Relationships Between Myocardial Bioenergetic and Left Ventricular Function in Hearts With Volume-Overload Hypertrophy

Zhang, Jianyi J; Toher, Cynthia; Erhard, Mark; Zhang, Yi; Uğurbil, Kâmil; Bache, Robert J.; Lange, Thomas; Homans, D. C.

doi:10.1161/01.cir.96.1.334

Cited by 48 publications

(26 citation statements)

References 24 publications

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“…In hearts with cardiac hypertrophy, we have previously reported that myocardial PCr/ATP is significantly decreased, which is linearly related to the severity of hypertrophy and LV dysfunction and is independent from a persistent myocardial ischemia (35)(36)(37)39). These LVH hearts are also associated with a significant lower myocardial total creatine level (36 -39), which, in principle, can cause the reduction of the myocardial creatine phosphate level.…”

Section: Discussionmentioning

confidence: 95%

Long-term functional improvement and gene expression changes after bone marrow-derived multipotent progenitor cell transplantation in myocardial infarction

Jameel

Mansoor

et al. 2010

American Journal of Physiology-Heart and Circulatory Physiology

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. Long-term functional improvement and gene expression changes after bone marrow-derived multipotent progenitor cell transplantation in myocardial infarction. Am J Physiol Heart Circ Physiol 298: H1348 -H1356, 2010. First published February 19, 2010 doi:10.1152/ajpheart.01100.2009The study examined the longterm outcome of cardiac stem cell transplantation in hearts with postinfarction left ventricular (LV) remodeling. Myocardial infarction (MI) was created by ligating the first and second diagonal branches of the left anterior descending coronary artery in miniature swines. Intramyocardial injections of 50 million LacZ-labeled bone marrowderived multipotent progenitor cells (MPC) were performed in the periscar region (Cell, n ϭ 7) immediately after MI, whereas, in control animals (Cont, n ϭ 7), saline was injected. Functional outcome was assessed monthly for 4 mo with MRI and 31 P-magnetic resonance spectroscopy. Engraftment was studied on histology, and gene chip (Affymetrix) array analysis was used to study differential expression of genes in the two groups. MPC treatment resulted in improvement of ejection fraction as early as 10 days after MI (Cell, 43.4 Ϯ 5.1% vs. Cont, 32.2 Ϯ 5.5%; P Ͻ 0.05). This improvement was seen each month and persisted to 4 mo (Cell, 51.2 Ϯ 4.8% vs. Cont, 35.7 Ϯ 5.0%; P Ͻ 0.05). PCr-to-ATP ratio (PCr/ATP) improved with MPC transplantation, which was most pronounced at high cardiac work states (subendocardial PCr/ATP was 1.70 Ϯ 0.10 vs. 1.34 Ϯ 0.14, P Ͻ 0.05). There was no significant difference in scar size (scar/LV area ‫ء‬ 100) at 10 days postinfarction. However, at 4 mo, there was a significant decrease in scar size in the Cell group (Cell, 4.6 Ϯ 1.0% vs. Cont, 8.6 Ϯ 2.4%; P Ͻ 0.05). No significant engraftment of MPC was observed. MPC transplantation was associated with a downregulation of mitochondrial oxidative enzymes and increased levels of myocyte enhancer factor 2a and zinc finger protein 91. In conclusion, MPC transplantation leads to long-term functional and bioenergetic improvement in a porcine model of postinfarction LV remodeling, despite no significant engraftment of stem cells in the heart. MPC transplantation reduces regional wall stresses and infarct size and mitigates the adverse effects of LV remodeling, as seen by a reduction in LV hypertrophy and LV dilatation, and is associated with differential expression of genes relating to metabolism and apoptosis.energetics; metabolism; heart failure; scar size STEM CELL TRANSPLANTATION has emerged as a potential therapy for limiting postinfarction left ventricular (LV) remodeling and the consequent development of congestive heart failure in both animal (1,13,15,33) and clinical (2, 3, 12, 24, 31) studies.Clinical studies have shown mixed results on LV function with stem cell therapy, with some showing benefit (3, 24, 31) and some no difference in LV ejection fraction (12,14). In the bone marrow transfer to enhance ST-elevation infarct regeneration study, the treated group showed significant short-term increase of LV eje...

