysis was performed with catheters positioned in the left ventricular wall. (45) Ca(2+) was included in the microperfusate in order to assess local calcium uptake into myocardial cells. The microdialysate was analysed for glucose, lactate, pyruvate, glycerol, and for (45) Ca(2+) recovery. During ischaemia, there were no differences in microdialysate-measured parameters between control animals and milrinone- or levosimendan-treated groups. In the pre-ischaemic period, arterial blood pressure decreased in all groups while myocardial oxygen consumption remained stable. These findings reject the hypothesis of an immediate energy-conserving effect of milrinone and levosimendan during acute myocardial ischaemia. On the other hand, the data show that inotropic support with milrinone and levosimendan does not worsen the metabolic parameters that were measured in the ischaemic myocardium.

Right ventricular–pulmonary arterial coupling in patients after repair of tetralogy of Fallot

Right ventricular-pulmonary arterial coupling is an important determinant in the development of right ventricular failure. The purpose of our study was to assess right ventricular-pulmonary arterial coupling in children and adolescents with dilatation of the right ventricle after repair of tetralogy of Fallot. Right ventricular-pulmonary arterial coupling was quantified as the ratio of pulmonary arterial elastance (an index of arterial load) and right ventricular end-systolic elastance (an index of contractility) using pressure-volume loops with conductance catheters at the baseline level and during dobutamine infusion. A total of 24 patients (mean age, 16.7 ± 7.0 years) after tetralogy of Fallot repair were enrolled in the present study. End-systolic elastance showed an appropriate increase under inotropic stimulation from 0.24 ± 0.18 to 0.47 ± 0.39 mm Hg/mL/m(2) (P<.01). Simultaneously, the arterial elastance increased from 0.50 ± 0.28 to 0.72 ± 0.48 mm Hg/mL/m(2) (P<.01). Right ventricular-pulmonary arterial coupling was impaired at rest and did not improve significantly under dobutamine stress in the entire study population (arterial elastance/end-systolic elastance decreased from 3.0 ± 2.8 to 2.7 ± 3.1; P=.70). Patients with transannular patch repair (n=11) showed significant uncoupling in response to dobutamine (arterial elastance/end-systolic elastance increased from 2.0 ± 0.8 to 3.7 ± 4.1), and coupling even improved with dobutamine in patients who had undergone a transatrial approach (arterial elastance/end-systolic elastance decreased from 1.6 ± 1.0 to 0.9 ± 0.6; P=.04). Our study demonstrated that right ventricular-pulmonary arterial coupling is impaired in patients with tetralogy of Fallot and is mainly affected by the surgical strategy used at the primary repair. These results elucidate the emerging role of ventricular-arterial interactions as a contributing mechanism for deterioration in right ventricular performance and impaired response to inotropic drugs in patients with tetralogy of Fallot.

Aldosterone Blockade Reduces Mortality without Changing Cardiac Remodeling in Spontaneously Hypertensive Rats

Background: The role of aldosterone blockers during transition from long-term compensated hypertrophy to dilated failure is not completely understood. In this study we evaluated the effects of early administration of spironolactone on cardiac remodeling, myocardial function, and mortality in spontaneously hypertensive rats (SHR). Methods: Sixteen-month-old SHR received no treatment (SHR-C, n=72) or spironolactone (SHR-SPR, 20 mg/kg/day, n=34) for six months. Echocardiogram was performed before and after treatment. Myocardial function was analyzed in left ventricular (LV) papillary muscle preparations. Myocardial collagen and hydroxyproline concentration were evaluated by morphometry and spectrophotometry, respectively. LV gene expression was assessed by real time RT-PCR. Statistics: Student's t test; Log rank test (Kaplan Meyer). Results: SHR-C and SHR-SPR presented mortality rates of 71 and 38%, respectively (p=0.004). Systolic arterial pressure did not differ between groups (SHR-C 199±43; SHR-SPR 200±35 mmHg). Initial and final echocardiograms did not show significant differences in cardiac structures or LV function between groups. Myocardial function was similar between groups at basal and after inotropic stimulation. Collagen fractional area, hydroxyproline concentration, gene expression for α- and β-myosin heavy chain, atrial natriuretic peptide, and Serca2a were not different between groups. Conclusion: Early spironolactone administration reduces mortality without changing cardiac remodeling in spontaneous hypertensive 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.

