[The hybrid strategy for complete myocardial revascularization in the frail elderly patient]. / La strategia "ibrida" per il conseguimento di una rivascolarizzazione miocardica completa nel paziente anziano fragile.

The hybrid strategy allows for a complete myocardial revascularization in patients with multivessel coronary artery disease and a high frailty index. These patients, due to their old age and multi-comorbidities, are evaluated with inadequate tools for their clinical complexity and destined to an incomplete revascularization for increased surgical or procedural risk. Hybrid revascularization enables to use the best techniques resulting from the surgical and percutaneous approach defining a tailored strategy for the patient. In the frail patient, this strategy is associated with favorable outcomes and a lower exposure to periprocedural complications.

Impaired flow-mediated dilation in hospitalized patients with community-acquired pneumonia.

BACKGROUND: Community-acquired pneumonia (CAP) is complicated by cardiovascular events as myocardial infarction and stroke but the underlying mechanism is still unclear. We hypothesized that endothelial dysfunction may be implicated and that endotoxemia may have a role. METHODS: Fifty patients with CAP and 50 controls were enrolled. At admission and at discharge, flow-mediated dilation (FMD), serum levels of endotoxins and oxidative stress, as assessed by serum levels of nitrite/nitrate (NOx) and isoprostanes, were studied. RESULTS: At admission, a significant difference between patients with CAP and controls was observed for FMD (2.1±0.3 vs 4.0±0.3%, p<0.001), serum endotoxins (157.8±7.6 vs 33.1±4.8pg/ml), serum isoprostanes (341±14 vs 286±10 pM, p=0.009) and NOx (24.3±1.1 vs 29.7±2.2µM). Simple linear correlation analysis showed that serum endotoxins significantly correlated with Pneumonia Severity Index score (Rs=0.386, p=0.006). Compared to baseline, at discharge CAP patients showed a significant increase of FMD and NOx (from 2.1±0.3 to 4.6±0.4%, p<0.001 and from 24.3±1.1 to 31.1±1.5µM, p<0.001, respectively) and a significant decrease of serum endotoxins and isoprostanes (from 157.8±7.6 to 55.5±2.3pg/ml, p<0.001, and from 341±14 to 312±14 pM, p<0.001, respectively). Conversely, no changes for FMD, NOx, serum endotoxins and isoprostanes were observed in controls between baseline and discharge. Changes of FMD significantly correlated with changes of serum endotoxins (Rs=-0.315; p=0.001). CONCLUSIONS: The study provides the first evidence that CAP is characterized by impaired FMD with a mechanism potentially involving endotoxin production and oxidative stress.

[Pulmonary stenosis and atrial septal defect: a rare association in the elderly]. / Stenosi dell'arteria polmonare e difetto interatriale: una rara associazione nel paziente anziano.

We report the case of an elderly woman with persistent unrepaired atrial septal defect and moderate pulmonary stenosis. The diagnostic work-up and the echocardiographic findings of such a rare case are reported, along with a brief description of heart failure pathophysiology in this grown-up congenital heart disease.To the best of our knowledge, this is the first case with the greater longevity in an elderly patient with unrepaired atrial septal defect and pulmonary stenosis ever reported in the literature.

An unrepaired persistent truncus arteriosus in a 62-year-old adult.

: In this image focus, we describe the case an old woman with persistent unrepaired truncus arteriosus type III and Eisenmenger syndrome.

Role of platelets in NOX2 activation mediated by TNFα in heart failure.

