Myocardial Segment Length Research Articles

Direct in vivo assessment of global and regional mechanoelectric feedback in the intact human heart

BackgroundInhomogeneity of ventricular contraction is associated with sudden cardiac death, but the underlying mechanisms are unclear. Alterations in cardiac contraction impact electrophysiological parameters through mechanoelectric feedback. This has been shown to promote arrhythmias in experimental studies, but its effect in the in vivo human heart is unclear.ObjectiveThe purpose of this study was to quantify the impact of regional myocardial deformation provoked by a sudden increase in ventricular loading (aortic occlusion) on human cardiac electrophysiology.MethodsIn 10 patients undergoing open heart cardiac surgery, left ventricular (LV) afterload was modified by transient aortic occlusion. Simultaneous assessment of whole-heart electrophysiology and LV deformation was performed using an epicardial sock (240 electrodes) and speckle-tracking transesophageal echocardiography. Parameters were matched to 6 American Heart Association LV model segments. The association between changes in regional myocardial segment length and activation-recovery interval (ARI; a conventional surrogate for action potential duration) was studied using mixed-effect models.ResultsIncreased ventricular loading reduced longitudinal shortening (P = .01) and shortened ARI (P = .02), but changes were heterogeneous between cardiac segments. Increased regional longitudinal shortening was associated with ARI shortening (effect size 0.20 [0.01–0.38] ms/%; P = .04) and increased local ARI dispersion (effect size –0.13 [–0.23 to –0.03] ms/%; P = .04). At the whole organ level, increased mechanical dispersion translated into increased dispersion of repolarization (correlation coefficient r = 0.81; P = .01).ConclusionMechanoelectric feedback can establish a potentially proarrhythmic substrate in the human heart and should be considered to advance our understanding and prevention of cardiac arrhythmias.

Assessment of wasted myocardial work: a novel method to quantify energy loss due to uncoordinated left ventricular contractions

Left ventricular (LV) dyssynchrony reduces myocardial efficiency because work performed by one segment is wasted by stretching other segments. In the present study, we introduce a novel noninvasive clinical method that quantifies wasted energy as the ratio between work consumed during segmental lengthening (wasted work) divided by work during segmental shortening. The wasted work ratio (WWR) principle was studied in 6 anesthetized dogs with left bundle branch block (LBBB) and in 28 patients with cardiomyopathy, including 12 patients with LBBB and 10 patients with cardiac resynchronization therapy. Twenty healthy individuals served as controls. Myocardial strain was measured by speckle tracking echocardiography, and LV pressure (LVP) was measured by micromanometer and a previously validated noninvasive method. Segmental work was calculated by multiplying strain rate and LVP to get instantaneous power, which was integrated to give work as a function of time. A global WWR was also calculated. In dogs, WWR by estimated LVP and strain showed a strong correlation (r = 0.94) and good agreement with WWR by the LV micromanometer and myocardial segment length by sonomicrometry. In patients, noninvasive WWR showed a strong correlation (r = 0.96) and good agreement with WWR using the LV micromanometer. Global WWR was 0.09 ± 0.03 in healthy control subjects, 0.36 ± 0.16 in patients with LBBB, and 0.21 ± 0.09 in cardiomyopathy patients without LBBB. Cardiac resynchronization therapy reduced global WWR from 0.36 ± 0.16 to 0.17 ± 0.07 (P < 0.001). In conclusion, energy loss due to incoordinated contractions can be quantified noninvasively as the LV WWR. This method may be applied to evaluate the mechanical impact of dyssynchrony.

La distensión de la región isquémica predice una mayor inducibilidad de fibrilación ventricular tras la oclusión coronaria en el modelo porcino

Introduction and objectivesDistension of the ischemic region has been related to an increased incidence of spontaneous ventricular arrhythmias following coronary occlusion. This study analyzed whether regional ischemic distension predicts increased ventricular fibrillation inducibility after coronary occlusion in swine. MethodsIn 18 anesthetized, open-chest pigs, the left anterior descending coronary artery was ligated for 60min. Myocardial segment length in the ischemic region was monitored by means of ultrasonic crystals. Programmed stimulation was applied at baseline and then continuously between 10 and 60min after coronary occlusion. ResultsCoronary occlusion induced a rapid increase in end-diastolic length in the ischemic region, which reached 109.4% (0,9%) of baseline values 10min after occlusion (P<.001). On average, 6.6 (0,5) stimulation protocols were completed and 5.4 (0,6) ventricular fibrillation episodes induced between 10 and 60min of coronary occlusion. Neither baseline serum potassium levels nor the size of the ischemic region were significantly related to ventricular fibrillation inducibility. In contrast, the increase in end-diastolic length 10min after coronary occlusion was associated directly (r=0,67; P=.002) with the number of induced ventricular fibrillation episodes and inversely (r=–0,55; P=.018) with the number of extrastimuli needed for ventricular fibrillation induction. ConclusionsRegional ischemic expansion predicts increased ventricular fibrillation inducibility following coronary occlusion. These results highlight the potential influence of mechanical factors, acting not only on the triggers but also on the substrate, in the genesis of malignant ventricular arrhythmias during acute ischemia.Full English text available from: www.revespcardiol.org/en

