Echocardiographic and cardiac single photon emission computed tomography predictors of left ventricle reverse remodeling after surgical revascularization in patients with ischemic cardiomyopathy and left ventricle systolic dysfunction

Background: The extent of scar or viable hypocontractile myocardial tissue determines postinfarction left ventricle remodeling. The aim of this pilot study was to evaluate the revascularization effect in a group of patients with ischemic cardiomyopathy and LV systolic dysfunction indicated for surgical revascularization, based on evidence for multivessel disease on coronarography and viable myocardium (CMR, SPECT). Aims: To evaluate the revascularization effect in patients with ischemic LV systolic dysfunction and to find preoperative predictors of revascularization effect. Methods: 33 patients (64+/-11 years) with baseline LVEF 34.9+/-9.3 % were included in the study. After a follow-up of 10.7+/-1.2 months, ECHO and SPECT were performed again. The whole group of patients was divided according to revascularization effect (postoperative increase LVEF > 5 % and postoperative decrease LVESV > 5 % compared with baseline) into revascularization responders (R, n = 22) and nonresponders (NR, n = 11). Results: At baseline there was no difference between the subgroups in LVEF (R = 35.7+/-11.0 % vs. NR = 34.3+/-8.2 %), EDV (R = 183.6+/-43.2 vs. NR = 180.2+/-80.5 ml), ESV (R = 118.5+/-40.4 vs. NR = 119.7+/-55.2 ml). The responders showed in a revascularization effect subanalysis differences in the values of LVEF (+9.8+/-8.1 %, p < 0.009), reduction of EDV (-39.9+/-50.9 ml, p = 0.05) and ESV (-35.4+/-42.6 ml, p = 0,002) compared with baseline. The only preoperative parameters predicting LV reverse remodeling were the T(E-Em) (R = -10.6+/-44.1 vs. NR = 29.7+/-43.7 ms, p = 0.037) and the size of fixed perfusion defect (FPD) (R = 11.9+/-13.5 vs. NR = 22.9+/-15.3 % of LV, p = 0.044). Conclusions: Patients with ischemic LV systolic dysfunction with a preoperatively determined myocardial viability develop LV reverse remodeling. The only preoperative parameters predicting LV reverse remodeling were echocardiographic T(E-Em) and FPD on SPECT.     

Risk stratification for sudden cardiac death in patients with non-ischemic dilated cardiomyopathy

Non ischemic dilated cardiomyopathy (NIDCM) is a disorder of myocardium. It has varying etiologies. Albeit the varying etiologies of this heart muscle disorder, it presents with symptoms of heart failure, and rarely as sudden cardiac death (SCD). Manifestations of this disorder are in many ways similar to its counterpart, ischemic dilated cardiomyopathy (IDCM). A proportion of patients with NIDCM carries a grave prognosis and is prone to sudden cardiac death from sustained ventricular arrhythmias. Identification of this subgroup of patients who carry the risk of sudden cardiac death despite adequate medical management is a challenge. Yet another method is a blanket treatment of patients with this disorder with anti arrhythmic medications or anti tachyarrhythmia devices like implantable cardioverter defibrillators (ICD). However this modality of treatment could be a costly exercise even for affluent economies. In this review we try to analyze the existing data of risk stratification of NIDCM and its clinical implications in practice.     

Cardiac magnetic resonance imaging of myocardial contrast uptake and blood flow in patients affected with idiopathic or familial dilated cardiomyopathy