Tumor necrosis factor (TNF) α may contribute to the deterioration of cardiovascular function in heart failure (HF) through various mechanisms, including the generation of reactive oxygen species (ROS). NADPH oxidase is the major source of ROS in the vascular system, but the interplay between TNFα and NADPH oxidase activation is elusive. As platelets possess NADPH oxidase enzyme, they represent an important tool to investigate the interplay between NADPH oxidase and TNFα in patients with HF. Serum gp91phox (NOX2), the catalytic core of NADPH oxidase, and serum TNFα were measured in 120 HF patients and in 60 healthy subjects. Compared with healthy subjects, HF patients had higher blood levels of NOX2 and TNFα with a progressive increase from NYHA I to NYHA IV classes. NOX2 levels in blood were independently associated with TNFα in HF patients. An in vitro study, performed on platelets from a subgroup of HF patients, shows that TNFα, at concentrations commonly found in HF patients' peripheral circulation, activates platelet NOX2. Thus, TNFα increases ROS production and the extracellular levels of NOX2. These phenomena are inhibited by the NOX2-specific blocking peptide gp91ds-tat. The study provides evidence that circulating NOX2, as well as the activation of NOX2 on platelets, is increased in HF likely as a consequence of the underlying inflammatory process.

Is NOX2 upregulation implicated in myocardial injury in patients with pneumonia?

In the present study, we tested the hypothesis that oxidative stress could be implicated in myocardial damage during the acute phase of pneumonia. NOX2 activation, the catalytic subunit of NADPH oxidase, and high-sensitivity cardiac troponin T (hs-cTnT) elevation have been analyzed in two hundred forty-eight consecutive patients hospitalized for community-acquired pneumonia. Serum NOX2-derived peptide (sNOX2-dp), a marker of NOX2 activation, and 8-isoprostaglandin F2α (8-iso-PGF2α), a marker of oxidative stress, were measured upon admission; serum hs-cTnT and ECG were measured every 12 and 24 h, respectively. One hundred thirty-five patients (54%) showed elevated serum levels of hs-cTnT (>0.014 µg/L). A logistic regression analysis showed sNOX2-dp (p<0.001), Pneumonia Severity Index score (p<0.001), renal failure (p=0.024), and ejection fraction (p<0.001) as independent predictors of elevated serum levels of hs-cTnT. Serum sNOX2-dp was linearly correlated with hs-cTnT (Rs=0.538; p<0.001) and 8-iso-PGF2α (Rs=0.354; p<0.001). The study provides the first evidence of a significant association between serum cardiac Troponin T elevation and NOX2 upregulation in patients with pneumonia. This finding raises the hypothesis that NOX2-derived oxidative stress may be implicated in myocardial injury and that its inhibition could be a novel therapeutic strategy to limit it.

Patients with microvascular obstruction after primary percutaneous coronary intervention show a gp91phox (NOX2) mediated persistent oxidative stress after reperfusion.

BACKGROUND: Persistent oxidative stress may play a key role in microvascular obstruction (MVO). We aimed at assessing the role of platelet gp91phox (NOX2), the catalytic subunit of NADPH oxidase in MVO. METHODS: We enrolled 40 patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention within 12 h from symptoms onset, either with angiographic MVO (n=20) or good angiographic myocardial reperfusion (MR) (n=20). Angiographic MVO was defined as a final thrombolysis in myocardial infarction (TIMI) flow ≤2 or TIMI flow of 3 with myocardial blush grade <2. NOX2 and isoprostanes (8-iso-PGF2α) levels, as assessed by enzyme-linked immunoadsorbent assay (ELISA) or by an enzyme immunoassays, respectively, were measured on admission, at 24 h and pre-discharge. RESULTS: NOX2 levels increased from baseline to pre-discharge in patients with angiographic MVO (20.25 (15-24.75) pg/ml vs 25.50 (17-29.25) pg/ml, p=0.02), but not in MR patients (p=0.45), with a significant interaction between baseline and pre-discharge levels among the two groups (p=0.04). The levels of 8-iso-PGF2α showed a trend to increase from baseline to pre-discharge in angiographic MVO patients (295 (183.50-389.25) pmol/l vs 322 (206-370) pmol/l, p=0.06), but not in patients with MR (p=0.56), with a trend for interaction between baseline and pre-discharge levels among the two groups (p=0.09). CONCLUSION: Patients with MVO, but not those with myocardial reperfusion, have a sustained increase of NOX2 and 8-iso-PGF2α. Therapies targeting NOX2 or high dosage antioxidants should be tested for MVO prevention and treatment.

