Antonio Abbate

High dose dipyridamole echocardiography test in effort angina pectoris

The dipyridamole echocardiography test (intravenous dipyridamole with two-dimensional echocardiographic monitoring) was performed in 93 patients with effort chest pain and in 10 control subjects. The test was considered positive when regional asynergy appeared after dipyridamole administration. When negative at the low dose (0.56 mg/kg body weight in 4 minutes), the test was repeated on a different day with a higher dose (0.84 mg/kg in 10 minutes). All 93 patients underwent coronary arteriography; 72 of them had significant (greater than 70% luminal reduction) coronary artery disease. Thirty-eight of the 93 patients had a positive low dose dipyridamole echocardiography test; 15 other patients with a negative low dose test had a positive high dose test. All 53 patients with a positive test had significant coronary artery disease; 12 of them had a negative exercise stress test. In relation to the presence of coronary artery disease, the dipyridamole echocardiography test had an overall specificity higher than that of the exercise stress test (100 versus 71%) and a similar overall sensitivity (74 versus 69%). The dipyridamole echocardiography test is feasible in all patients with a good baseline echocardiogram. It detects the site of apparent ischemia more precisely than does an exercise stress test, and can unmask electrocardiographically silent ischemia. If performed in patients with a negative low dose dipyridamole echocardiography test, the high dose test adds sensitivity (probably by achieving maximal dilation in patients in whom the low dose is only partially effective), without any loss in specificity and with no apparent increase in risk.

Low-T3 Syndrome A Strong Prognostic Predictor of Death in Patients With Heart Disease

Background—Clinical and experimental data have suggested a potential negative impact of low-T3 state on the prognosis of cardiac diseases. The aim of the present prospective study was to assess the role of thyroid hormones in the prognosis of patient population with heart disease. Methods and Results—A total of 573 consecutive cardiac patients underwent thyroid function profile evaluation. They were divided in two subgroups: group I, 173 patients with low T3, ie, with free T3 (fT3) <3.1 pmol/L, and group II, 400 patients with normal fT3 (≥3.1 pmol/L). We considered cumulative and cardiac death events. During the 1-year follow-up, there were 25 cumulative deaths in group I and 12 in group II (14.4% versus 3%, P <0.0001); cardiac deaths were 13 in group I and 6 in group II (7.5% versus 1.5%, P =0.0006). According to the Cox model, fT3 was the most important predictor of cumulative death (hazard ratio [HR] 3.582, P <0.0001), followed by dyslipidemia (HR 2.955, P =0.023), age (HR 1.051, P <0.005), and left ventricular ejection fraction (HR 1.037, P =0.006). At the logistic multivariate analysis, fT3 was the highest independent predictor of death (HR 0.395, P =0.003). A prevalence of low fT3 levels was found in patients with NYHA class III-IV illness compared with patients with NYHA class I-II (&khgr;2 5.65, P =0.019). Conclusions—Low-T3 syndrome is a strong predictor of death in cardiac patients and might be directly implicated in the poor prognosis of cardiac patients.

The inflammasome promotes adverse cardiac remodeling following acute myocardial infarction in the mouse

Acute myocardial infarction (AMI) initiates an intense inflammatory response that promotes cardiac dysfunction, cell death, and ventricular remodeling. The molecular events underlying this inflammatory response, however, are incompletely understood. In experimental models of sterile inflammation, ATP released from dying cells triggers, through activation of the purinergic P2X7 receptor, the formation of the inflammasome, a multiprotein complex necessary for caspase-1 activation and amplification of the inflammatory response. Here we describe the presence of the inflammasome in the heart in an experimental mouse model of AMI as evidenced by increased caspase-1 activity and cytoplasmic aggregates of the three components of the inflammasome—apoptosis speck-like protein containing a caspase-recruitment domain (ASC), cryopyrin, and caspase-1, localized to the granulation tissue and cardiomyocytes bordering the infarct. Cultured adult murine cardiomyocytes also showed the inducible formation of the inflammasome associated with increased cell death. P2X7 and cryopyrin inhibition (using silencing RNA or a pharmacologic inhibitor) prevented the formation of the inflammasome and limited infarct size and cardiac enlargement after AMI. The formation of the inflammasome in the mouse heart during AMI causes additional loss of functional myocardium, leading to heart failure. Modulation of the inflammasome may therefore represent a unique therapeutic strategy to limit cell death and prevent heart failure after AMI.