Idiopathic dilated cardiomyopathy (IDC) is characterized by left ventricular (LV) enlargement with systolic dysfunction, other causes excluded. When inherited, it represents familial dilated cardiomyopathy (FDC). We hypothesized that IDC or FDC would show with cardiac magnetic resonance (CMR) increased myocardial accumulation of gadolinium contrast at steady state and decreased baseline myocardial blood flow (MBF) due to structural alterations of the extracellular matrix compared with normal myocardium. CMR was performed in nine persons affected with IDC/FDC. Healthy controls came from the general population (n = 6) or were unaffected family members of FDC patients (n = 3) without signs or symptoms of IDC/FDC or any structural cardiac abnormalities. The myocardial partition coefficient for gadolinium contrast (lambda(Gd)) was determined by T1 measurements. LV shape and function and MBF were assessed by standard CMR methods. lambda(Gd) was elevated in IDC/FDC patients vs. healthy controls (lambda(Gd) = 0.56 +/- 0.15 vs. 0.41 +/- 0.06; P = 0.002), and correlated with LV enlargement (r = 0.61 for lambda(Gd) vs. end-diastolic volume indexed by height; P < 0.01) and with ejection fraction (r = -0.80; P < 0.001). The extracellular volume fraction was higher in IDC patients than in healthy controls (0.31 +/- 0.05 vs. 0.24 +/- 0.03; P = 0.002). Resting MBF was lower in IDC patients (0.64 +/- 0.13 vs. 0.91 +/- 0.22; P = 0.01) than unaffected controls and correlated with both the partition coefficient (r = -0.57; P = 0.012) and the extracellular volume fraction (r = -0.56; P = 0.019). The expansion of the extracellular space correlated with reduced MBF and ventricular dilation. Expansion of the extracellular matrix may be a key contributor to contractile dysfunction in IDC patients.     

Intracoronary infusion of Gd3+ into ischemic region does not suppress phase Ib ventricular arrhythmias after coronary occlusion in swine

Increased mechanical tension in the ischemic region during acute coronary occlusion might favor the occurrence of phase Ib ventricular arrhythmias. We aimed to investigate whether intracoronary administration of Gd(3+), a stretch-activated channel blocker, into the ischemic zone reduces the incidence of these arrhythmias. In thiopental-anesthetized, open-chest pigs, the left anterior descending coronary artery (LAD) was ligated for 45 or 48 min. Phosphate-free, HEPES-buffered saline bubbled with 100% N(2) was infused into the ischemic region for 4 min, starting 5 min (series A; n = 16) or 20 min (series B; n = 16) after coronary occlusion, at a rate doubling the baseline blood flow. Animals were blindly allocated to receive 40 muM Gd(3+) or only the buffer during the final 2 min of the infusion. There were no differences between groups with respect to hemodynamic variables, plasma K(+) levels, or size of the ischemic region. In neither series was the number of phase Ib premature ventricular beats reduced by Gd(3+) (46 +/- 20 in untreated vs. 91 +/- 37 in Gd(3+)-treated animals in series A and 19 +/- 7 vs. 22 +/- 13, respectively, in series B; both P = not significant). The occurrence of ventricular tachycardia or fibrillation was significantly associated with the magnitude of early ischemic expansion of the LAD region, as measured by ultrasonic crystals, but was also not prevented by Gd(3+). These results argue against a major role of stretch-activated channels inside the area at risk in the genesis of phase Ib ischemic ventricular arrhythmias.     

Ischemic cardiomyopathy in pigs with two-vessel occlusion and viable, chronically dysfunctional myocardium

A chronic left anterior descending coronary artery (LAD) stenosis leads to the development of hibernating myocardium with severe regional hypokinesis but normal global ventricular function after 3 mo. We hypothesized that two-vessel occlusion would accelerate the progression to hibernating myocardium and lead to global left ventricular (LV) dysfunction and heart failure. Pigs were instrumented with a fixed 1.5-mm constrictor on the proximal LAD and circumflex arteries. After 2 mo, there were no overt signs of right-heart failure and triphenyl tetrazolium chloride infarction was trivial (1.4 +/- 0.1% of the LV). Compared with shams, regional function [myocardial systolic excursion (DeltaWT); 2.1 +/- 0.3 vs. 4.6 +/- 0.4 mm, P < 0.05] and resting perfusion (0.90 +/- 0.13 vs. 1.32 +/- 0.09 ml small middle dot min(-1) small middle dot g(-1), P < 0.05) were reduced, consistent with hibernating myocardium. Pulmonary systolic (45.9 +/- 3.3 vs. 36.5 +/- 2.2 mmHg, P < 0.05) and wedge pressures (19.1 +/- 1.6 vs. 11.2 +/- 0.9 mmHg, P < 0.05) were increased with global ventricular dysfunction (ejection fraction 43 +/- 2 vs. 50 +/- 2%, P < 0.05). Early LV remodeling was present with increased cavity size and mass. Reductions in sarcoplasmic reticulum Ca(2+)-ATPase and phospholamban were confined to the dysfunctional LAD region with no change in calsequestrin. Thus combined stenoses of the LAD and circumflex arteries accelerate the development of hibernating myocardium and result in compensated heart failure.     