Distension of the Ischemic Region Predicts Increased Ventricular Fibrillation Inducibility Following Coronary Occlusion in Swine

Introduction and objectivesDistension of the ischemic region has been related to an increased incidence of spontaneous ventricular arrhythmias following coronary occlusion. This study analyzed whether regional ischemic distension predicts increased ventricular fibrillation inducibility after coronary occlusion in swine. MethodsIn 18 anesthetized, open-chest pigs, the left anterior descending coronary artery was ligated for 60min. Myocardial segment length in the ischemic region was monitored by means of ultrasonic crystals. Programmed stimulation was applied at baseline and then continuously between 10 and 60min after coronary occlusion. ResultsCoronary occlusion induced a rapid increase in end-diastolic length in the ischemic region, which reached 109.4% (0.9%) of baseline values 10min after occlusion (P<.001). On average, 6.6 (0.5) stimulation protocols were completed and 5.4 (0.6) ventricular fibrillation episodes induced between 10 and 60min of coronary occlusion. Neither baseline serum potassium levels nor the size of the ischemic region were significantly related to ventricular fibrillation inducibility. In contrast, the increase in end-diastolic length 10min after coronary occlusion was associated directly (r=0.67; P=.002) with the number of induced ventricular fibrillation episodes and inversely (r=–0.55; P=.018) with the number of extrastimuli needed for ventricular fibrillation induction. ConclusionsRegional ischemic expansion predicts increased ventricular fibrillation inducibility following coronary occlusion. These results highlight the potential influence of mechanical factors, acting not only on the triggers but also on the substrate, in the genesis of malignant ventricular arrhythmias during acute ischemia.

Intraventricular pressure gradients throughout the cardiac cycle: effects of ischaemia and modulation by afterload

The aim of the present study was to characterize the intraventricular pressure gradients (IVPGs) througout the cardiac cycle, to correlate them with myocardial segmental asynchrony and to evaluate the effects of ischaemia and modulation by afterload. Open-chest anaesthetized rabbits (n = 6) were instrumented with pressure-tip micromanometers placed in the apex and outflow tract of the left ventricular (LV) cavity and with sonomicrometer crystals placed in the apex and base of the LV free wall to measure IVPGs and myocardial segment length changes during basal, afterloaded (aortic cross-clamping) and ischaemic conditions (left anterior descending coronary artery ligation). During early diastole (rapid filling), we recorded an IVPG (4.6 ± 0.7 mmHg) from the cardiac base towards the apex followed by an apex-to-outflow pressure gradient (3.6 ± 0.2 mmHg). During systole, we recorded an IVPG (0.6 ± 0.1 mmHg) from apex to outflow during early rapid ejection, which inverted during late slow ejection. Interestingly, the maximal rate of LV pressure fall occurred earlier and relaxation rate was faster in the base than in the apex. While shortening of basal segments was complete at the end of ejection, apical segments always showed a significant amount of postsystolic shortening. The IVPGs were entirely lost during ischaemia and attenuated by afterload elevations. During ischaemia, systolic shortening of the apical segment decreased, while postsystolic shortening increased. The present study confirms the existence of diastolic and systolic IVPGs in the LV and demonstrates, for the first time, that this normal gradient pattern is related to physiological asynchrony between basal and apical myocardial segments. Moreover, we show that the IVPG, a marker of normal left ventricular function, can be attenuated, lost entirely or even reversed after regional acute ischaemia and afterload elevations.

