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Biomedical subjects

Tiziano M Scarabelli

Publications and source records attributed to Tiziano M Scarabelli.

At least 19 recordsLinked to original sources
PubMed2007

Peripartum cardiomyopathy: a comprehensive review.

Peripartum cardiomyopathy (PPCM) is a rare disorder in which left ventricular dysfunction and symptoms of heart failure occur in the peripartum period in previously healthy women. Incidence of PPCM ranges from 1 in 1300 to 1 in 15,000 pregnancies. The etiology of PPCM is unknown, but viral, autoimmune, and idiopathic causes may contribute. The diagnostic criteria are onset of heart failure in the last month of pregnancy or in first 5 months postpartum, absence of determinable cause for cardiac failure, and absence of a demonstrable heart disease before the last month of pregnancy. Risk factors for PPCM include advanced maternal age, multiparity, African race, twinning, gestational hypertension, and long-term tocolysis. The clinical presentation of patients with PPCM is similar to that of patients with dilated cardiomyopathy. Early diagnosis and initiation of treatment are essential to optimize pregnancy outcome. Treatment is similar to medical therapy for other forms of dilated cardiomyopathy. About half the patients of PPCM recover without complications. The prognosis is poor in patients with persistent cardiomyopathy. Persistence of disease after 6 months indicates irreversible cardiomyopathy and portends worse survival.

Adult↗
PubMed2006

Urocortin inhibits Beclin1-mediated autophagic cell death in cardiac myocytes exposed to ischaemia/reperfusion injury.

Autophagy is known to be a feature of cardiomyopathies and chronic ischaemia. Here we demonstrate that autophagy is also induced by a single cycle of ischaemia/reperfusion (I/R in neonatal and adult rat cardiac myocytes). Consistent with the critical role for Beclin1 in autophagocytosis, reduction of Beclin1 expression in cardiac myocytes by RNAi reduces I/R-induced autophagy and this is associated with enhanced cell survival. Autophagy is also reduced by urocortin, an endogenous cardiac peptide which we have previously shown to reduce other forms of myocyte cell death induced by I/R. The inhibition of autophagy by urocortin is mediated in part by inhibition of Beclin1 expression, an effect which is mediated by activation of the PI3 kinase/Akt pathway but which does not involve activation of p42/p44 MAPK.

Animals↗
PubMed2006

Clinical implications of apoptosis in ischemic myocardium.

Apoptosis, a genetically programmed form of cell death, contributes to myocyte cell loss in a variety of cardiac pathologies, including cardiac failure and those related to ischemia/reperfusion injury. The apoptotic program is complex, involving both pro- and anti-apoptotic proteins, and apoptosis occurs when the equilibrium between these opposing factors is perturbed. Some of these factors are intrinsic to the apoptotic pathway, such as the pro- and anti-apoptotic members of the Bcl2 family. Other, extrinsic, cellular factors can also modify the outcome of the response to an apoptotic stimulus. In this review, we have focused on some of these extrinsic factors, such as STAT-1 as a pro-apoptotic agent and the urocortins and Bag-1 as anti-apoptotic factors, since these may be potential therapeutic targets. In addition, we discuss the profound cytoprotective effects of the antibiotic, minocycline.

Animals↗
PubMed2006

Suboptimal glycemic control, independently of QT interval duration, is associated with increased risk of ventricular arrhythmias in a high-risk population.

BACKGROUND: Although cardiovascular disease is the leading cause of mortality in diabetic patients, little is known about the impact of glycemic control on ventricular tachycardia (VT). OBJECTIVE: To investigate whether hemoglobin A1c (HbA1c) is associated with increased incidence of VT. METHODS: A retrospective study of 336 implantable cardioverter-defibrillator patients (both diabetes mellitus (DM) and non-DM) was conducted. RESULTS: HbA1c levels between 8% and 10% had a significant association with spontaneous VT, but not with QT/QTc. CONCLUSIONS: Glycemic index is a significant predictor of spontaneous VT, independently of QT interval. Optimal glycemic control may help reduce occurrence of VT and sudden cardiac death in high-risk DM patients.