Cardiac dysfunction in aging conscious rats: altered cardiac cytoskeletal proteins as a potential mechanism

The objective of this study was to test the hypothesis that the mechanism mediating left ventricular (LV) dysfunction in the aging rat heart involves, in part, changes in cardiac cytoskeletal components. Our results show that there were no significant differences in heart rate, LV pressure, or LV diameter between conscious, instrumented young [5.9 +/- 0.3 mo (n = 9)] and old rats [30.6 +/- 0.1 mo (n = 10)]. However, the first derivative of LV pressure (LV dP/dt) was reduced (8,309 +/- 790 vs. 11,106 +/- 555 mmHg/s, P < 0.05) and isovolumic relaxation time (tau) was increased (8.7 +/- 0.7 vs. 6.3 +/- 0.6 ms, P < 0.05) in old vs. young rats, respectively. The differences in baseline LV function in young and old rats, which were modest, were accentuated after beta-adrenergic receptor stimulation with dobutamine (20 mug/kg), which increased LV dP/dt by 170 +/- 9% in young rats, significantly more (P < 0.05) than observed in old rats (115 +/- 5%). Volume loading in anesthetized rats demonstrated significantly impaired LV compliance in old rats, as measured by the LV end-diastolic pressure and dimension relationship. In old rat hearts, there was a significant (P < 0.05) increase in the percentage of LV collagen (2.4 +/- 0.2 vs. 1.3 +/- 0.2%), alpha-tubulin (92%), and beta-tubulin (2.3-fold), whereas intact desmin decreased by 51%. Thus the cardiomyopathy of aging in old, conscious rats may be due not only to increases in collagen but also to alterations in cytoskeletal proteins.     

Comparison of thallium deposition with segmental perfusion in pigs with chronic hibernating myocardium

Viable, chronically dysfunctional myocardium with reduced resting flow (or hibernating myocardium) is an important prognostic factor in ischemic heart disease. Although thallium-201 imaging is frequently used to assess myocardial viability in patients with ischemic cardiomyopathy, there are limited data regarding its deposition in hibernating myocardium, and this data suggest that thallium retention may be supernormal compared with control myocardium. Accordingly, pigs (n=7) were chronically instrumented with a 1.5 mm Delrin stenosis on the proximal left anterior descending coronary artery (LAD) to produce hibernating myocardium. Four months later, severe anteroapical hypokinesis was documented with contrast ventriculography (wall motion score, 0.7+/-0.8; normal=3), and microsphere measurements confirmed reduced resting flow (LAD subendocardium, 0.78+/-0.34 vs. 0.96+/-0.24 ml.min(-1).g(-1) in remote; P<0.001). Absolute deposition of thallium-201 and insulin-stimulated [18F]-2 fluoro-2-deoxyglucose (FDG) were assessed over 1 h and compared with resting flow (n=704 samples). Thallium-201 deposition was only weakly correlated with perfusion (r2=0.20; P<0.001) and was more homogeneously distributed (relative dispersion, 0.12+/-0.03 vs. 0.29+/-0.10 for microsphere flow; P<0.01). Thus after 1 h relative thallium-201 (subendocardium LAD/remote, 0.96+/-0.16) overestimated relative perfusion (0.78+/-0.32; P<0.0001) and underestimated the relative reduction in flow. Viability was confirmed by both histology and preserved FDG uptake. We conclude that under resting conditions, thallium-201 redistribution in hibernating myocardium is nearly complete within 1 h, with similar deposition to remote myocardium despite regional differences in flow. These data suggest that in this time frame thallium-201 deposition may not discriminate hibernating myocardium from dysfunction myocardium with normal resting flow. Since hibernating myocardium has been associated with a worse prognosis, this limitation could have significant clinical implications.     

Effects of dietary phytoestrogens on cardiac remodeling secondary to chronic volume overload in female rats.