Left atrial diastolic dysfunction: A new complication after catheter ablation for atrial fibrillation?

a c p d t ( p n d P r p r n Atrial fibrillation (AF) is a complex phenomenon associated with electrical, contractile, and structural remodeling. Alhough paroxysmal AF may occur in patients with apparently tructurally normal atria, the most frequent clinical setting of ersistent AF is hypertension, coronary artery disease, heart ailure, and valvular heart disease. A common pathophysiolgy of these risk factors for AF is volume or pressure overload f the left atrium (LA). According to the concept termed echano-electrical feedback, increased hemodynamic load ay be associated with changes in myocardial segment length, hich in turn result in decreased resting diastolic potential, hanges in cardiac action potential (AP) contour, shortening of P duration, and development of afterdepolarizations that riginate in the region of greatest stretch. As shown in an animal model, excessive loading conditions lead to increased dispersion of atrial refractory periods, which predisposes to atrial fibrillation. A recent study by Yoshida et al showed that F dominant frequency (DF) is directly related to LA pressure n patients with persistent AF, and that LA pressure is an ndependent predictor of DFmax in the LA appendage. These ndings support the notion that atrial stretch may stabilize igh-frequency sources necessary for maintenance of AF. It is widely accepted that AF causes many hemodynamic bnormalities, including an irregular and often rapid venricular rate, decreased stroke volume, increased LA presure and volume, shortened diastolic ventricular filling eriod, and atrioventricular valvular regurgitation. To counter these deleterious hemodynamic consequences, AF ablation has evolved as an effective therapeutic strategy for patients with symptomatic AF. The goal of AF ablation is to allow synchronized and efficient transport of blood from the atria to the ventricles. In accordance with the Frank-Starling principle, atrial systole augments left ventricular (LV) stroke volume and cardiac performance. In theory, one of the benefits of radiofrequency catheter ablation for AF is more effective LA function. Given that ablation lesions, by their nature, result in LA scarring, prior studies have investigated the impact of radiofrequency

Direct Left Ventricle to Great Cardiac Vein Retroperfusion: A Novel Alternative to Myocardial Revascularization

As the number of patients with diffuse coronary artery disease continues to grow, there is renewed interest in alternative methods of perfusing the ischemic myocardium. We tested the feasibility of myocardial retroperfusion via a direct left ventricle-to-great cardiac vein (LV-GCV) conduit to support regional contractility in this setting. LV-GCV flow was established using an extracorporeal circuit in 5 dogs. Left ventricle (LV) pressure, aortic pressure, regional myocardial segment length, and circuit blood flow were measured prior to left anterior descending coronary artery (LAD) ligation, following LAD ligation, and after LV-GCV circuit placement. To eliminate backward flow during diastole, an in-line flow regulator was placed. Regional myocardial function was quantified by pressure-segment length loop area divided by end-diastolic segment length (PSLA/EDSL). LAD ligation reduced PSLA/EDSL from 10.0 +/- 1.2 mm Hg mm to 1.6 +/- 0.3 mm Hg mm (P < .05). With LV-GCV retroperfusion, mean peak systolic flow was +152 +/- 14 mL/min, mean peak diastolic flow was -39 +/- 11 mL/min, and net mean flow was +36 +/- 13 mL/min. Regional function recovered to approximately 39% of baseline (3.9 +/- 0.4 mm Hg mm, P < .05). Upon elimination of backflow, mean flow increased to +41 +/- 12 mL/min and regional function recovered even further to approximately 47% of baseline (4.6 +/- 0.7 mm Hg mm, P < .05). A LV-GCV circuit can significantly restore regional function to the acutely ischemic myocardium. An inline valve that eliminates backward diastolic flow improves regional function even further. This approach may provide an effective therapy for diffuse coronary disease not amenable to traditional revascularization strategies.

Antagonizing reactive oxygen by treatment with a manganese (III) metalloporphyrin–based superoxide dismutase mimetic in cardiac transplants