Aged↗
PubMed2005

A case of fatal ephedra intake associated with lipofuscin accumulation, caspase activation and cleavage of myofibrillary proteins.

Ephedra, a herb reported to suppress appetite and stimulate the sympathetic nervous system as well as cardiac performance, has recently been related to several adverse events, including seizure, stroke, hypertension, myocardial infarction, and sudden death. Here, we describe the case of a 45-year-old woman who died of cardiovascular collapse while taking ephedra. Tissue analysis revealed non-specific degenerative alterations in the myocardium (lipofuscin accumulation, basophilic degeneration and vacuolation of myocytes, as well as myofibrillary loss), associated with myocyte apoptosis, caspase activation, and extensive cleavage of miofibrillary proteins alpha-actin, alpha-actinin, and cardiac troponin T. Healthcare professionals are therefore urged to warn their patients about the risk of serious adverse effects, which may follow ephedra intake.

Apoptosis↗
PubMed2004

Epigallocatechin-3-gallate inhibits STAT-1 activation and protects cardiac myocytes from ischemia/reperfusion-induced apoptosis.

We have previously demonstrated that STAT-1 plays a critical role in promoting apoptotic cell death in cardiac myocytes following ischemia/reperfusion (I/R) injury. Epigallocatechin-3-gallate (EGCG), the major constituent of green tea, has recently been reported to inhibit STAT-1 activity in noncardiac cells. In the present study, we have assessed the protective effects of EGCG and green tea extract (GTE) infusion on both cultures of cardiac myocytes and the isolated rat heart. EGCG reduced STAT-1 phosphorylation and protected cardiac myocytes against I/R-induced apoptotic cell death. Moreover, EGCG reduced the expression of a known STAT-1 pro-apoptotic target gene, Fas receptor. More interestingly, oral administration of GTE as well as EGCG infusion limited the extent of infarct size and attenuated the magnitude of myocyte apoptosis in the isolated rat heart exposed to I/R injury. This reduction cell death was associated with improved hemodynamic recovery and ventricular function in the ischemic/reperfused rat heart. This is the first report to show that consumption of green tea is able to mediate cardioprotection and enhance cardiac function during I/R injury. Because GTE-mediated cardioprotection is achieved, at least in part, through inhibition of STAT-1 activity, we may postulate that a similar action can be implemented in the clinical setting to minimize STAT-1 activation levels in patients with acute coronary artery disease (CAD).

Administration, Oral↗
PubMed2004

Effect of amino acid mixture on the isolated ischemic heart.

Data show that uptake of amino acids correlates with myocardial oxygen consumption after aortic cross-clamp in humans; this suggests a direct link between amino acids and myocardial energy metabolism. The aim of this preliminary study was to investigate the anti-ischemic effects of immediate and long-term supplementation of an amino acid mixture. We tested this hypothesis on isolated rats hearts subjected to global ischemia for 30 minutes. Long-term treatment with an amino acid mixture achieved the following: (1) reduced the increase of diastolic pressure (48 +/- 3 mm Hg vs 21 +/- 4 mm Hg; p <0.05); (2) maintained the tissue content of adenosine triphosphate during ischemia (2.5 +/- 0.6 micromol/g wet wt [gww] vs 7.0 +/- 1.2 micromol/gww; p <0.05); and (3) improved the recovery of developed pressure at the end of postischemic reperfusion (11 +/- 2 mm Hg vs 38 +/- 3 mm Hg; p <0.05), reducing the release of creatine kinase (375 +/- 30 microU/min/gww vs 196 +/- 15 microU/min/gww; p <0.05) and lactate (15 +/- 1.5 mg/min/gww vs 5 +/- 1 mg/min/gww; p <0.05). We conclude that long-term supplementation of an amino acid mixture reduced myocardial ischemic damage.

Adenosine Triphosphate↗
PubMed2004

Nutritional supplementation with mixed essential amino acids enhances myocyte survival, preserving mitochondrial functional capacity during ischemia-reperfusion injury.