Different behaviour of NOX2 activation in patients with paroxysmal/persistent or permanent atrial fibrillation.

BACKGROUND: NOX2, the catalytic subunit of NADPH oxidase, is suggested to play a role in favouring the occurrence of atrial fibrillation (AF) after cardiac surgery via formation of reactive oxidant species. However, its role in spontaneous AF is still unclear. OBJECTIVE: To define the role of NOX2 and isoprostanes, a marker of oxidative stress, in the different settings of AF. METHODS: The study was performed on 174 patients with AF (82 with paroxysmal/persistent AF and 92 with permanent AF) and 90 controls matched for sex, age and atherosclerotic risk factors. Urinary isoprostanes and serum levels of soluble NOX2-derived peptide (sNOX2-dp) were measured in each patient. RESULTS: Urinary isoprostanes and sNOX2-dp concentrations were significantly higher in patients with paroxysmal/persistent AF than in those with permanent AF and controls. Compared with controls, patients with permanent AF showed a weak increase in sNOX2-dp and no difference in isoprostanes. Multivariable analyses demonstrated that baseline values of sNOX2-dp and urinary isoprostanes were independently associated with the type of AF (paroxysmal/persistent vs permanent; ß=-224, p=0.007 and ß=-231, p=0.005, respectively). A significant correlation between sNOX2-dp levels and urinary excretion of isoprostanes was also detected (R=0.707, p<0.001). CONCLUSIONS: This study provides evidence that NOX2 is upregulated only in patients with paroxysmal/persistent AF and is responsible for overproduction of isoprostanes. This finding warrants further study to see if inhibition of NOX2 may reduce the risk of paroxysmal/persistent AF.

A case for assessment of oscillatory breathing during cardiopulmonary exercise test in risk stratification of elderly patients with chronic heart failure.

UNLABELLED: The prognostic value of exercise oscillatory breathing (EOB) during cardiopulmonary test (CPX) has been described in young chronic heart failure (HF) patients. We assessed the prognostic role of EOB vs other clinical and ventilatory parameters in elderly HF patients performing a maximal CPX. METHODS AND RESULTS: We prospectively followed-up 370 HF outpatients ≥ 65 years after a symptom limited CPX. We tested the predictive value of clinical and ventilatory parameters for all-cause mortality and a composite of all-cause mortality and HF hospitalizations. Median age was 74 years, 51% had ischemic heart disease, 25% NYHA class III; ejection fraction was 41% [34-50]. Peak oxygen consumption (PVO(2)) was 11.9 [9.9-14] mL/kg/min, the slope of the regression line relating ventilation to CO(2) output, (VE/VCO(2) slope) was 33.9 [29.8-39.2]. EOB was found in 58% of patients. At follow-up, 84 patients died and overall 158, using a time-to-first event approach, met the composite end-point. Independent predictors of all-cause mortality were CPX EOB and the ratio of VE/VCO(2) slope to peak VO(2), hemoglobin, creatinine and body mass index. The area under the ROC curve (AUC) of the Cox multivariable model was 0.80 (95% CI 0.73 to 0.87). Independent predictors of the composite end-point were EOB, VE/VCO(2) slope, hemoglobin and HF admissions in the previous year (Model AUC 0.75) (95% CI 0.69 to 0.81). CONCLUSIONS: Among elderly HF patients, EOB prevalence is higher than middle-aged cohorts. EOB and the ratio of VE/VCO(2) slope to peak VO(2) resulted the strongest ventilatory predictor of all-cause mortality, independent of ventricular function.

Ascorbic acid infusion blunts CD40L upregulation in patients undergoing coronary stent.