Oxidative stress might be an important factor contributing to injury during alloimmune activation. Herein, we evaluated the efficacy of a superoxide dismutase mimetic, manganese (III) tetrakis (1-methyl-4-pyridyl) porphyrin pentachloride (MnTmPyP), on cytokine gene expression and apoptotic signaling in a rat model of cardiac transplantation. Lewis-->Lewis (isografts) or Wistar-Furth-->Lewis (allografts) heterotopic rat transplants without and with treatment with MnTmPyP were used. Reactive oxygen formation was determined on the basis of dihydroethidine fluorescence and lucigenin-enhanced chemiluminescence. In situ graft function was determined by means of sonomicrometry. Inflammatory cytokine, proapoptotic, and antiapoptotic gene expression at either postoperative day 4 (early rejection) or postoperative day 6 (late rejection) was determined by means of reverse transcriptase polymerase chain reaction. An increased production of reactive oxygen in allografts was inhibited to isograft control levels by MnTmPyP. MnTmPyP restored either the percentage of fractional shortening, the distended diastolic and systolic myocardial segment lengths, or both in allografts. Of the increases in cytokine and proapoptotic gene expression in allografts, only interleukin 6 was decreased by MnTmPyP. MnTmPyP inhibited antiapoptotic gene expression (Bcl-2 and Bcl-xL) during early rejection but restored expression at later stages. The increase in activated caspase-3 levels in allografts was inhibited by MnTmPyP. The mechanism of the beneficial effect of MnTmPyP on graft function appear related, in part, to scavenging O2*- and by decreasing apoptotic signaling rather than an effect on inflammatory cytokine gene expression.

Gonadectomy and Androgen Replacement Alter Cardiac Performance in Conscious Adult Male Rats

Gender disparities in cardiac function have been described. Yet the extent to which gender related differences in cardiac performance are due to the presence of sex-specific biological factors are unclear. We used a longitudinal study aimed at examining whether castration and androgen replacement affects cardiac performance in conscious adult male rats. Adult male rats were implanted with Piezoelectric transit-time gauges and radio telemetry devices to measure regional myocardial segment length and hemodynamic variables before and after castration and after androgen replacement. Androgen withdrawal accelerated average heart rates by 7% (p = 0.010). Heart rate was lowered to intact values when androgens were restored to normal physiological levels (p = 0.004). Mean arterial pressure was not affected by androgen deprivation and androgen replacement. However, androgen withdrawal produced a 40% decrease in the velocity of circumferential shortening and a 46% reduction in the rate of myocardial relaxation. Androgen supplementation completely restored contractile function. These results provide the first evidence that androgen withdrawal and androgen replacement produces dramatic alterations on cardiac performance in conscious animals and demonstrates the significance of androgens as a cardioregulatory hormone in males. Sex steroids are likely contributors to gender-related differences in cardiac function.

Serotonin aggravates exercise-induced cardiac ischemia in the dog: effect of serotonin receptor antagonists

We investigated the effects of serotonin (5-HT), SL65.0472 (7-fluoro-2-oxo-4-[2-[4-thieno[3,2- c]pyridine-4-yl)piperazin-1-yl]ethyl]-1,2-dihydroquinoline-1-acetamide, a 5-HT 1B/5-HT 2A receptor antagonist) and ketanserin (a 5-HT 2A receptor antagonist) during exercise-induced cardiac ischemia in conscious dogs. Dogs were administered a hypercholesterolemic diet and an inhibitor of nitric oxide synthetase to produce chronic endothelial dysfunction. Myocardial ischemia was induced by a treadmill exercise test associated with limitation of left anterior descending coronary blood flow. Infusion of serotonin during exercise produced dose-related cardiovascular changes (after 10 μg/kg/min; heart rate +27±6 bpm, systolic blood pressure +18±3 mm Hg, left circumflex coronary blood flow +64±8 ml/min, myocardial segment length shortening in the ischemic zone −5.9±1.9%, P<0.05). SL65.0472 blocked serotonin-induced increases in blood pressure, rate pressure product and circumflex coronary artery flow (100 μg/kg i.v., P<0.05) and reduced serotonin-induced ischemic myocardial segment length shortening (300 μg/kg i.v., P<0.05). Ketanserin (30–300 μg/kg i.v.) had no significant effect on any serotonin-induced changes during exercise. Thus, SL65.0472 opposes serotonin-induced myocardial dysfunction in a dog model of exercise-induced ischemia.

Effect of antecedent systemic hypertension on subsequent left ventricular dilation after acute myocardial infarction (from the Survival and Ventricular Enlargement trial)