In patients undergoing coronary surgery, the uptake of amino acids, which has been shown to correlate with oxygen consumption, is a mechanism of cardiac adaptation to the iatrogenic ischemia-reperfusion injury associated with cardioplegic arrest. Based on these premises, we sought to determine whether oral supplementation with mixed amino acids may protect the rat heart exposed to ischemia-reperfusion and to address whether this hypothesized cardioprotection is achieved, at least in part, through preservation of the energy-producing properties of mitochondria. Sprague-Dawley rats were fed (by enteral route) a liquid diet, with or without mixed essential amino acids (daily dose of 1 g/kg) for 30 days. Hearts from anesthetized rats were perfused by the Langendorff method and randomized to 3 groups. The control group was perfused with buffer for 60 minutes; the ischemia-reperfusion control and the amino acid-treated groups were exposed to 35 minutes of ischemia, followed by 60 or 120 minutes of reperfusion. Amino acid supplements minimized infarct size (22 +/- 1.8% vs 33 +/- 2.5%; p <0.05) and occurrence of cardiomyocyte apoptosis, as assessed by co-localization of terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) and caspase-3-positive staining (p <0.01). Long-term treatment with amino acids also reduced the proportion of cardiomyocytes exhibiting immunostaining for cleaved caspase-9 (p <0.01) but was ineffective on processing of caspase-8. Similar results were obtained in the whole heart by caspase activity assays (p <0.01). The lessened activation of caspase-9 detected in amino acid-treated hearts paralleled a strong reduction in mitochondrial release of cytochrome c. Adenosine triphosphate (ATP) content and rate of ATP production in isolated mitochondria were reduced by >75% in control hearts after 2 hours of reperfusion (p <0.05 vs control hearts); these values returned toward those of the control group in hearts supplemented with amino acids (p <0.01). Finally, the oxygen consumption rate in myocardial skinned bundles was markedly reduced in ischemia-reperfusion control hearts and almost normalized in amino acid-treated hearts (approximately 20% and 93% of the value for normoxic hearts; p <0.01). These results suggest that oral amino acid supplementation attenuates the extent of ischemia-reperfusion injury in the rat heart, through preservation of the mitochondria-generated production of high-energy phosphates.

Amino Acids, Essential↗
PubMed2004

Minocycline inhibits caspase activation and reactivation, increases the ratio of XIAP to smac/DIABLO, and reduces the mitochondrial leakage of cytochrome C and smac/DIABLO.

OBJECTIVES: This study is aimed at investigating the novel use of minocycline for cardiac protection during ischemia/reperfusion (I/R) injury, as well as its mechanism of action. BACKGROUND: Minocycline is a tetracycline with anti-inflammatory properties, which is used clinically for the treatment of diseases such as urethritis and rheumatoid arthritis. Experimentally, minocycline has also been shown to be neuroprotective in animal models of cerebral ischemia and to delay progression and improve survival in mouse models of neurodegenerative diseases. METHODS: We studied 62 rat intact hearts exposed to I/R and cell cultures of neonatal and adult rat ventricular myocytes. RESULTS: Minocycline significantly reduced necrotic and apoptotic cell death, both in neonatal and adult myocytes, not only when given prior to hypoxia (p < 0.001), but also at reoxygenation (p < 0.05). Moreover, in the intact heart exposed to I/R, in vivo treatment with minocycline promoted hemodynamic recovery (p < 0.001) and cell survival, with reduction of infarct size (p < 0.001), cardiac release of creatine phosphokinase (p < 0.001), and apoptotic cell death (p < 0.001). In regard to its antiapoptotic mechanism of action, minocycline significantly reduced the expression level of initiator caspases, increased the ratio of XIAP to Smac/DIABLO at both the messenger RNA and protein level, and prevented mitochondrial release of cytochrome c and Smac/DIABLO (all, p < 0.05). These synergistic actions dramatically prevent the post-ischemic induction of caspase activity associated with cardiac I/R injury. CONCLUSIONS: Because of its safety record and multiple novel mechanisms of action, minocycline may be a valuable cardioprotective agent to ameliorate cardiac dysfunction and cell loss associated with I/R injury.

Animals↗
PubMed2004

BAG-1 proteins protect cardiac myocytes from simulated ischemia/reperfusion-induced apoptosis via an alternate mechanism of cell survival independent of the proteasome.