OBJECTIVES: To reduce the increase of oxidative stress and the upregulation of CD40L during stenting procedure using ascorbic acid infusion. BACKGROUND: CD40L upregulation occurring after coronary percutaneous coronary intervention predicts vascular events but the underlying mechanism is still unclear. METHODS: Fifty-six patients undergoing elective coronary stenting were randomly allocated to intravenous infusion of the antioxidant ascorbic acid or placebo. Platelet CD40L and plasma levels of soluble CD40L and of 8-hydroxy-2'-deoxyguanosine, a marker of oxidative stress, were measured before and after coronary stenting. In vitro study was also done to measure reactive oxidant species and CD40L expression in platelets exposed to anoxia-reoxygenation. RESULTS: Placebo-treated patients showed a significant increase of platelet CD40L, soluble CD40L and 8-hydroxy-2'-deoxyguanosine compared to baseline values. Patients given ascorbic acid showed no change of soluble CD40L and platelet CD40L but a significant decrease of 8-hydroxy-2'-deoxyguanosine. After 60 and 120 min, soluble CD40L, platelet CD40L and 8-hydroxy-2'-deoxyguanosine were significantly lower in the ascorbic acid-treated group compared to the placebo-treated one. A significant correlation between platelet CD40L and soluble CD40L and between soluble CD40L and 8-hydroxy-2'-deoxyguanosine was observed. Platelets, in vitro exposed to anoxia-reoxygenation, had a burst of ROS and an upregulation of CD40L that were inhibited by ascorbic acid or apocynin, an inhibitor of NADPH oxidase. CONCLUSIONS: This study shows that in patients undergoing coronary stenting CD40L is upregulated with a mechanism which is likely mediated by oxidative stress.

Hyperfibrinolysis in liver disease.

The incidence of hyperfibrinolysis in patients with cirrhosis is still debated. The reasons for this uncertainty probably lie in the lack of appropriate laboratory tests for its evaluation. There is a relative consensus, however, that hyperfibrinolysis can complicate the clinical course of liver cirrhosis, especially in cases of moderate to severe liver failure. Hyperfibrinolysis correlates positively with the severity of underlying liver disease, and low-grade systemic fibrinolysis is found in 30% to 46% of patients who have end-stage liver disease. Accelerated intravascular coagulation with secondary hyperfibrinolysis has been reported in patients who have liver failure. Hyperfibrinolysis may delay primary hemostasis, thereby aggravating variceal bleeding and facilitating recurrence.

Additive prognostic value of cardiopulmonary exercise testing in elderly patients with heart failure.

To date, the role of CPET (cardiopulmonary exercise testing) for risk stratification in elderly patients with HF (heart failure) with depressed or preserved ventricular function has not been evaluated. In the present study, we analysed whether CPET is useful in predicting outcome in this population. A total of 220 NYHA (New York Heart Association) class I-III patients with HF > or =70 years of age [median age, 75 years; 23% had NYHA class III; and 59% had preserved ventricular systolic function (left ventricular ejection fraction > or =40%)] performed maximal CPET (peak expiratory exchange ratio >1.00). Median peak oxygen uptake was 11.9 ml.kg(-1) of body weight.min(-1), median VE/VCO(2) slope (slope of the minute ventilation/carbon dioxide production ratio) was 33.2 and 45% had an EVR (enhanced ventilatory response) to exercise (VE/VCO(2) slope > or =34). During 19 months of follow-up, 94 patients (43%) met the combined end point of death and hospital admission for worsening HF, arrhythmias or acute coronary syndromes. By Cox multivariable analysis, a creatinine clearance of <50 ml/min {HR (hazard ratio), 1.657 [95% CI (confidence interval), 1.055-2.602]} and EVR [HR, 1.965 (95% CI, 1.195-3.231)] were the best predictors of outcome, while ventricular function had no influence on prognosis. In conclusion, in elderly patients with HF, a steeper VE/VCO(2) slope provides additional information for risk stratification across the spectrum of ventricular function and identifies a high-risk population, commonly not considered in exercise testing guidelines.

Prognostic value of brain natriuretic peptide and enhanced ventilatory response to exercise in patients with chronic heart failure.