Cardiac magnetic resonance myocardial feature tracking correlates with natural radial strain and corresponds to inotropic stimulation

Summary We have demonstrated that cardiac magnetic resonance (CMR) myocardial feature tracking (FT) and natural radial strain correlate and correspond to inotropic stimulation. CMR-FT has the potential for quantitative wall motion assessment at rest and during dobutamine stress magnetic resonance (DSMR) imaging. Background CMR-FT is a recently introduced technique for tissue voxel motion tracking on standard steady-state free precession (SSFP) images to derive radial myocardial mechanics. CMR-FT has the potential to facilitate DSMR analysis however has not yet been compared to external reference standards (with stress) such as SSFP derived natural radial strain. Methods 10 healthy subjects were studied at 1.5 Tesla. LV shortaxis radial strain ErrSAX was derived from SSFP cine images using dedicated CMR-FT software (Diogenes MRI prototype, Tomtec, Germany) at rest and during dobutamine stress (10 and 20 μg * kg-1* min-1). Natural radial strain values (loge [End-systolic wall thickness/ end-diastolic wall thickness]) were calculated in identical segments as analysed for ErrSAX using commercially available software (Philips View Forum, The Netherlands). 95% confidence intervals (CI) of the difference and p-values were calculated to compare the 2 techniques. Results In all volunteers strain parameters could be derived from the SSFP images at rest and stress. ErrSAX values showed significantly increased contraction with DSMR (rest: 19.6±14.6; 10 μg: 31.8±20.9; 20 μg: 42.4±25.5, p<0.05). Natural radial strain values increased with dobutamine (rest: 24±8.9; 10 μg: 36.5±8.9; 20 μg: 44.2 ±8.5, p<0.05). There was reasonable agreement between mean ErrSAX and natural radial strain at rest and with dobutamine stress (figure 1 and table 1) as determined by 95% CI of the difference. Conclusions

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.

Oral Abstract Sessions: Young Investigator Award session * Thursday 8 December 2011, 12:45-13:45 * Location: Pecs

Oral Abstract Sessions: Young Investigator Award session * Thursday 8 December 2011, 12:45-13:45 * Location: Pecs

Changing Reflections of the Coronary Microcirculation After Percutaneous Aortic Valve Replacement

In this issue of Circulation , Davies et al1 assess the changes in coronary blood flow and reserve after the relief of aortic stenosis (AS) by percutaneous aortic valve replacement (PAVR) and implicate these findings as additional mechanisms bearing on the critical role of the coronary microcirculation in this population. Article see p 1565 One cannot help but be intrigued by the novel physiological insights that pulsed wave analysis brings to one of the oldest cardiovascular diseases, AS, and one of the newest procedures in interventional cardiology, namely PAVR. For decades, the diagnosis and treatment of AS have rightly focused on identifying and then ameliorating the adverse consequences of abnormal transvalvular pressure and flow. In the absence of coronary artery disease, the mechanisms of angina in AS were debated and attributed mostly to microvascular insufficiency with ischemia resulting from myocardial oxygen supply/demand imbalance. Left ventricular (LV) muscle mass was increased out of proportion to myocardial capillary oxygen supply.2,3 As one might expect in medical science, this is not the end of the story. Examining the arterial pulsed wave dynamics that characterize features of both epicardial and microcirculatory blood flow, Davies et al detail additional mechanisms beyond coronary reserve impairment to better understand why angina may occur in the AS patient with normal coronary arteries. PAVR produced not only a fall in myocardial microvascular resistance, but also improved diastolic filling waves related to favorable changes in LV wall stress as another postulated mechanism for a reduction in …

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.

Assessment of Cardiac Dynamics During Stress Echocardiography By the Peak Power output-to-left Ventricular Mass Ratio