BAG-1 (Bcl-2-associated athanogene-1) proteins interact with the HSC70 and HSP70 heat shock proteins and have been proposed to promote cell survival by coordinating the function of these chaperones with the proteasome to facilitate protein degradation. Consistent with this proposal, previous analyses in cancer cells have demonstrated that BAG-1 requires protein domains important for HSC70/HSP70 and proteasome binding in order to interfere with the growth inhibition induced by heat shock (Townsend, P. A., Cutress, R. I., Sharp, A., Brimmell, M., and Packham, G. (2003) Cancer Res., 63, 4150-4157). Moreover, cellular stress triggered the relocalization of the cytoplasmic BAG-1S (approximately 36 kDa) isoform to the nucleus, and both BAG-1S and the constitutively nuclear localized BAG-1L (approximately 50 kDa) isoform suppressed heat shock-induced apoptosis to the same extent, suggesting a critical role in the nucleus. Because ischemia (I) and reperfusion (R) are important stress signals in acute and chronic heart disease, we have examined the expression and function of BAG-1 proteins in primary cardiac myocytes (CMs) and the Langendorff-perfused intact heart. The expression of both BAG-1 isoforms, BAG-1S and BAG-1L, was rapidly induced following ischemia in rat CM, and this was maintained during subsequent reperfusion. In control hearts, BAG-1S and BAG-1L were readily detectable in both the nucleus and the cytoplasm. However, BAG-1S did not relocate to the nucleus following simulated I/R. BAG-1 interacted with both RAF-1 and HSC70 in CMs and the whole heart, and binding to HSC70 was increased following I/R. Overexpression of the human BAG-1S and BAG-1 M isoforms significantly reduced CM apoptosis following simulated I/R. By contrast, BAG-1L or BAG-1S fused to a heterologous nuclear localization sequence failed to protect CM. Finally, overexpression of BAG-1 deletion and point mutants unable to bind HSC70/HSP70 failed to offer cardioprotection. Surprisingly, a deletion mutant lacking the N-terminal ubiquitin-like domain, which mediates interaction with the proteasome, still promoted cardioprotection. Therefore, BAG-1 has a novel cardioprotective role, mediated via association with HSC70/HSP70, which is critical upon cytoplasmic localization but independent of the BAG-1 ubiquitin-like domain. Our studies demonstrate that BAG-1 can influence cellular response to stress by multiple mechanisms, potentially influenced by the cell type and nature of the stress signal.

Animals↗
PubMed2004

Warm blood cardioplegic arrest induces mitochondrial-mediated cardiomyocyte apoptosis associated with increased urocortin expression in viable cells.

OBJECTIVES: This study assesses the mechanisms of apoptosis in patients after on-pump coronary artery bypass graft surgery and the potential involvement of the endogenous cardiac peptide urocortin as a cardiomyocyte salvage mechanism. We have previously described the mechanisms of apoptosis after ischemia-reperfusion injury in the rat heart and shown that endogenous urocortin is cardioprotective. Here we extend these findings to the human heart exposed to ischemic-reperfusion injury. METHODS: Two sequential biopsy specimens were obtained from the right atriums of 24 patients undergoing coronary artery bypass grafting at the start of grafting and 10 minutes after release of the aortic clamp. Apoptosis was identified by means of immunocytochemical colocalization between terminal deoxynucleotidyl transferase-mediated nick end-labeling positivity and active caspase-3. Immunostaining for active caspase-9 and caspase-8 was performed to identify the pathways of apoptosis induction. Urocortin and adenosine triphosphate-dependent potassium channel expression was also assessed by means of immunocytochemistry. RESULTS: Myocyte apoptosis (<0.1% before coronary artery bypass grafting) was increased after coronary artery bypass grafting and reperfusion and was greater in patients with longer periods of cardioplegic arrest (3.3% +/- 0.5% with <55 minutes and 5.1% +/- 0.9% with 85-100 minutes, P <.001). Processing of caspase-9 was always more pronounced than that of caspase-8 (P <.05). Cardioplegic arrest was also associated with increased urocortin expression (up to 29% +/- 3.5% vs <3% in samples obtained before coronary artery bypass grafting, P <.001) but only in nonapoptotic myocytes. These and surrounding viable myocytes also showed increased Kir6.1 adenosine triphosphate-dependent potassium channel expression. CONCLUSIONS: Cardioplegic arrest and subsequent reperfusion result in cardiomyocyte apoptosis, largely through mitochondrial injury, as well as exclusive urocortin expression in viable cells. This finding might suggest a cardioprotective role for endogenous urocortin in human subjects.