Whether antecedent systemic hypertension influences the risk of subsequent left ventricular (LV) dilation in patients after an acute myocardial infarction with LV systolic dysfunction is unclear. We assessed echocardiographic evidence of ventricular remodeling from baseline (mean ± SD 11 ± 3 days) to 2 years after an acute myocardial infarction in 122 hypertensive (defined as a history of treated hypertension, baseline systolic blood pressure ≥140 or baseline diastolic blood pressure ≥90 mm Hg) and 334 nonhypertensive patients in the Survival and Ventricular Enlargement echocardiographic substudy. Compared with nonhypertensives, baseline heart size, defined as the sum of the average short- and long-axis LV cavity areas, was similar (70.1 ± 11.9 vs 68.8 ± 11.2 cm 2, p = 0.33 at end-diastole; 50.1 ± 11.3 vs 48.8 ± 10.8 cm 2, p = 0.31 at end-systole), but short-axis LV myocardial area (24.7 ± 4.3 vs 25.7 ± 5.0 cm 2, p = 0.043) and wall thickness (1.15 ± 0.16 vs 1.21 ± 0.17 cm, p = 0.004) at end-diastole were greater among hypertensives. The myocardial infarct segment lengths were similar in the 2 groups (p = 0.22). Although LV cavity areas increased significantly in the 2 groups from baseline to 2 years (p ≤0.001), the increase was significantly greater in hypertensives than in nonhypertensives (+5.6 ± 11.5 vs +2.2 ± 10.7 cm 2, p = 0.005 at end-diastole; +6.23 ± 12.75 vs +2.94 ± 11.4 cm 2, p = 0.012 at end-systole). There was no concomitant difference in the change in LV myocardial area or LV wall thickness between the 2 groups (p >0.30). After adjusting for known confounders, antecedent hypertension was associated with a doubling of the risk of LV dilation (50.8% vs 37.7%, odds ratio 2.09, 95% confidence interval 1.27 to 3.45, p = 0.004). This association was not modified by diabetes mellitus, myocardial infarct segment length, or captopril use (all p values for interaction >0.10). We conclude that antecedent hypertension is associated with subsequent LV dilation in patients after acute myocardial infarction with LV systolic dysfunction.

Quantification of left ventricular systolic function by tissue Doppler echocardiography: added value of measuring pre- and postejection velocities in ischemic myocardium.

Tissue Doppler imaging (TDI) is a potentially powerful method for diagnosing myocardial ischemia. This study was designed to investigate how velocity patterns in ischemic myocardium relates to regional function, and to determine whether timing of velocity measurements relative to ejection and isovolumic phases may increase the diagnostic power of TDI. In 17 open-chest anesthetized dogs we measured pressures by micromanometers, myocardial longitudinal segment lengths by sonomicrometry, and velocities by TDI. Myocardial longitudinal strain rate was calculated as velocity divided by distance to the left ventricle apex. Moderate ischemia (left anterior descending coronary artery stenosis) caused parallel reductions in regional systolic shortening by sonomicrometry (P<0.05) and in peak systolic velocities by TDI (P<0.05). Severe ischemia (left anterior descending coronary artery occlusion), however, induced systolic lengthening by sonomicrometry (P<0.001), whereas peak TDI velocity during ejection remained positive (P<0.05). When velocities during isovolumic contraction (IVC) and isovolumic relaxation (IVR) were included, TDI correlated well with sonomicrometry; ie, systolic lengthening occurred predominantly during IVC and was evident as negative velocities (r=0.70, P<0.001), and postsystolic shortening during IVR (r=0.72, P<0.001) as positive velocities. In nonischemic myocardium peak systolic strain rates were more uniform than velocities. The present results indicate that peak ejection velocity is an inappropriate measure of function in severely ischemic myocardium. Dyskinetic myocardium deforms predominantly during the isovolumic phases, and therefore IVC and IVR velocities are better markers of function. When isovolumic as well as ejection velocities are measured, TDI has excellent ability to quantify regional myocardial dysfunction. Longitudinal strain rates are more uniform than velocities and may further improve the diagnostic power of TDI.

Effect of the calcium sensitizer levosimendan on the performance of ischaemic myocardium in anaesthetised pigs.

The calcium sensitizer levosimendan (LEV) improves the function of stunned myocardium, cardiac performance in heart failure, and possibly the efficiency of myocardial work. The present experiments investigated the effect of LEV on myocardial contraction and metabolism of acutely ischaemic myocardium distal to a functionally effective coronary artery stenosis. Anaesthetised open chest pigs (n = 14) were instrumented to assess heart rate (HR), aortic pressure (AoP), cardiac output (CO), blood flow in the left descending (QLAD) and circumflex (QLCX) coronary artery, myocardial end-diastolic segment length and systolic shortening (edL, MSS by sonomicrometry) in the LAD- and LCX-territory. Systemic vascular resistance (SVR), and a myocardial power index (PowI) for the LAD- and LCX-region were calculated. Following obstruction of QLAD by an external snare proximal to the first diagonal branch LEV was given intravenously (10 + 20 + 30 microg/kg 15 min apart, n = 8) or the vehicle of LEV (n = 6). Following LEV haemodynamics and regional myocardial performance changed significantly: HR +22 min(-1), AoP -6 mmHg, CO +17%, SVR -21%; intact myocardium: QLCX +15%, RLCX -24%, PowILCX + 39%; ischaemic myocardium: QLAD -7%, MSSLAD -42%, PowILAD -27%. The data confirm the pharmacological profile of LEV: positive chronotropy, positive inotropy, and vasodilatation. The pump function of acutely ischaemic myocardium worsened following LEV. The efficiency of myocardial performance did not improve. A beneficial effect of LEV on the function of ischaemic myocardium was possibly outmanoeuvred by the increase in heart rate.