Peak cardiac power-to-mass and peak mass-to-power are variables that couple cardiac power output with left ventricular (LV) mass at peak exercise or during maximal inotropic stimulation. Quantitative stress echocardiography enables the calculation of power output according to the formula: 133 × 10(-6) × stroke volume per second (ml) × mean blood pressure (BP; mmHg) × heart rate. Power-to-mass may be calculated as LV power output per 100 g of LV mass: 100 g × LV power output divided by LV mass (W/100 g). Conversely, mass-to-power may be estimated by dividing LV mass index by LV power output (g/m(2)/W). With a little rearrangement of the formulas we can write: power-to-mass (W/100 g) = 0.222 × cardiac output (l/min) × mean BP (mmHg)/LV mass (g) and mass-to-power (g/m(2)/W) = LV mass index/0.00222 × cardiac output (l/min) × mean BP (mmHg). These parameters reflect the energy delivery of ventricular myocardium with respect to potential energy that is stored in LV mass. The assessment of peak power-to-mass and peak mass-to-power indices may be useful to distinguish compensatory versus maladaptive remodeling in patients with LV dysfunction. When the integrity of myocardial structure is compromised, a disproportion becomes apparent between maximal cardiac power output and LV mass and this leads to either a reduction of peak power-to-mass or an increase of peak mass-to-power. Preliminary reports have demonstrated the usefulness and the prognostic value of peak power-to-mass and peak mass-to-power in patients with LV systolic dysfunction and coronary artery disease.

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.

Réunion commune : Société française neurovasculaire (SFNV) – Société française d’hypertension artérielle (SFHTA)

This study assesses the prognostic value of myocardial viability recognized as a contractile response to inotropic stimulation in patients with left ventricular (LV) dysfunction in a large-scale prospective, multicenter, observational study. Four hundred twenty-five patients (mean age 61 ± 10 years) with angiographically proven coronary artery disease, previous (>3 months) myocardial infarction, and severe LV dysfunction (ejection fraction <35%; mean 28 ± 6%) were enrolled in the study. Each patient underwent low-dose dobutamine echocardiography (up to 10 μg/kg/min). Myocardial viability was identified as a rest–stress variation (Δ) in the wall motion score index (WMSI), in which each segment was scored from 1 = normal to 4 = dyskinetic in a 16-segment model of the left ventricle. Myocardial viability was identified as an improvement of ≥0.40 in WMSI. All patients were followed for a median of 3.1 years. One hundred eighty-eight were revascularized either by coronary artery bypass grafting (n = 118) or coronary angioplasty (n = 70). The only end point analyzed was cardiac death. In the revascularized group, cardiac death occurred in 4 of the 52 patients with and in 37 of the 136 patients without myocardial viability (7.7% vs 27.2%, p <0.003). Kaplan-Meier survival estimates showed a better outcome for those patients with compared to patients without myocardial viability who underwent coronary revascularization (90.1% vs 62%, p <0.0078). Thus, in severe LV ischemic dysfunction, myocardial viability by low-dose dobutamine echocardiography is associated with improved survival in revascularized patients.

Cardiac inotropes: current agents and future directions

Intrinsic inotropic stimulation of the heart is central to the regulation of cardiovascular function, and exogenous inotropic therapies have been used clinically for decades. Unfortunately, current inotropic drugs have consistently failed to show beneficial effects beyond short-term haemodynamic improvement in patients with heart failure. To address these limitations, new agents targeting novel mechanisms are being developed: (i) istaroxime has been developed as a non-glycoside inhibitor of the sodium-potassium-ATPase with additional stimulatory effects on the sarcoplasmic reticulum calcium pump (SERCA) and has shown lusitropic and inotropic properties in experimental and early clinical studies; (ii) from a mechanistic point of view, the cardiac myosin activators, directly activating the acto-myosin cross-bridges, are most appealing with improved cardiac performance in both animal and early clinical studies; (iii) gene therapy approaches have been successfully employed to increase myocardial SERCA2a; (iv) nitroxyl donors have been developed and have shown evidence of positive lusitropic and inotropic, as well as potent vasodilatory effects in early animal studies; (v) the ryanodine receptor stabilizers reduce pathological leak of calcium from the sarcoplasmic reticulum with initial promising pre-clinical results; and finally, (vi) metabolic energy modulation may represent a promising means to improve contractile performance of the heart. There is an urgent clinical need for agents that improve cardiac performance with a favourable safety profile. These current novel approaches to improving cardiac function provide the hope that such agents may soon be available.