Whether brain natriuretic peptide (BNP), combined with a cardiopulmonary exercise test (CPx) parameters or echocardiography improves prognostic stratification in mild-to-moderate systolic heart failure (HF) is currently unclear. In 156 consecutive stable outpatients with mild to moderate HF and left ventricular ejection fraction (LVEF) <40%, we assessed the impact of BNP assay, Doppler echocardiography and CPx on survival. Median BNP plasma levels were 207 [90-520] pg/mL. Mean LVEF was 33 +/- 7%. Left bundle branch block (LBBB) was present in 52 patients (33%) and a restrictive filling pattern in 35 (22%). The slope of the relation between minute ventilation and carbon dioxide production (VE/VCO(2) slope) averaged 35 +/- 8; an enhanced ventilatory response (EVR) to exercise (VE/VCO(2) slope >35) was found in 67 patients (43%). During 759 +/- 346 days of follow-up, 24 patients died. By multivariate analysis, the strongest independent predictors of all-cause death among clinical, echocardiographic variables and BNP were LBBB and beta-blocker treatment. When CPx variables were added, the best predictors of mortality were LBBB, beta-blockade and VE/VCO(2) slope. This study highlights the value of a sequential approach, based on clinical, laboratory and functional data to identify high-risk HF patients. BNP assay might constitute a simple alternative tool for patients with an inability or with clinical contraindications to exercise, advanced physical deconditioning and unreliable CPx results. However, whenever feasible, CPx with assessment of EVR is recommended for a more accurate prediction of prognosis.

Tumour necrosis factor alpha upregulates platelet CD40L in patients with heart failure.

AIMS: Patients with heart failure (HF) have elevated values of the pro-inflammatory protein CD40L but the underlying mechanism is unclear. This study was performed to evaluate the interplay between tumour necrosis factor alpha (TNFalpha) and CD40L in HF. METHODS AND RESULTS: In patients with HF (n=86) and healthy subjects (HS, n=43), plasma levels of soluble CD40L (sCD40L), TNFalpha, soluble receptors of TNFalpha such as soluble TNF receptors I and II (sTNFR1 and sTNFR2), and 8OH-dG, a marker of oxidative stress, were determined. Also, an in vitro study was performed by determining platelet CD40L regulation upon platelet stimulation with TNFalpha. Compared with HS, HF patients had higher plasma values of sCD40L, TNFalpha, sTNFR1 and sTNFR2, and higher platelet expression of TNFR1 and TNFR2 with a progressive increase from NYHA I to NYHA IV classification. sCD40L significantly correlated with TNFalpha, sTNFR1, and sTNFR2; plasma levels of TNFalpha significantly correlated with sCD40L. Incubation of platelets from HF patients with a TNFalpha receptor inhibitor significantly decreased platelet CD40L expression. The in vitro study demonstrated that TNFalpha significantly increased CD40L expression, an effect weakly influenced by aspirin but significantly reduced by AACOCF3, an inhibitor of PLA(2), apocynin, an inhibitor of NADPH oxidase, or staurosporine, an inhibitor of PKC. CONCLUSION: The study shows that in HF patients, platelet CD40L is upregulated by TNFalpha via a cyclooxygenase-1-independent, arachidonic acid-mediated oxidative stress mechanism.

A review of picotamide in the reduction of cardiovascular events in diabetic patients.

Picotamide is an antiplatelet drug with a dual inhibitory action. Thus, picotamide inhibits both thromboxane A2 (TxA2) receptors and TxA2 synthase and, at variance with aspirin, does not interfere with endothelial prostacyclin (PGI2) production. Two large randomized trials have been performed to assess the clinical efficacy of picotamide in patients at risk of atherothrombosis. The ADEP study compared peripheral artery disease (PAD) patients randomized to picotamide or placebo. This study did not show a significant reduction of cardiovascular events by picotamide but a subgroup analysis showed its potential usefulness in patients with diabetes. To investigate this issue further, the DAVID study recently enrolled diabetic patients with PAD randomized to picotamide versus aspirin; the results showed a significant reduction of overall mortality in the picotamide group. Moreover long-term picotamide treatment in diabetes promotes the reduction of microalbuminuria and the inhibition of growth of carotid plaques. These data suggest that picotamide may represent an interesting drug to be further investigated in future trials in the atherothrombotic setting.