Apoptosis↗
PubMed2003

STAT-1 interacts with p53 to enhance DNA damage-induced apoptosis.

The STAT-1 transcription factor has been implicated as a tumor suppressor by virtue of its ability to inhibit cell growth and promoting apoptosis. However, the mechanisms by which STAT-1 mediates these effects remain unclear. Using human and mouse STAT-1-deficient cells, we show here that STAT-1 is required for optimal DNA damage-induced apoptosis. The basal level of the p53 inhibitor Mdm2 is increased in STAT-1(-/-) cells, suggesting that STAT-1 is a negative regulator of Mdm2 expression. Correspondingly, both basal p53 levels, and those induced by DNA damage were lower in STAT-1(-/-) cells. In agreement with this lower p53 response to DNA damage in cells lacking STAT-1, the induction of p53 responsive genes, such as Bax, Noxa, and Fas, was reduced in STAT-1-deficient cells. Conversely, STAT-1 overexpression enhances transcription of these genes, an effect that is abolished if the p53 response element in their promoters is mutated. Moreover, STAT-1 interacts directly with p53, an association, which is enhanced following DNA damage. Therefore, in addition to negatively regulating Mdm2, STAT-1 also acts as a coactivator for p53. Hence STAT-1 is another member of a growing family of protein partners able to modulate the p53-activated apoptotic pathway.

Animals↗
PubMed2003

Influence of type 2 diabetes on functional and structural properties of coronary artery bypass conduits.

Recent studies have reported a high incidence of postoperative unfavorable cardiac-related events in patients with diabetes who underwent coronary artery bypass grafting (CABG). Structural and functional characteristics of CABG conduits, which have been shown to play an important role in patient outcome after myocardial revascularization, have not been fully investigated in diabetic subjects. Therefore, we sought to determine the influence of adult-onset diabetes on vasoreactivity and morphological profile of venous and arterial grafts. Of the 160 consecutive patients enrolled in the study, 90 were diagnosed with type 2 diabetes and 70 did not have diabetes (control group). All patients underwent evaluation of glucose control before surgery. Tissue specimens were collected from left internal thoracic artery (LITA) and saphenous vein (SV) grafts harvested during elective CABG. Functional tests were performed to assess contractile and vasodilative responses of bypass conduits. Histological evaluation was carried out to examine vessel wall structure. Univariate and multivariate analyses were performed to correlate the preoperative factors related to the control of the endocrine disorder with histological findings. Patient medical history and demographics did not differ between the groups. Diabetic patients showed significant microalbuminuria and higher plasma levels of C-peptide and GHb as compared with nondiabetic subjects. Functional tests of the LITA segments revealed no difference between groups with regard to contractile and vasodilative responses. In contrast, significant impairment in the endothelium-related vasodilation of the SV grafts was observed in diabetic subjects. Histological studies showed structural preservation of the arterial conduits in both groups. However, marked intimal abnormalities (also atherosclerotic calcified plaques) were detected in SV grafts harvested from diabetic patients. Logistic regression analysis showed that high levels of proteinuria and GHb were independent predictors of advanced structural degeneration of SV conduits. Treatment modality, duration of diabetes, and other demographic or metabolic factors were found to have no influence on the morphological characteristics of SV conduits. In conclusion, biological properties of LITA conduits for CABG were preserved in diabetic patients. However, these patients frequently showed impairment of the endothelium-dependent vasorelaxation and intimal degeneration of SV grafts. The extent of structural abnormalities of SV grafts was inversely correlated with the efficacy of the metabolic control of the endocrine disorder. Further studies are required to conclusively correlate preoperative SV graft abnormalities with postoperative conduit patency rate and the occurrence of adverse cardiac-related events in diabetic subjects.

Administration, Oral↗