Myocardial Dysfunction in Donor Hearts

Owen, Virginia; Burton, Paul; Michel, Martin C.; Zolk, Oliver; Böhm, Michael; Pepper, John; Barton, Paul J.R.; Yacoub, Magdi H.; Harding, Siân E.

doi:10.1161/01.cir.99.19.2565

Cited by 50 publications

(24 citation statements)

References 32 publications

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“…2 Treatment of rat cardiomyocytes with TNF-␣ causes a concentration-dependent increase in G i␣ , 17 and this previously documented rise in G i␣ may be a consequence of TNF-␣ expression, thus providing a pathway linking elevated TNF-␣ to impaired myocardial function. TNF-␣ may act through several different mechanisms.…”

Section: Discussionmentioning

confidence: 91%

“…Total RNA was extracted with the Qiagen RNeasy minicolumn procedure and eluted in diethylpyrocarbonate-treated dH 2 O, following the manufacturer's instructions. RNA quality and quantity was assessed by EtBr-agarose gel electrophoresis and by relative absorbance at 260 nm versus 280 nm.…”

Section: Real-time Quantitative Reverse Transcription-polymerase Chaimentioning

confidence: 99%

“…Trabeculae and isolated myocytes from dysfunctional donors demonstrate a slowed relaxation and a poor force-frequency response in vitro comparable to that of hearts from patients with advanced heart failure. 2 Patients with chronic heart failure due to a variety of causes have been found to have elevated expression of proinflammatory cytokines including tumor necrosis factor (TNF)-␣ both in the serum and myocardium. [3][4][5][6][7] TNF-␣ expression has been demonstrated 6,7 in the ventricles of patients with dilated cardiomyopathy, where it was seen in cardiac myocytes, endothelial cells, and in the vascular smooth muscle cells of intramyocardial blood vessels.…”

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confidence: 99%

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Elevated Tumor Necrosis Factor- and Interleukin-6 in Myocardium and Serum of Malfunctioning Donor Hearts

Birks

Burton²,

Owen³

et al. 2000

Circulation

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Background-Myocardial dysfunction is a common and important problem in donor hearts. The mechanisms responsible remain unclear. We have studied the cytokines tumor necrosis factor (TNF)-␣ and interleukin-6 (IL-6) in the myocardium and serum from donors with myocardial dysfunction (unused donors) and compared them with donors with good ventricular function (used donors) and patients with advanced heart failure (HF). Methods and Results-Clinical details and ventricular function were assessed in 46 donors (31 used, 15 unused). Real-time reverse transcription-polymerase chain reaction, Western blotting, and immunocytochemistry were performed on myocardium and immunoassays on serum. TNF-␣ mRNA was 1.6-fold higher in unused than in used donors (PϽ0.005) and 1.74-fold higher than in 36 patients with HF. IL-6 mRNA was 2.4-fold higher in unused than in used donors (PϽ0.0001) and 4.67-fold higher than in HF (PϽ0.0001). Western blotting showed higher TNF-␣ in unused (218.3Ϯ6.4, nϭ4 versus 187.3Ϯ5.4, nϭ3 OD units) than used donors (PϽ0.05). TNF-␣ expression was localized to cardiac myocytes. Serum TNF-␣ was higher in unused (8.72Ϯ1.3 pg/mL, nϭ13) than in used (6.12Ϯ0.8 pg/mL, nϭ25, PϽ0.05) donors and HF (4.0Ϯ0.4 pg/mL, nϭ17, PϽ0.005). Serum TNF-␣ receptors did not differ between unused (4.3Ϯ0.8 and 8.6Ϯ1.6 ng/mL, nϭ10) and used (3.5Ϯ0.4 and 6.5Ϯ1.1 ng/mL, nϭ24) donors. There was a trend for higher serum IL-6 in unused (16.5Ϯ2.9 pg/mL, nϭ9) compared with used (13.9Ϯ1.6 pg/mL, nϭ26, PϭNS) donors. Conclusions-This

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Section: Discussionmentioning

confidence: 91%

Section: Real-time Quantitative Reverse Transcription-polymerase Chaimentioning

confidence: 99%

mentioning

confidence: 99%

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Elevated Tumor Necrosis Factor- and Interleukin-6 in Myocardium and Serum of Malfunctioning Donor Hearts

Birks

Burton²,

Owen³

et al. 2000

Circulation

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“…In vitro it is associated with impaired contractility, decreased b-adrenoreceptor sensitivity and increased activity of the inhibitory G protein G 1a (Owen et al 1999). Consequently, the possibility exists that a donor's heart may already be compromised at some molecular level; however, since it is apparently performing well mechanically, it is implanted, and later develops clinical evidence of myocardial dysfunction.…”