Inhibition of platelet aggregation by aspirin progressively decreases in long-term treated patients.

OBJECTIVES: We sought to investigate, during a two-year follow-up period, the effects of aspirin on platelet aggregation. BACKGROUND: The platelets of patients given aspirin may be less sensitive to antiplatelet treatment, although the extent of such phenomenon over long-term follow-up is unclear. METHODS: Adenosine diphosphate (ADP) and collagen-induced platelet aggregation was periodically monitored before and after 2, 6, 12, and 24 months of treatment with aspirin (n = 150) or ticlopidine (n = 80) in patients matched for gender, age, and risk factors for atherothrombosis. RESULTS: Compared with baseline values, two months of aspirin treatment significantly inhibited platelet aggregation; thereafter, this inhibitory effect progressively decreased. At 24-month follow-up, collagen-induced platelet aggregation was significantly higher than that observed at two months (p < 0.05); a more pronounced difference was observed when collagen-induced lag phase was considered (p < 0.01). Restoration of platelet aggregation was less evident when ADP was used as an agonist. Conversely, the inhibition induced by ticlopidine was constant throughout follow-up with both agonists. CONCLUSIONS: The study demonstrates that a long-term treatment with aspirin is associated with a progressive reduction in platelet sensitivity to this drug.

[Syndrome of cholesterol crystal embolism: clinical case]. / Sindrome da embolia di cristalli di colesterolo: un caso clinico.

Cholesterol crystal embolization syndrome is a multiorgan disease that frequently occurs as a complication of invasive cardiovascular procedures and of thrombolytic or anticoagulant therapy. The symptoms are due to the displacement of atheromatous material dislodged from unstable or injured, by mechanical manipulation, plaque to arteriolar vessels. The real incidence of cholesterol embolization is not known. Often the diagnosis is missed because of the time between intervention and clinical findings and because the organs involved can be many and various. The most common clinical manifestations are acute renal failure and hypereosinophilia. The prognosis is poor and the mortality high because of the progression of renal failure. In this case report we present the clinical history of a 62-year-old male patient with a history of cigarette smoking and hypertension who was submitted to emergency surgery following the acute dissection of a type A aortic aneurysm. About 2 weeks after surgical intervention the patient developed a multiorgan disorder (gastroenteric, neuromuscular and renal involvement) associated with hypereosinophilia and with increased levels of the markers of inflammation. The symptoms were transient and probably due to embolization of cholesterol crystals; no specific therapy was administered. On the other hand, no therapeutic regimen has been codified to date. The best clinical approach is prophylactic, that means identifying those patients who are at high risk for an invasive vascular procedure.

Vitamin E potentiates the antiplatelet activity of aspirin in collagen-stimulated platelets.

BACKGROUND AND OBJECTIVES: The combination of vitamin E with aspirin is becoming an attractive therapeutic approach to prevent thrombotic vascular accidents. In this study we investigated the capacity of vitamin E (50 and 100 M) to enhance the antiplatelet effect of aspirin. DESIGN AND METHODS: The dose-response curves of platelet aggregation, dense body secretion, phospholipase C activation and calcium mobilization were measured in aspirin-treated platelets with and without added vitamin E (50 and 100 M). The role of vitamin E in reducing platelet adhesion to collagen was also studied. RESULTS: We demonstrated that, in platelets incubated with 100 M vitamin E, collagen-concentration ( g/mL) able to induce 50% of the maximal platelet aggregation and of the calcium mobilization was higher than in controls (11.6 versus 3.8 and 21.3 versus 9.8, respectively). Furthermore, 50 M vitamin E reduced platelet adhesion to collagen by about 80%. INTERPRETATION AND CONCLUSIONS: These data demonstrate that vitamin E can potentiate the antiplatelet activity of aspirin by inhibiting the early events of platelet activation pathways induced by collagen. This finding provides a rationale for combining aspirin and vitamin E to prevent thrombotic complications in atherosclerotic patients.