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Section: Discussionmentioning

confidence: 95%

Long-term functional improvement and gene expression changes after bone marrow-derived multipotent progenitor cell transplantation in myocardial infarction

Jameel

Mansoor

et al. 2010

American Journal of Physiology-Heart and Circulatory Physiology

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“…A possible explanation for the detrimental effects of early β-blockade in chronic organic MR may be that β-blockade depresses LV systolic function and myocardial contractility, 32 which is normally maintained by the sympathetic nervous system. 33 Long-term depression of myocardial contractility could lead to failure to maintain a normal LVESD in the condition of significant volume overload imposed by severe MR. Dilation of LVESD increases LV wall stress and mechanical stretching of myocytes.…”

Section: Future Studiesmentioning

confidence: 99%

Effects of Early, Late, and Long-term Nonselective β-Blockade on Left Ventricular Remodeling, Function, and Survival in Chronic Organic Mitral Regurgitation

Gao

et al. 2013

Circ: Heart Failure

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Background-Mitral regurgitation (MR) produces sympathetic nervous system activation which is detrimental in other causes of heart failure. However, whether β-blockade is beneficial in MR has not been determined. Methods and Results-Eighty-seven rats with significant organic MR were randomized to the β-blockade group (n=43) or the control group (n=44). Carvedilol was started in week 2 post MR induction and given for 23 to 35 weeks in the β-blockade group. Echocardiography was performed at baseline and at weeks 2, 6, 12, 24, 30, and 36 after MR induction. After 23 weeks of β-blockade, heart rates were significantly reduced by carvedilol (308±25 versus 351±31 beats per minute; P<0.001). Left ventricular end-diastolic (2.2±0.7 versus 1.59±0.6 mL; P<0.001), end-systolic volumes (0.72±0.42 versus 0.40±0.19 mL; P<0.001), and mass index (2.40±0.55 versus 2.06±0.62 g/kg; P<0.001) were significantly higher, and left ventricular fraction shortening (33±7% versus 38±7%; P<0.001) and ejection fraction (69±11% versus 75±7%; P<0.001) were significantly lower in the β-blockade group than in the control group. Systolic blood pressure was lower in the β-blockade group than in the control group (114±10 versus 93±12 mm Hg; P<0.005). Survival probability was significantly lower in the early β-blockade group than in the control group (88% versus 96%; P=0.03). 14 This dissociation creates a possible pathophysiological contradiction because adverse LV remolding is often associated with LV dysfunction and poor long-term outcome in all forms of congestive heart failure. Therefore, it is important to determine whether beneficial effects of β-blockade could be demonstrated if chronic organic MR was treated in the early stages before the development of LV dysfunction and if treatment is long-term. It is also imperative to determine whether LV remodeling associated with β-blocker therapy could ultimately have a negative impact on LV function in chronic organic MR or if the early improvement in LV function and myocardial contractility observed in prior studies could lead to improvement in LV remodeling if treatment was initiated early and long-term. To clarify this important issue, we performed a prospective study to determine the effects of early, late, and long-term β-blockade on LV remodeling, systolic function, and survival in experimental chronic MR. The study design had the following unique characteristics: (1) the study used a unique rat model of chronic MR developed in our laboratory, 15 allowing us to use a large numbers of animals to test the hypothesis; (2) carvedilol (a nonselective β-adrenergic blocking agent with α 1 -blocking activity) was administered early before the development of LV systolic dysfunction; and (3) a long-term treatment strategy was applied. Conclusions-Early Methods Rat Model of MRThe study protocol was approved by the Institution's Animal Care and Use Committee of the Pennsylvania State University College of Medicine (assurance number A3045-01). The study was performed according to the guidelines of the Amer...