Compromised Myocardial Energetics in Hypertrophied Mouse Hearts Diminish the Beneficial Effect of Overexpressing SERCA2a

The sarcoplasmic reticulum calcium ATPase (SERCA) plays a central role in regulating intracellular Ca(2+) homeostasis and myocardial contractility. Several studies show that improving Ca(2+) handling in hypertrophied rodent hearts by increasing SERCA activity results in enhanced contractile function. This suggests that SERCA is a potential target for gene therapy in cardiac hypertrophy and failure. However, it raises the issue of increased energy cost resulting from a higher ATPase activity. In this study, we determined whether SERCA overexpression alters the energy cost of increasing myocardial contraction in mouse hearts with pressure-overload hypertrophy using (31)P NMR spectroscopy. We isolated and perfused mouse hearts from wild-type (WT) and transgenic (TG) mice overexpressing the cardiac isoform of SERCA (SERCA2a) 8 weeks after ascending aortic constriction (left ventricular hypertrophy (LVH)) or sham operation. We found that overexpressing SERCA2a enhances myocardial contraction and relaxation in normal mouse hearts during inotropic stimulation with isoproterenol. Energy consumption was proportionate to the increase in contractile function. Thus, increasing SERCA2a expression in the normal heart allows an enhanced inotropic response with no compromise in energy supply and demand. However, this advantage was not sustained in LVH hearts in which the energetic status was compromised. Although the overexpression of SERCA2a prevented the down-regulation of SERCA protein in LVH hearts, TG-LVH hearts showed no increase in inotropic response when compared with WT-LVH hearts. Our results suggest that energy supply may be a limiting factor for the benefit of SERCA overexpression in hypertrophied hearts. Thus, strategies combining energetic support with increasing SERCA activity may improve the therapeutic effectiveness for heart failure.

Functional antagonism of β‐adrenoceptor subtypes in the catecholamine‐induced automatism in rat myocardium

Myocardial automatism and arrhythmias may ensue during strong sympathetic stimulation. We sought to investigate the relevant types of adrenoceptor, as well as the role of phosphodiesterase (PDE) activity, in the production of catecholaminergic automatism in atrial and ventricular rat myocardium. The effects of adrenoceptor agonists on the rate of spontaneous contractions (automatic response) and the amplitude of electrically evoked contractions (inotropic response) were determined in left atria and ventricular myocytes isolated from Wistar rats. Catecholaminergic automatism was Ca(2+) -dependent, as it required a functional sarcoplasmic reticulum to be exhibited. Although both α- and β-adrenoceptor activation caused inotropic stimulation, only β(1) -adrenoceptors seemed to mediate the induction of spontaneous activity. Catecholaminergic automatism was enhanced and suppressed by β(2) -adrenoceptor blockade and stimulation respectively. Inhibition of either PDE3 or PDE4 (by milrinone and rolipram, respectively) potentiated the automatic response of myocytes to catecholamines. However, only rolipram abolished the attenuation of automatism produced by β(2) -adrenoceptor stimulation. α- and β(2) -adrenoceptors do not seem to be involved in the mediation of catecholaminergic stimulation of spontaneous activity in atrial and ventricular myocardium. However, a functional antagonism of β(1) - and β(2) -adrenoceptor activation was identified, the former mediating catecholaminergic myocardial automatism and the latter attenuating this effect. Results suggest that hydrolysis of cAMP by PDE4 is involved in the protective effect mediated by β(2) -adrenoceptor stimulation.

Impact of R4496C RyR2 Mutation on Myocardial Contractility

Cardiac Ryanodine Receptor (RyR2) is a crucial determinant of Ca2+ availability in myofilament activation and force generation. To investigate the impact of RyR2 arrhythmia-related mutations on contractile function, atrial and ventricular trabeculae and ventricular myocytes from Wild Type (WT) and heterozygous R4496C RyR2 mutant (RyRR4496C+/-) mice were isolated and studied. Although under basal conditions contractility and Ca2+-transient amplitude are normal, RyRR4496C+/- preparations show reduced inotropic responses to high stimulation frequency, isoproterenol and other experimental interventions that potentiate contraction. The diminished inotropic response results from a smaller Sarcoplasmic Reticulum (SR) calcium load after inotropic stimulation than that of WT preparations. Moreover, RyRR4496C+/- muscles have faster mechanical restitution and shorter recovery of the amplitude of Ca2+release. In RyRR4496C+/- vs. WT myocytes sarcolemmal Ca2+-fluxes (ICa-L and INCX) and SR Ca2+-uptake are unchanged. We suggest that changes in gating of the mutant RyR2 Ca2+ channel are directly responsible for these observations. Fitting our experimental data for the R4496C mutation into a cardiomyocyte model, where the RyR2 gating properties are represented by a four state equilibrium and are modulated by luminal [Ca2+] ([Ca2+]SR), we predict an increase in sensitivity to [Ca2+]SR of both opening and closing channel transitions rates of mutant channels. Specifically, increasing [Ca2+]SR-sensitivity of closed-to-open transitions leads to SR-calcium depletion, blunted simulated inotropic responses and faster mechanical restitution. However, for the model to fully emulate our experimental results, [Ca2+]SR-sensitivity of open-to-closed transition also has to be increased, suggesting an effect of the R4496C mutation on RyR2-deactivation and Ca2+-release termination.

