Angiotensin-converting enzyme inhibition improves cardiac fatty acid metabolism in patients with congestive heart failure.

This study aimed to examine whether angiotensin-converting enzyme (ACE) inhibition improved cardiac fatty acid metabolism in patients with congestive heart failure (CHF). Myocardial 123I-beta-methyl-iodophenylpentadecanoic acid (123I-BMIPP) imaging was performed in 25 patients with CHF and in 10 control subjects. Myocardial 123I-BMIPP images were obtained 30 min and 4 h after tracer injection. The heart-to-mediastinum (H/M) ratio of 123I-BMIPP uptake and the washout rate of 123I-BMIPP from the myocardium were calculated. Patients were given enalapril for 6 months, and 123I-BMIPP imaging was repeated. H/M ratios on early and delayed images were lower in CHF patients than in normal controls (P<0.01). The washout rate of 123I-BMIPP from the myocardium was faster in CHF patients than in controls (P<0.01). As the severity of the New York Heart Association (NYHA) functional class increased, the H/M ratio decreased and the washout rate increased. The washout rate of 123I-BMIPP was inversely correlated with left ventricular fractional shortening (R=-0.62, P<0.01). ACE inhibition with enalapril increased the H/M ratio on delayed images (P<0.05) and reduced the washout rate of 123I-BMIPP (P<0.05) in CHF patients. These data suggest that: (1) angiotensin II-mediated intracellular signalling activation may be a possible mechanism for the decreased myocardial uptake and enhanced washout of 123I-BMIPP in heart failure patients; and (2) the improvement in fatty acid metabolism by ACE inhibition may represent a new mechanism for the beneficial effect of this therapy in heart failure.

Apoptosis in rat cardiac myocytes induced by Fas ligand: priming for Fas-mediated apoptosis with doxorubicin.

Fas/Fas ligand (FasL) is well known for its role in delivering apoptotic signals; however, it is unclear whether FasL can mediate apoptosis in cardiomyocytes. We hypothesized that apoptosis via Fas/FasL system may be augmented in damaged cardiomyocytes. To determine whether FasL mediates cardiomyocyte apoptosis, recombinant FasL (rFasL) was added to the culture of neonatal rat ventricular myocytes pretreated with and without doxorubicin. Without doxorubicin, high dose of rFasL caused an increase in TUNEL-positive cardiomyocytes and a mild decrease in MTT activities. When cardiomyocytes were pretreated with doxorubicin (0.5 microM), rFasL dramatically augmented TUNEL-positive cardiomyocytes in a concentration-dependent manner, which was accompanied with nuclear fragmentations. The rFasL also caused a concentration-dependent reduction in MTT activities in cardiomyocytes. The rFasL-induced caspase-8 activity was greatly facilitated by pretreatment of doxorubicin. TUNEL-positive nuclei with rFasL was inhibited by Fas-Fc, neutralizing agent of rFasL, and Z-IETD-FMK, caspase-8 inhibitor. Fas mRNA transcript by RT-PCR was up-regulated in cardiomyocytes with doxorubicin. We conclude that FasL can induce cardiomyocyte apoptosis particularly when cardiomyocyte becomes susceptible for Fas-mediated apoptosis.

Nitric oxide enhances expression and shedding of tumor necrosis factor receptor I (p55) in endothelial cells.

The biological actions of tumor necrosis factor-alpha (TNF-alpha) are mediated by 2 distinct receptors, TNF-RI (p55) and TNF-RII (p75). The extracellular domains of both receptors are shed in soluble form (sTNF-RI and sTNF-RII). The soluble receptors are involved in regulating TNF-alpha activities and may have therapeutic potential as TNF-neutralizing agents. However, it remains unclear as to what kind of physiological molecule can regulate TNF receptors. Nitric oxide (NO) mediates a variety of biological and pathophysiological functions. We hypothesized that NO may modulate the expression and shedding of TNF-RI. An NO donor, diethylamine/NO complex (NOC 5), increased sTNF-RI in the supernatants of ECV304, a human umbilical vein cell line, in a dose-dependent manner. TNF-RI mRNA in these cells was upregulated by NOC 5. 8-Br-cGMP and peroxynitrate had no effect on sTNF-RI release. Genistein and herbimycin A, inhibitors of tyrosine kinase, inhibited sTNF-RI release. Herbimycin A inhibited the levels of TNF-RI mRNA enhanced by NOC 5, which downregulated the surface expression of TNF-RI, indicating that NO is also involved in the shedding process of TNF-RI. The shedding of TNF-RI was abolished by a synthetic inhibitor of matrix metalloproteinase, KB-R8301. In conclusion, NO enhanced the release of sTNF-RI from endothelial cells by a cGMP-independent mechanism. Dual pathways suggested for NO-induced sTNF-RI release include (1) enhanced expression of TNF-RI, at least partially, by a tyrosine kinase-dependent mechanism and (2) increased shedding of TNF-RI by a type of metalloproteinase.

Fatty acid imaging with 123I-15-(p-iodophenyl)-9-R,S-methylpentadecanoic acid in acute coronary syndrome.

UNLABELLED: 123I-15-(p-iodophenyl)-9-R,S-methylpentadecanoic acid (9-MPA) has recently been developed as a tracer for myocardial fatty acid uptake. The aim of this study, which was performed as part of a phase III clinical trial of 9-MPA, was to test the usefulness of 9-MPA for the assessment of myocardial viability in patients with acute coronary syndrome (ACS). METHODS: Fifteen patients with ACS who had undergone direct percutaneous transluminal coronary angioplasty were examined. Myocardial SPECT with 9-MPA and 99mTc-sestamibi and low-dose dobutamine echocardiography were performed within 2 wk after onset. The 9-MPA images were obtained 10 and 60 min after tracer administration, and sestamibi imaging was begun 60 min after the injection. The left ventricle was divided into 9 segments, and 9-MPA and sestamibi uptake were scored from 0 (normal) to 3 (no activity) in each segment. Lower uptake of 9-MPA than of sestamibi was defined as a mismatch. Myocardial segments showing improvement in wall motion during low-dose dobutamine infusion (5-10 microg/kg/ min) were considered viable. RESULTS: The 9-MPA images were of high quality for all patients. Myocardial uptake of 9-MPA was lower in ischemic myocardium than in nonischemic myocardium (58.2%+/-14.2% versus 91.9%+/-6.5%, P<0.0001). Clearance of 9-MPA from ischemic myocardium was slower than that from nonischemic myocardium (10.2%+/-11.7% versus 19.1%+/-5.9%, P<0.01). A mismatch was seen in 10 of 15 patients, and 18 of 20 (90%) mismatched segments were defined as viable by dobutamine echocardiography. Conversely, 18 of 20 (90%) matched segments did not show any improvement in function during dobutamine stimulation (P<0.0001). Uptake of 9-MPA in nonviable segments was lower than that in dysfunctional but viable segments (P<0.05), and 9-MPA clearance from nonviable segments was slower than that from viable segments (P<0.05). CONCLUSION: The imaging characteristics of 9-MPA for SPECT are excellent, allowing noninvasive assessment of myocardial fatty acid uptake. Myocardial imaging with 9-MPA may reveal impaired fatty acid uptake in dysfunctional but viable myocardium and thus provide useful information for clinical decision making in ACS.