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“…Other laboratories have demonstrated attenuation of metabolism that is not limited by oxygen delivery in pacing-induced heart failure, 21 left ventricular remodeling, 22 and decompensated hypertrophy. 23 Hibernating myocardium appears to have a similar regional cellular phenotype as these global states, characterized by impaired energy utilization, cellular hypertrophy, and reductions in the sarcoplasmic reticulum calcium uptake proteins. 10,24 The similarity of the cellular, molecular, and metabolic responses raises the possibility that they reflect a common myocardial response to stress.…”

Section: Relation Between Perfusion and Oxygen Consumption At Rest Anmentioning

confidence: 99%

Hibernating Myocardium Retains Metabolic and Contractile Reserve Despite Regional Reductions in Flow, Function, and Oxygen Consumption at Rest

Fallavollita

Malm

Canty

2003

Circulation Research

105

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Abstract-Hibernating myocardium, characterized by reductions in flow and function at rest, has limited contractile reserve in response to increases in external workload. We hypothesized that this attenuation of function reflects an adaptive downregulation that prevents the development of metabolic evidence of ischemia during stress. To test this hypothesis, pigs were chronically instrumented with a proximal left anterior descending artery stenosis for 3 months, resulting in severe anteroapical hypokinesis with reduced resting perfusion (0.78Ϯ0.05 versus 0.94Ϯ0.07 mL · min Ϫ1 · g Ϫ1 in remote, PϽ0.01; and 0.99Ϯ0.08 in controls, PϽ0.05). Open-chest studies confirmed resting dysfunction compared with normal controls (segment shortening 9.2Ϯ2.2% versus 23.5Ϯ1.1%, PϽ0.05). Resting myocardial oxygen consumption was reduced (63Ϯ3 versus 77Ϯ6 L · g Ϫ1 · min Ϫ1 in controls, PϽ0.05), yet lactate consumption was normal. Although subendocardial perfusion failed to increase during graded, intravenous epinephrine infusion (nϭ8), peak segment shortening (to 17.3Ϯ3.1%, PϽ0.05) and oxygen consumption (to 90Ϯ6 L · g Ϫ1 · min Ϫ1 , PϽ0.01) increased from the depressed resting levels. There was no lactate production in hibernating myocardium, and lactate uptake increased during stress (0.7Ϯ0.1 to 1.2Ϯ0.1 mol · g Ϫ1 · min Ϫ1 , PϽ0.05). The absence of metabolic evidence of ischemia was also confirmed during atrial pacing to a rate of 120 bpm (nϭ8). Thus, despite reductions in function and oxygen consumption at rest, hibernating myocardium retains the ability to increase metabolism without the development of acute ischemia. This supports the hypothesis that the downregulation of oxygen consumption and function in hibernating myocardium is an adaptive response that prevents a supply-demand imbalance during submaximal increases in cardiac workload when coronary flow reserve is limited. Key Words: hibernating myocardium Ⅲ oxygen consumption Ⅲ lactate Ⅲ contractile reserve Ⅲ ␤-adrenergic stimulation H ibernating myocardium is characterized by chronic reductions in flow and function that occur in the absence of infarction or subjective evidence of acute ischemia. 1 Although flow is reduced at rest, the myocardium retains the ability to at least transiently respond to increases in external workload. While considerable attention has focused on assessing contractile reserve in hibernating myocardium, the metabolic responses at rest and during increases in the external determinants of myocardial oxygen consumption are largely unknown. In normal hearts, acute transient ischemia causes dysfunction that is accompanied by a rapid fall in high-energy phosphate levels and a switch to anaerobic glycolysis as evidenced by regional lactate production. When moderate ischemia is maintained for hours, however, reductions in regional function match the reduced levels of oxygen delivery. This prevents irreversible injury by reestablishing a balance between supply and demand, a phenomenon termed "short-term hibernation." 2 Although this reverses lactate rel...

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Relationships Between Myocardial Bioenergetic and Left Ventricular Function in Hearts With Volume-Overload Hypertrophy

Abstract: In volume-overloaded LV hypertrophied hearts, alterations in myocardial high-energy phosphate levels do not induce abnormal mechanical performance at rest but may be related to a decreased contractile reserve during exercise.

Cited by 48 publications

References 24 publications

Long-term functional improvement and gene expression changes after bone marrow-derived multipotent progenitor cell transplantation in myocardial infarction

Long-term functional improvement and gene expression changes after bone marrow-derived multipotent progenitor cell transplantation in myocardial infarction

Effects of Early, Late, and Long-term Nonselective β-Blockade on Left Ventricular Remodeling, Function, and Survival in Chronic Organic Mitral Regurgitation

Hibernating Myocardium Retains Metabolic and Contractile Reserve Despite Regional Reductions in Flow, Function, and Oxygen Consumption at Rest

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