Section: Left Ventricular Dysfunctionmentioning

confidence: 99%

Exercise after heart transplantation

Marconi¹,

Marzorati²

2003

European Journal of Applied Physiology

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Exercise intolerance in heart transplant recipients (HTR) has a multifactorial origin, involving complex interactions among cardiac, neurohormonal, vascular, skeletal muscle and pulmonary abnormalities. However, the role of these abnormalities may differ as a function of time after transplantation and of many other variables. The present review is aimed at evaluating the role of cardiac, pulmonary and muscular factors in limiting maximal aerobic performance of HTR, and the benefits of chronic exercise. Whereas pulmonary function does not seem to affect gas exchange until a critical value of diffusing lung capacity is attained, cardiac and skeletal muscle function deterioration may represent relevant factors limiting maximal and submaximal aerobic performance. Cardiac function is mainly limited by chronotropic incompetence and diastolic dysfunction, whereas muscle activity seems to be limited by impaired oxygen supply as a consequence of the reduced capillary network. The latter may be due to either immunosuppressive regimen or deconditioning. Endurance and strength training may greatly improve muscle function and maximal aerobic performance of HTR, and may also reduce side effects of immunosuppressive therapy and control risk factors for cardiac allograft vasculopathy. For the above reasons exercise should be considered an important therapeutic tool in the long-term treatment of heart transplant recipients.

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“…However, whether depressed myofilament function contributes to reduced ventricular myocyte contractility in CHF is less clear (5). Studies probing myofilament activation in failing human myocardium must be interpreted with caution because tissue quality, pharmacological treatment, and brain death of donors may confound experimental findings (15,30,44). For these reasons, investigators have employed animal models that allow for the study of myofilament function under more carefully controlled circumstances.…”

mentioning

confidence: 99%

Left ventricular myofilament dysfunction in rat experimental hypertrophy and congestive heart failure

Belin¹,

Sumandea²,

Kobayashi³

et al. 2006

American Journal of Physiology-Heart and Circulatory Physiology

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(LVH) or congestive heart failure (CHF). To address this issue, we studied pressure overload-induced LV hypertrophy (POLVH) and myocardial infarction-elicited congestive heart failure (MICHF) in rats. LV myocytes were isolated from control, POLVH, and MICHF hearts by mechanical homogenization, skinned with Triton, and attached to micropipettes that projected from a sensitive force transducer and high-speed motor. sensitivity toward levels observed in control cells. In contrast, integration of cTn purified from failing ventricles into control myocytes increased EC50 to levels observed in failing myocytes. The Fmax parameter was not markedly affected by troponin exchange. cTnI phosphorylation was increased in both POLVH and MICHF left ventricles. We conclude that depressed myofilament Ca 2ϩ sensitivity in experimental LVH and CHF is due, in part, to a decreased functional role of cTn that likely involves augmented phosphorylation of cTnI. left ventricle; troponin; phosphorylation; cardiac disease CONGESTIVE HEART FAILURE (CHF) is characterized by reduced ventricular pump function, which is due, in part, to cardiac myocyte dysfunction. It has been widely reported that Ca 2ϩ homeostasis is impaired in CHF (14). However, whether depressed myofilament function contributes to reduced ventricular myocyte contractility in CHF is less clear (5). Studies probing myofilament activation in failing human myocardium must be interpreted with caution because tissue quality, pharmacological treatment, and brain death of donors may confound experimental findings (15,30,44). For these reasons, investigators have employed animal models that allow for the study of myofilament function under more carefully controlled circumstances. For instance, studies in the pacing-induced canine model of CHF indicate that the myofilaments generate more force for a given level of activator Ca 2ϩ (increased Ca 2ϩ sensitivity) compared with controls (45). Examination of myofilament activity in the spontaneously hypertensive heart failure prone (SHHF) rat demonstrates that myofilament function is either augmented or unchanged depending on when studies are performed during the disease progression (32). In contrast, Pérez and coworkers (31) found reduced myofilament function in right ventricular (RV) trabeculae of the SHHF rat. Similarly, de Tombe et al. (7) have also shown reduced myofilament function in RV trabeculae obtained from rats with large left ventricular (LV) infarcts and in skinned RV myocytes isolated from rats with chronic RV hypertrophy induced by pulmonary artery banding (9). However, the impact of experimental LV hypertrophy (LVH) or CHF on myofilament function in the more clinically relevant left ventricle has not been carefully studied. The molecular basis for altered myofilament function in LVH and CHF likely involves changes in thick and thin filament proteins. It has been reported that protein kinase C (PKC) is upregulated in cardiac disease (6,13,43). In addition, recent work from our group indicates that PKC-mediated phosphoryla...

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Myocardial Dysfunction in Donor Hearts

Cited by 50 publications

References 32 publications

Elevated Tumor Necrosis Factor- and Interleukin-6 in Myocardium and Serum of Malfunctioning Donor Hearts

Elevated Tumor Necrosis Factor- and Interleukin-6 in Myocardium and Serum of Malfunctioning Donor Hearts

Exercise after heart transplantation

Left ventricular myofilament dysfunction in rat experimental hypertrophy and congestive heart failure

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