L-Arginine administration prevents reperfusion-induced cardiomyocyte hypercontracture and reduces infarct size in the pig.

Stimulation of cGMP synthesis protects cardiomyocytes against reoxygenation-induced hypercontracture. The purpose of this study was to determine whether L-arginine supplementation has a protective effect against reperfusion-induced hypercontracture and necrosis in the intact animal. Twenty-four Large-White pigs were randomized to receive either 100 mg/kg of L-arginine i.v. or vehicle 10 min before 48 min of coronary occlusion and 2 h of reperfusion. Hemodynamic variables, coronary blood flow and myocardial segment length changes (piezoelectric crystals) were monitored. Postmortem studies included quantification of myocardium at risk (in vivo fluorescein), infarct size (triphenyltetrazolium reaction), myocardial myeloperoxidase activity and histological analysis. Systemic, coronary vein, and myocardial cGMP concentration were measured in additional animals. Administration of L-arginine had no significant effect in hemodynamics or coronary blood flow. During reperfusion, myocardial cGMP content was reduced in the LAD as compared to control myocardium (P=0.02). L-Arginine increased myocardial cGMP content and caused a transient increase in plasma cGMP concentration during the initial minutes of reperfusion (P=0.02). The reduction in end-diastolic segment length induced by reperfusion, reflecting hypercontracture, was less pronounced in the L-arginine group (P=0.02). Infarct size was smaller in pigs receiving L-arginine (47.9+/-7.2% of the area at risk) than in controls (62.9+/-4.9%, P=0.047). There were no differences between groups in leukocyte accumulation in reperfused myocardium (P=0.80). L-Arginine supplementation reduces myocardial necrosis secondary to in situ ischemia-reperfusion by a direct protective effect against myocyte hypercontracture.

Calcitonin gene–related peptide enhances the recovery of contractile function in stunned myocardium

Introduction: Calcitonin gene-related peptide, a potent vasodilating inotropic agent, increases coronary artery perfusion when administered exogenously and reduces ischemic injury in nonmyocardial tissue. However, it is unclear whether this agent improves recovery of myocardial performance after reversible myocardial ischemia. Methods: Nine dogs underwent complete occlusion of the left anterior descending coronary artery for 15 minutes and were monitored during 24 hours of reperfusion. Calcitonin gene–related peptide (0.07 μg · kg –1 · min –1), nitroglycerin (65 μg · kg –1 · min –1), or saline solution placebo was infused intravenously during initial reperfusion. Ischemia/reperfusion was repeated in concurrent 24-hour periods until all animals received infusions in random order. Micromanometry and sonomicrometry determined left ventricular pressure and myocardial segment length. Myocardial performance, based on the linear relationship between stroke work and end-diastolic segment length, was estimated with the preload recruitable work area.Results were analyzed as percent control and compared statistically with the use of repeated measures analysis of variance. Results: Recovery of myocardial performance was augmented during reperfusion with calcitonin gene–related peptide infusion relative to placebo ( P = .005; mean preload recruitable work area ± SE after calcitonin gene–related peptide infusion, 2484 ± 705 mm Hg at 90 minutes of reperfusion versus 1473 ± 300 mm Hg for placebo. Recovery of performance after nitroglycerin infusion was similar to recovery after placebo. Conclusions: Calcitonin gene–related peptide infusion improves recovery of contractile function in stunned myocardium. Unlike inotropic agents that impair recovery from reversible ischemia, calcitonin gene–related peptide may confer cardioprotective effects on ischemic myocardium. (J Thorac Cardiovasc Surg 2000;119:1246-54)