Alteration of Left Ventricular Function with Dobutamine Challenge in Patients with Myocardial Bridge

Background/AimsThe aim of this study was to identify changes in left ventricular (LV) performance in patients with a myocardial bridge (MB) in the left anterior descending coronary artery during resting and in an inotropic state.MethodsMyocardial strain measurement by speckle-tracking echocardiography and conventional LV wall-motion scoring was performed in 18 patients with MB (mean age, 48.1 ± 1.7 years, eight female) during resting and intravenous dobutamine challenge (10 and 20 µg/kg/min).ResultsConventional LV wall-motion scoring was normal in all patients during resting and in an inotropic state. Peak regional circumferential strain increased dose dependently upon dobutamine challenge. Longitudinal strains of the anterior and anteroseptal segments were, however, reduced at 20 µg/kg/min and showed a dyssynchronous pattern at 20 µg/kg/min. Although there were no significant differences in radial strain and displacement of all segments at rest compared with under 10 µg/kg/min challenge, radial strain and displacement of anterior segments at 20 µg/kg/min were significantly reduced compared with posterior segments at the papillary muscle level (44.8 ± 14.9% vs. 78.4 ± 20.1% and 5.3 ± 2.3 mm vs. 8.5 ± 1.8 mm, respectively; all p < 0.001), and showed plateau (40%) or biphasic (62%) patterns.ConclusionsReduced LV strain of patients with MB after inotropic stimulation was identified. Speckle-tracking strain echocardiography identified a LV myocardial dyssynchrony that was not demonstrated by conventional echocardiography in patients with MB.

Isoproterenol stimulates 5′-AMP-activated protein kinase and fatty acid oxidation in neonatal hearts

Isoproterenol increases phosphorylation of LKB, 5'-AMP-activated protein kinase (AMPK), and acetyl-CoA carboxylase (ACC), enzymes involved in regulating fatty acid oxidation. However, inotropic stimulation selectively increases glucose oxidation in adult hearts. In the neonatal heart, fatty acid oxidation becomes a major energy source, while glucose oxidation remains low. This study tested the hypothesis that increased energy demand imposed by isoproterenol originates from fatty acid oxidation, secondary to increased LKB, AMPK, and ACC phosphorylation. Isolated working hearts from 7-day-old rabbits were perfused with Krebs solution (0.4 mM palmitate, 11 mM glucose, 0.5 mM lactate, and 100 mU/l insulin) with or without isoproterenol (300 nM). Isoproterenol increased myocardial O(2) consumption (in J·g dry wt(-1)·min(-1); 11.0 ± 1.4, n = 8 vs. 7.5 ± 0.8, n = 6, P < 0.05), and the phosphorylation of LKB (in arbitrary density units; 0.87 ± 0.09, n = 6 vs. 0.59 ± 0.08, n = 6, P < 0.05), AMPK (0.82 ± 0.08, n = 6 vs. 0.51 ± 0.06, n = 6, P < 0.05), and ACC-β (1.47 ± 0.14, n = 6 vs. 0.97 ± 0.07, n = 6, P < 0.05), with a concomitant decrease in malonyl-CoA levels (in nmol/g dry wt; 0.9 ± 0.9, n = 8 vs. 7.5 ± 1.3, n = 8, P < 0.05) and increase in palmitate oxidation (in nmol·g dry wt(-1)·min(-1); 272 ± 45, n = 8 vs. 114 ± 9, n = 6, P < 0.05). Glucose and lactate oxidation were increased (in nmol·g dry wt(-1)·min(-1); 253 ± 75, n = 8 vs. 63 ± 15, n = 9, P < 0.05 and 246 ± 43, n = 8 vs. 82 ± 11, n = 6, P < 0.05, respectively), independent of alterations in pyruvate dehydrogenase phosphorylation, but occurred secondary to a decrease in acetyl-CoA content and acetyl-CoA-to-free CoA ratio. As acetyl-CoA levels decrease in response to isoproterenol, despite an acceleration of the rates of palmitate and carbohydrate oxidation, these data suggest net rates of acetyl-CoA utilization exceed the net rates of acetyl-CoA generation.