Previously, we demonstrated that intact female rats fed a standard rodent diet containing soybean products exhibit essentially no adverse left ventricular (LV) remodeling in response to aortocaval fistula-induced chronic volume overload. We hypothesized that phytoestrogenic compounds in the diet contributed to the female cardioprotection. To test this hypothesis, four groups of female rats were studied: sham-operated (Sham) and fistula (Fist) rats fed a diet with [P(+)] or without [P(-)] phytoestrogens. Eight weeks postfistula, systolic and diastolic cardiac function was assessed by using a blood-perfused, isolated heart preparation. High-phytoestrogen diet had no effect on body, heart, and lung weights, or cardiac function in Sham rats. Fistula groups developed LV hypertrophy, which was not reduced by dietary phytoestrogens [1,184 +/- 229 mg Fist-P(-) and 1,079 +/- 199 mg Fist-P(+) vs. 620 +/- 47 mg for combined Sham groups, P < 0.05]. Unstressed LV volume increased in Fist-P(-) rats (428 +/- 16 vs. 300 +/- 14 microl Sham, P < 0.0001), but it was not different from Sham for Fist-P(+) animals (286 +/- 17 microl). Fist-P(-) rats developed increased ventricular compliance (5.3 +/- 0.8 vs. 2.3 +/- 0.3 microl/mmHg Sham, P < 0.01), whereas Fist-P(+) rats had no change in compliance (2.8 +/- 0.4 mul/mmHg). Intrinsic ventricular contractility was maintained in the Fist-P(+) rats, but it was reduced (P < 0.001) in the Fist-P(-) rats [systolic pressure-volume slope: 1.04 +/- 0.03, 0.60 +/- 0.06, and 0.99 +/- 0.08 mmHg/microl, for Fist-P(+), Fist-P(-), and Sham, respectively]. These data indicate that dietary phytoestrogens contribute significantly to female cardioprotection against volume overload-induced adverse ventricular remodeling and that studies evaluating gender differences in cardiovascular remodeling must consider the influence of dietary phytoestrogens.     

Steeper restitution slopes across right ventricular endocardium in patients with cardiomyopathy at high risk of ventricular arrhythmias

Steep action potential duration (APD) restitution slopes (>1) and spatial APD restitution heterogeneity provide the substrate for ventricular fibrillation in computational models and experimental studies. Their relationship to ventricular arrhythmia vulnerability in human cardiomyopathy has not been defined. Patients with cardiomyopathy [left ventricular (LV) ejection fraction <40%] and no history of ventricular arrhythmias underwent risk stratification with programmed electrical stimulation or T wave alternans (TWA). Low-risk patients (n = 10) had no inducible ventricular tachycardia (VT) or negative TWA, while high-risk patients (n = 8) had inducible VT or positive TWA. Activation recovery interval (ARI) restitution slopes were measured simultaneously from 10 right ventricular (RV) endocardial sites during an S1-S2 pacing protocol. ARI restitution slope heterogeneity was defined as the coefficient of variation of slopes. Mean ARI restitution slope was significantly steeper in the high-risk group compared with the low-risk group [1.16 (SD 0.31) vs. 0.59 (SD 0.19), P = 0.0002]. The proportion of endocardial recording sites with a slope >1 was significantly larger in the high-risk patients [47% (SD 35) vs. 13% (SD 21), P = 0.022]. Spatial heterogeneity of ARI restitution slopes was similar between the two groups [29% (SD 16) vs. 39% (SD 34), P = 0.48]. There was an inverse linear relationship between the ARI restitution slope and the minimum diastolic interval (P < 0.001). In cardiomyopathic patients at high risk of ventricular arrhythmias, ARI restitution slopes along the RV endocardium are steeper, but restitution slope heterogeneity is similar compared with those at low risk. Steeper ARI restitution slopes may increase the propensity for ventricular arrhythmias in patients with impaired left ventricular function.     

Investigating the dual nature of endothelin-1: ischemia or direct arrhythmogenic effect?