Cellular Cardiomyoplasty Improves Diastolic Properties of Injured Heart

Background. Acute myocardial infarction leads to loss of functional myocytes and structural integrity that often decreases diastolic compliance and increases resting myocardial segment length (diastolic creep). Successfully engrafting autologous skeletal myoblasts could improve compliance and potentially reverse creep. Thus, we transplanted myoblasts into cryoinjured rabbit heart (n = 15, CRYO) and measured regional diastolic properties in the presence (n = 9, +ENG) or absence (n = 6, −ENG) of engraftment.Materials and methods. Left ventricular (LV) pressures (P) and myocardial segment lengths (SL) were measured in vivo by micromanometry and sonomicrometry after cryoinjury (CRYO) and again 3 weeks following transplantation of myoblasts. Performance was estimated from the relationships between end-diastolic (ED) P and strain (ϵ) or between EDP and EDSL. Compliance was characterized by strain (ϵ8) and dynamic stiffness (dP/dL8) at 8 mm Hg. Creep was characterized by resting myocardial segment length (EDSL0) and static stiffness at 8 mm Hg (mstat8).Results. Successful myoblast engraftment was determined via histologic examination. In nine +ENG animals, diastolic properties improved. Regional strain (ϵ8) increased (0.06 ± 0.02 CRYO vs 0.10 ± 0.04 +ENG; P = 0.0009) while dynamic stiffness (dP/dL8) decreased (43 ± 23 mm Hg/mm CRYO vs 23 ± 14 mm Hg/mm +ENG; P = 0.009). Static stiffness (mstat8) was unaffected (0.78 ± 0.2 mm Hg/mm CRYO vs 0.72 ± 0.1 mm Hg/mm +ENG; P = 0.08), and creep did not occur (EDSL0 = 10.3 ± 2.8 CRYO vs 10.4 ± 2.3 +ENG; P = 0.74). In the absence of myoblast engraftment (n = 6, −ENG), strain decreased (ϵ8 = 0.06 ± 0.02 CRYO vs 0.05 ± 0.02 −ENG; P = 0.048), but dynamic stiffness (dP/dL8) did not (36 ± 19 mm Hg/mm CRYO vs 28 ± 12 mm Hg/mm −ENG; P = 0.20). Furthermore, static stiffness decreased (0.78 ± 0.3 mm Hg/mm CRYO vs 0.65 ± 0.2 mm Hg/mm −ENG; P = 0.05) and creep was obvious (EDSL0 = 10.8 ± 3.6 mm CRYO vs 13.0 ± 4.4 mm −ENG, P = 0.04).Conclusions. Myoblast engraftment may partially overcome the loss of myocytes and structural integrity that often follow chronic myocardial ischemia. Improved compliance and reversal of diastolic creep suggest regeneration of viable muscle within once infarcted myocardium.

Right coronary pressure modulates right ventricular systolic stiffness and oxygen consumption.

The low transmural pressure of the thin right ventricular (RV) wall may render it responsive to right coronary (RC) pressure-induced changes in systolic stiffness and account for the dependence of RV MVO2 on RC pressure (RCP). In eight dogs anesthetized with pentobarbital and fentanyl, RCP was lowered from the baseline to 30 mmHg in 10 mmHg steps by adjusting an occluder on the proximal RC. Myocardial segment length and isometric developed force were measured, and the slope of the force-length curve during ejection period (delta F/ delta SL) was used as an index of systolic myocardial stiffness. MVO2 was calculated from RC flow and arteriovenous O2 difference. As RCP was varied from 120 to 40 mmHg with positive lactate uptake, RC flow, maximum developed force (Fmax), delta F, and MVO2 decreased linearly, whereas end-diastolic length, delta SL, and other hemodynamic variables stayed constant. Thus, RV systolic stiffness fell linearly with RC pressure. When RCP was further lowered from 40 to 30 mmHg, Fmax and delta F continued to fall, end-diastolic segment length and right atrial pressure increased significantly, delta SL and RV dp/dtmax fell significantly, and delta F/delta SL reached its lowest value. RV systolic stiffness was 22% of previously reported left ventricular systolic stiffness for coronary perfusion pressure at 100 mmHg, and varied less steeply with coronary pressure. (1) Reductions in RV systolic stiffness preserve delta SL as coronary pressure is reduced over a wide range. (2) The resulting increase in RV efficiency reduces oxygen demand as oxygen supply is reduced, so ischemia is avoided. (3) RV systolic stiffness is much less than left ventricular stiffness, consistent with their anatomical and functional differences.

A load-independent in vivo model for evaluating therapeutic interventions in injured myocardium.