Comparison of the T-tubule system in adult rat ventricular and atrial myocytes, and its role in excitation–contraction coupling and inotropic stimulation

Narrow, tubular, inward projections of the sarcolemma (‘T-tubules’) are an established feature of adult mammalian ventricular myocytes that enables them to generate the whole-cell Ca 2+ transients and produce coordinated contraction. Loss of T-tubules can occur during ageing and under pathological conditions, leading to altered cardiac excitation–contraction coupling. In contrast to adult ventricular cells, atrial myocytes do not generally express an extensive T-tubule system at any stage of development, and therefore rely on Ca 2+ channels around their periphery for the induction of Ca 2+ signalling and excitation–contraction coupling. Consequently, the characteristics of systolic Ca 2+ signals in adult ventricular and atrial myocytes are temporally and spatially distinct. However, although atrial myocytes do not have the same regularly spaced convoluted T-tubule structures as adult ventricular cells, it has been suggested that a proportion of adult atrial cells have a more rudimentary tubule system. We examined the structure and function of these atrial tubules, and explored their impact on the initiation and recovery of Ca 2+ signalling in electrically paced myocytes. The atrial responses were compared to those in adult ventricular cells that had intact T-tubules, or that had been chemically detubulated. We found that tubular structures were present in a significant minority of adult atrial myocytes, and were unlike the T-tubules in adult ventricular cells. In those cells where they were present, the atrial tubules significantly altered the on-set, amplitude, homogeneity and recovery of Ca 2+ transients. The properties of adult atrial myocyte Ca 2+ signals were different from those in adult ventricular cells, whether intact or detubulated. Excitation–contraction coupling in detubulated adult ventricular myocytes, therefore, does not approximate to atrial signalling, even though Ca 2+ signals are initiated in the periphery of the cells in both of these situations. Furthermore, inotropic responses to endothelin-1 were entirely dependent on T-tubules in adult ventricular myocytes, but not in atrial cells. Our data reveal that that the T-tubules in atrial cells impart significant functional properties, but loss of these tubular membranes does not affect Ca 2+ signalling as dramatically as detubulation in ventricular myocytes.

Validation of a new transpulmonary thermodilution system to assess global end-diastolic volume and extravascular lung water

IntroductionA new system has been developed to assess global end-diastolic volume (GEDV), a volumetric marker of cardiac preload, and extravascular lung water (EVLW) from a transpulmonary thermodilution curve. Our goal was to compare this new system with the system currently in clinical use.MethodsEleven anesthetized and mechanically ventilated pigs were instrumented with a central venous catheter and a right (PulsioCath; Pulsion, Munich, Germany) and a left (VolumeView™; Edwards Lifesciences, Irvine, CA, USA) thermistor-tipped femoral arterial catheter. The right femoral catheter was used to measure GEDV and EVLW using the PiCCO2™ (Pulsion) method (GEDV1 and EVLW1, respectively). The left femoral catheter was used to measure the same parameters using the new VolumeView™ (Edwards Lifesciences) method (GEDV2 and EVLW2, respectively). Measurements were made during inotropic stimulation (dobutamine), during hypovolemia (bleeding), during hypervolemia (fluid overload), and after inducing acute lung injury (intravenous oleic acid).ResultsOne hundred and thirty-seven paired measurements were analyzed. GEDV1 and GEDV2 ranged from 701 to 1,629 ml and from 774 to 1,645 ml, respectively. GEDV1 and GEDV2 were closely correlated (r2 = 0.79), with mean bias of -11 ± 80 ml and percentage error of 14%. EVLW1 and EVLW2 ranged from 507 to 2,379 ml and from 495 to 2,222 ml, respectively. EVLW1 and EVLW2 were closely correlated (r2 = 0.97), with mean bias of -5 ± 72 ml and percentage error of 15%.ConclusionsIn animals, and over a very wide range of values, a good agreement was found between the new VolumeView™ system and the PiCCO™ system to assess GEDV and EVLW.