Endothelin-1 (ET-1) is a potent vasoconstrictor peptide, which may also elicit severe ventricular arrhythmias. The aims of our study were to compare the effects of total left anterior descending coronary artery (LAD) occlusion to intracoronary (ic.) ET-1 administration and to investigate the pathomechanism of ET-1 induced arrhythmias in 3 groups of anesthetized, open-chest mongrel dogs. In group A (n=10) a total LAD occlusion was carried out for 30 min, followed by a 60 min reperfusion period. In groups B and C ET-1 was administered into LAD for 30 min at a rate of 30 pmol/min (n=6) and 60 pmol/min (n=8). Epi- and endocardial monophasic action potential (MAP) recordings were performed to detect electrophysiologic changes and ischemia Blood samples for lactate measurements were collected from the coronary sinus (CS) and from the femoral artery. Infrared imaging was applied to follow epimyocardial heat emission changes. At the end of the ET-1 infusion period coronary blood flow (CBF) was reduced significantly in groups B and C (deltaCBF30MIN B: 21+/-2%, p<0.05; C: 35+/-2%, p<0.05), paralleled by a significant epimyocardial temperature decrease in group C (deltaT30MIN: -0.65+/-0.29 degrees C, p<0.05). Two dogs died of ventricular fibrillation (VF) in the reperfusion period in group A. Ventricular premature contractions and non-sustained ventricular tachycardic episodes appeared in group B, whereas six dogs died of VF in group C. Significant CS lactate level elevation indicating ischemia was observed only in group A from the 30th min occlusion throughout the reperfusion period (control vs. 30 min: 1.3+/-0.29 vs. 2.2+/-0.37 mmol/l, p<0.05). Epi- and endocardial MAP durations (MAPD90) and left ventricular epicardial (LV(EPI)) upstroke velocity decreased significantly in group A in the occlusion period. ET-1 infusion significantly increased LV(EPI) MAPD90 in group B and both MAPD90-s in group C. In conclusion, ischemic MAP and CS lactate changes were observed only in group A. Although ET-1 reduced CBF significantly in groups B and C, neither MAP nor lactate indicated ischemic alterations. ET-1 induced major ventricular arrhythmias appeared before signs of myocardial ischemia developed, though reduced CBF presumably contributed to sustaining the arrhythmias.     

Effects of pre-, peri-, and postmyocardial infarction treatment with losartan in rats: effect of dose on survival, ventricular arrhythmias, function, and remodeling

Angiotensin receptor blockers (ARBs) reduce adverse left ventricular (LV) remodeling and improve LV function and survival when started postmyocardial infarction (MI). ARBs also reduce ventricular arrhythmias during ischemia-reperfusion injury when started pre-MI. No information exists regarding their efficacy and safety when started pre-MI and continued peri- and post-MI. We evaluated whether the ARB losartan improves the outcome when started pre-MI and continued peri- and post-MI. Male Wistar rats (n = 502) were treated for 7 days pre-MI with losartan at a high dose (30 mg.kg(-1).day(-1)), progressively increasing dose (3 mg.kg(-1).day(-1) increased to 10 mg.kg(-1).day(-1) 10 days and 30 mg.kg(-1).day(-1) 20 days post-MI), or no treatment. Ambulatory systolic blood pressure and Holter monitoring were performed for 24 h post-MI. Echocardiography was done 30 days post-MI, and LV remodeling, cardiac hemodynamics, and fetal gene expression were assessed 38 days post-MI. High-dose losartan reduced 24-h post-MI survival compared with the progressive dose and control (21.9% vs. 36.6% and 38.1%, P = 0.033 and P = 0.009, respectively). This was associated with greater hypotension in the high dose and no change in ventricular arrhythmias in all groups. In 24-h post-MI survivors, the progressive dose group had reduced mortality from 24 h to 38 days (8.5% vs. 28.6% for control vs. 38.9% for high dose, P = 0.032 and P = 0.01, respectively). Survivors of both losartan groups demonstrated improved LV remodeling, cardiac hemodynamics, preserved GLUT-4, and reduced cardiac fetal gene expression. Pretreatment with ARBs does not reduce 24-h post-MI ventricular arrhythmias or survival, and high doses increase mortality by causing excessive hypotension. In 24-h post-MI survivors, progressively increasing doses of losartan have multiple beneficial effects, including improved survival.     