Although cardiomyocyte damage is normally irreversible, gene therapy and somatic cell transfer offer potential for improving function in damaged regions of the heart. However, in ischemic models of injury, variability in depth, size, and location of damage compromises statistical evaluation of in vivo function. We have adapted cryoablation to create a reproducible, posterior, transmural lesion within rabbit myocardium in which small changes in function are measurable in vivo. Before and at 2 and 6 wk postinjury, in vivo left ventricular intracavitary pressure and myocardial segment length were measured. Regional indexes of performance, segmental stroke work (SW), and percent systolic shortening (SS) were significantly decreased (P < 0.001) postcryoinjury as was the slope (Mw) of the linear preload recruitable SW relationship between SW and end-diastolic segment length (P = 0.0001). Decreased SW, SS, and Mw correlated with wall thinning, loss of myocytes, presence of fibroblasts, and transmural scar formation. Reproducible changes in regional myocardial performance in vivo postcryoinjury suggest that this is a reasonable model for evaluating novel therapies for cardiovascular disease.

Prevention of ischemic rigor contracture during coronary occlusion by inhibition of Na(+)-H+ exchange.

To determine the effect of Na(+)-H+ exchange blockade on ischemic rigor contracture and reperfusion-induced hypercontracture. Thirty-six pigs were submitted to 55 min of coronary occlusion and 5 h reperfusion. Myocardial segment length analysis with ultrasonic microcrystals was used to detect ischemic rigor (reduction in passive segment length change) and hypercontracture (reduction in end-diastolic length). Pretreatment with the new, highly selective Na(+)-H+ exchange inhibitor HOE642 before occlusion reduced ischemic rigor (P < 0.05), attenuated segment shrinkage (P < 0.05) during subsequent reperfusion, dramatically reduced infarct size (P < 0.0001) and attenuated arrhythmias (P < 0.01). Inhibition of Na(+)-H+ exchange only during reperfusion by means of direct intracoronary infusion of HOE642 into the area at risk prevented reperfusion arrhythmias but had no effect on final infarct size, while treatment with intravenous HOE642 immediately before reperfusion had no detectable effects. These results indicate that inhibition of Na(+)-H+ exchange during ischemia is necessary to limit myocardial necrosis secondary to transient coronary occlusion, and that this action could by mediated by a protective effect against ischemic contracture. Inhibition of Na(+)-H+ exchange only during reperfusion has a partial and transient beneficial effect, but only when the inhibitor reaches the area at risk before reflow.

Myocardial mechanics and energetics during continuous positive airway pressure in sedated pigs.

To test the hypothesis that increased cardiac output with continuous positive airway pressure (CPAP) leads to increased myocardial metabolic cost. Prospective, repeated-measures, laboratory studies. University-affiliated hospital animal research laboratory. Eight sedated pigs that had been previously instrumented for collection of hemodynamic data. Application of CPAP at 0, 5, 10, and 15 cm H2O and recovery under conditions of normal blood volume (normovolemia) and after administration of hetastarch 35 mL/kg (hypervolemia). We measured mean arterial pressure, cardiac output, systemic vascular resistance index, the first derivative of the left ventricular pressure at a left ventricular pressure of 50 mm Hg, rate-pressure product, left ventricular tension-time index, stroke work index, myocardial pressure-myocardial segment length area, coronary artery blood flow and coronary vascular resistance, and myocardial oxygen consumption (four pigs). With normovolemia, cardiac output decreased with CPAP (4.9 +/- 1.2 L/min at CPAP of 0 cm H2O to 4.5 +/- 1.3 L/min at CPAP of 15 cm H2O, p < .005) and systemic vascular resistance index increased (2509 +/- 702 to 3095 +/- 1080 dyne.sec/cm5.m2, p < .01). With hypervolemia, cardiac output increased at low-level CPAP (5.7 +/- 1.4 L/min at CPAP of 0 cm H2O to 6.4 +/- 1.6 L/min at CPAP of 5 cm H2O, p < .05) and systemic vascular resistance index decreased (2412 +/- 552 to 2033 +/- 436 dyne.sec/cm5.m2, p < .01). There were no associated significant changes in myocardial oxygen consumption, or its major correlates when cardiac output increased with CPAP (hypervolemic conditions). In normal pigs, there is no change in myocardial oxygen demand with CPAP, whatever the change in cardiac output. Thus, increased cardiac output with CPAP carries little extra metabolic cost. Increased cardiac output with low-level CPAP in hypervolemia is associated with systemic vasodilation.