Mesenchymal stem cells from ischemic heart disease patients improve left ventricular function after acute myocardial infarction

Mesenchymal stem cells (MSCs) from healthy donors improve cardiac function in experimental acute myocardial infarction (AMI) models. However, little is known about the therapeutic capacity of human MSCs (hMSCs) from patients with ischemic heart disease (IHD). Therefore, the behavior of hMSCs from IHD patients in an immune-compromised mouse AMI model was studied. Enhanced green fluorescent protein-labeled hMSCs from IHD patients (hMSC group: 2 x 10(5) cells in 20 microl, n = 12) or vehicle only (medium group: n = 14) were injected into infarcted myocardium of NOD/scid mice. Sham-operated mice were used as the control (n = 10). Cardiac anatomy and function were serially assessed using 9.4-T magnetic resonance imaging (MRI); 2 wk after cell transplantation, immunohistological analysis was performed. At day 2, delayed-enhancement MRI showed no difference in myocardial infarction (MI) size between the hMSC and medium groups (33 +/- 2% vs. 36 +/- 2%; P = not significant). A comparable increase in left ventricular (LV) volume and decrease in ejection fraction (EF) was observed in both MI groups. However, at day 14, EF was higher in the hMSC than in the medium group (24 +/- 3% vs. 16 +/- 2%; P < 0.05). This was accompanied by increased vascularity and reduced thinning of the infarct scar. Engrafted hMSCs (4.1 +/- 0.3% of injected cells) expressed von Willebrand factor (16.9 +/- 2.7%) but no stringent cardiac or smooth muscle markers. hMSCs from patients with IHD engraft in infarcted mouse myocardium and preserve LV function 2 wk after AMI, potentially through an enhancement of scar vascularity and a reduction of wall thinning.     

Vascular beta-adrenergic receptor system is dysfunctional after myocardial infarction

We identified abnormalities in the vascular beta-adrenergic receptor (beta-AR) signaling pathway in heart failure after myocardial infarction (MI). To examine these abnormalities, we measured beta-AR-mediated hemodynamics, vascular reactivity, and the vascular beta-AR molecular signaling components in rats with heart failure after MI. Six weeks after MI, these rats had an increased left ventricular (LV) end-diastolic pressure, decreased LV systolic pressure, and decreased rate of LV pressure change (dP/dt). LV dP/dt responses to isoproterenol were shifted downward, although the responses for systemic vascular resistance were shifted upward in heart failure rats (P < 0.05). Isoproterenol- and IBMX-induced vasorelaxations were blunted in heart failure rats (P < 0.05) with no change in the forskolin-mediated vasorelaxation. These changes were associated with the following alterations in beta-AR signaling (P < 0.05): decreases in beta-AR density (aorta: 58.7 +/- 6.0 vs. 35.7 +/- 1.9 fmol/mg membrane protein; carotid: 29.6 +/- 5.6 vs. 18.0 +/- 3.9 fmol/mg membrane protein, n = 5), increases in G protein-coupled receptor kinase activity levels (relative phosphorimage counts of 191 +/- 39 vs. 259 +/- 26 in the aorta and 115 +/- 30 vs. 202 +/- 7 in the carotid artery, n = 5), and decreases in cGMP and cAMP in the carotid artery (0.85 +/- 0.10 vs. 0.31 +/- 0.06 pmol/mg protein and 2.3 +/- 0.3 vs. 1.2 +/- 0.1 pmol/mg protein, n = 5) with no change in Galpha(s) or Galpha(i )in the aorta. Thus in heart failure there are abnormalities in the vascular beta-AR system that are similar to those seen in the myocardium. This suggests a common neurohormonal mechanism and raises the possibility that treatment in heart failure focused on the myocardium may also affect the vasculature.     

Effects of nonselective endothelin-1 receptor antagonism on cardiac mast cell-mediated ventricular remodeling in rats

The objective of this study was to investigate the effect a nonselective endothelin-1 (ET-1) receptor antagonist (bosentan) had on the acute myocardial remodeling process including left ventricular (LV) mast cells and matrix metalloproteinase (MMP) activity secondary to volume overload. Additionally, we investigated the overall functional outcome of preventative endothelin receptor antagonism during 14 days of chronic volume overload. LV tissue from sham-operated (Sham), untreated-fistula (Fist), and bosentan (100 mg.kg(-1).day(-1))-treated animals (Fist + Bos) was analyzed for mast cell density, MMP activity, and myocardial collagen volume fraction at 1 and 5 days after the creation of an aortocaval fistula. When compared with untreated fistulas, bosentan treatment prevented the marked increase in LV mast cell density at 1 day postfistula (3.1 +/- 0.3 vs. 1.3 +/- 0.3 LV mast cells/mm2, Fist vs. Fist + Bos, P 相似文献   

Transmural distribution of FDG uptake in stunned myocardium

Fasting [(18)F]fluoro-2-deoxyglucose (FDG) uptake is increased in viable, chronically dysfunctional myocardium, but the relationship to acute episodes of ischemia remains undefined. To investigate FDG uptake in acute stunning, chronically instrumented pigs (n = 9) and sham controls (n = 8) were studied while in a fasted, closed-chest, anesthetized state. One-hour partial occlusion reduced subendocardial flow from 1.24 +/- 0.14 to 0.35 +/- 0.06 ml. min(-1). g(-1) and wall thickening from 16.8 +/- 2.1 to 3.7 +/- 0.7%. Regional function remained depressed during reperfusion (8.3 +/- 1. 4%) despite the return of flow to resting levels. Triphenyl tetrazolium chloride staining showed no irreversible injury. FDG uptake in stunned myocardium was variably increased and averaged 1. 5-fold higher than that of normal regions, with no consistent transmural variation. Subgroup analysis showed that variability in FDG uptake was related to alterations in insulin levels that varied directly with ischemic risk region.     

Interstitial myocardial fibrosis in a captive chimpanzee (Pan troglodytes) population

The clinical and necropsy records of 36 (25 male and 11 female) chimpanzees age 10 to 40 y old that died over a 6-y period (2001 to 2006) were reviewed. All animals had annual physical exams that included electrocardiograms and serial blood pressures. Nine of the 36 animals had a complete cardiac evaluation by a board certified veterinary cardiologist, and 7 of the 36 animals (19%) were diagnosed with some form of cardiomyopathy. Systemic hypertension was noted in 3 cases. Cardiac arrhythmias (ventricular ectopy) were seen in 15 (12 male and 3 female) of the 36 animals (42%). Sudden cardiac death (SCD) occurred in 13 (11 male and 2 female) chimps (36%) and was the leading cause of death (n = 13), followed by renal failure (n = 9) and septicemia (n = 3). Histologic examination of the hearts revealed interstitial myocardial fibrosis (IMF) in 29 chimpanzees (81%), and all of the animals that died suddenly due to cardiac causes had IMF to varying degrees. More data will be needed to identify the possible causes of IMF in captive chimpanzees, and IMF may be associated with arrhythmias and SCD in these animals.     

Shotgun lipidomics identifies cardiolipin depletion in diabetic myocardium linking altered substrate utilization with mitochondrial dysfunction

Diabetic cardiomyopathy is characterized by excessive utilization of fatty acid substrate, diminished glucose transport, and mitochondrial dysfunction. However, the chemical mechanisms linking altered substrate utilization to mitochondrial dysfunction are unknown. Herein, we use shotgun lipidomics and multidimensional mass spectrometry to identify dramatic decreases in the critical mitochondrial inner membrane lipid, cardiolipin, in diabetic murine myocardium (from 7.2 +/- 0.3 nmol/mg of protein in control hearts to 3.1 +/- 0.1 nmol/mg of protein in diabetic myocardium; p < 0.001, n = 7). Moreover, the direct metabolic precursor of cardiolipin, phosphatidylglycerol, was also substantially depleted (2.5 +/- 0.2 nmol/mg of protein in control hearts vs 1.3 +/- 0.1 nmol/mg of protein in diabetic myocardium; p < 0.001, n = 7). Similarly, glycerol 3-phosphate, necessary for the penultimate step in phosphatidylglycerol production, decreased by 58% in diabetic myocardium (from 4.9 +/- 0.9 to 2.2 +/- 0.3 nmol/mg of protein; n = 4). Since Barth's syndrome (a disorder of cardiolipin metabolism) induces mitochondrial dysfunction and cardiomyopathy, and since decreases in cardiolipin content precipitate mitochondrial dysfunction, these results provide a unifying hypothesis linking altered substrate utilization and metabolic flux in diabetic myocardium with altered lipid metabolism, cardiolipin depletion, mitochondrial dysfunction, and resultant hemodynamic compromise.     

SERCA2a activity correlates with the force-frequency relationship in human myocardium

The present investigation addresses whether protein expression and function of sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA2a) and phospholamban (PLB) correlate in failing and nonfailing human myocardium. SERCA2a activity and protein expression, PLB phosphorylation, and the force-frequency relationship (FFR) have been determined in right atrium (RA) and left ventricle (LV) from nonfailing (NF, n = 12) and terminally failing [dilated cardiomyopathy (DCM), n = 12] human hearts. Only in LV of DCM hearts was SERCA2a activity significantly decreased [maximal turnover rate (V(max)) = 196 +/- 11 and 396 +/- 30 nmol. mg(-1). min(-1) in LV and RA, respectively], whereas protein expression of SERCA2a in the different chambers was unchanged in NF (3.9 +/- 0.3 and 3.2 +/- 0.4 densitometric units in LV and RA, respectively) and DCM hearts (4.8 +/- 0.8 and 3.4 +/- 0.1 densitometric units in LV and RA, respectively). Phosphorylation of PLB was higher in LV than in RA in NF (Ser(16): 180.5 +/- 19.0 vs. 56.8 +/- 6.0 densitometric units; Thr(17): 174.6 +/- 11.2 vs. 37.4 +/- 8.9 densitometric units) and DCM hearts (Ser(16): 132.0 +/- 5.4 vs. 22.4 +/- 3.5 densitometric units; Thr(17): 131.2 +/- 10.9 vs. 9.2 +/- 2.4 densitometric units). SERCA2a function, but not protein expression, correlated well with the functional parameters of the FFR in DCM and NF human hearts. Regulation of SERCA2a function depends on the phosphorylation of PLB at Ser(16) and Thr(17). However, direct SERCA2a regulation might also be affected by an unknown mechanism.     

Cardiac-restricted overexpression of extracellular matrix metalloproteinase inducer causes myocardial remodeling and dysfunction in aging mice

The matrix metalloproteinases (MMPs) play a pivotal role in adverse left ventricular (LV) myocardial remodeling. The transmembrane protein extracellular MMP inducer (EMMPRIN) causes increased MMP expression in vitro, and elevated levels occur in patients with LV failure. However, the direct consequences of a prolonged increase in the myocardial expression of EMMPRIN in vivo remained unexplored. Cardiac-restricted EMMPRIN expression (EMMPRINexp) was constructed in mice using the full-length human EMMPRIN gene ligated to the myosin heavy chain promoter, which yielded approximately a twofold increase in EMMPRIN compared with that of the age/strain-matched wild-type (WT) mice; EMMPRINexp (n=27) and WT (n=33) mice were examined at 3.2+/-0.1 or at 13.3+/-0.5 mo of age (n=43 and 26, respectively). LV end-diastolic volume (EDV) was similar in young EMMPRINexp and WT mice (54+/-2 vs. 57+/-3 microl), but LV ejection fraction (EF) was reduced (51+/-1 vs. 57+/-1%; P<0.05). In old EMMPRINexp mice, LV EDV was increased compared with WT mice values (76+/-3 vs. 58+/-3 microl; P<0.05) and LV EF was significantly reduced (45+/-1 vs. 57+/-2%; P<0.05). In EMMPRINexp old mice, myocardial MMP-2 and membrane type-1 MMP levels were increased by >50% from WT values (P<0.05) and were accompanied by a twofold higher collagen content (P<0.05). Persistent myocardial EMMPRINexp in aging mice caused increased levels of both soluble and membrane type MMPs, fibrosis, and was associated with adverse LV remodeling. These findings suggest that EMMPRIN is an upstream signaling pathway that can play a mechanistic role in adverse remodeling within the myocardium.