Atherothrombosis, inflammation, and diabetes

Diabetes represents a major cause of cardiovascular morbidity and mortality in developed countries, and atherothrombosis accounts for most deaths among diabetics. Recent evidence has reliably shown the relevant etiopathogenetic role of inflammation in atherothrombotic disease. This review summarizes and discusses the possible synergistic effects of diabetes and inflammation in promoting atherothrombosis and its complications, as well as potential avenues for diagnostic, preventive, and therapeutic benefits in the modulation of inflammatory mechanisms in diabetic atherothrombotic disease.

Anakinra, a Recombinant Human Interleukin-1 Receptor Antagonist, Inhibits Apoptosis in Experimental Acute Myocardial Infarction

Background— Experimental interleukin-1 receptor antagonist gene overexpression has shown that interleukin-1 receptor antagonist is cardioprotective during global cardiac ischemia. The aim of the present study was to test the impact of an exogenous recombinant human interleukin-1 receptor antagonist (anakinra) in experimental acute myocardial infarction. Methods and Results— Two animal studies were conducted: one of immediate anakinra administration during ischemia in the mouse and one of delayed anakinra administration 24 hours after ischemia in the rat. Seventy-eight Institute of Cancer Research mice and 20 Wistar rats underwent surgical coronary artery ligation (or sham operation) and were treated with either anakinra 1 mg/kg or NaCl 0.9% (saline). Treatment was administered during surgery and then daily for 6 doses in the mice and starting on day 2 daily for 5 doses in the rats. Twenty-eight mice underwent infarct size assessment 24 hours after surgery, 6 saline-treated mice and 22 mice treated with increasing doses of anakinra (1 mg/kg [n=6], 10 mg/kg [n=6], and 100 mg/kg [n=10]); 6 mice were euthanized at 7 days for protein expression analysis. The remaining animals underwent transthoracic echocardiography before surgery and 7 days later just before death. Cardiomyocyte apoptosis was measured in the peri-infarct regions. The antiapoptotic effect of anakinra was tested in a primary rat cardiomyocyte culture during simulated ischemia and in vitro on caspase-1 and -9 activities. At 7 days, 15 of the 16 mice (94%) treated with anakinra were alive versus 11 of the 20 mice (55%) treated with saline (P=0.013). No differences in infarct size at 24 hours compared with saline were observed with the 1- and 10-mg/kg doses, whereas a 13% reduction in infarct size was found with the 100-mg/kg dose (P=0.015). Treatment with anakinra was associated with a significant reduction in cardiomyocyte apoptosis in both the immediate and delayed treatment groups (3.1±0.2% versus 0.5±0.3% [P<0.001] and 4.2±0.4% versus 1.1±0.2% [P<0.001], respectively). Compared with saline-treated animals, anakinra-treated mice and rats showed signs of more favorable ventricular remodeling. In vitro, anakinra significantly prevented apoptosis induced by simulated ischemia and inhibited caspase-1 and -9 activities. Conclusions— Administration of anakinra within 24 hours of acute myocardial infarction significantly ameliorates the remodeling process by inhibiting cardiomyocyte apoptosis in 2 different experimental animal models of AMI. This may open the door for using anakinra to prevent postischemic cardiac remodeling and heart failure.

Interleukin-1 Blockade With Anakinra to Prevent Adverse Cardiac Remodeling After Acute Myocardial Infarction (Virginia Commonwealth University Anakinra Remodeling Trial [VCU-ART] Pilot Study)

Acute myocardial infarction (AMI) initiates an intense inflammatory response in which interleukin-1 (IL-1) plays a central role. The IL-1 receptor antagonist is a naturally occurring antagonist, and anakinra is the recombinant form used to treat inflammatory diseases. The aim of the present pilot study was to test the safety and effects of IL-1 blockade with anakinra on left ventricular (LV) remodeling after AMI. Ten patients with ST-segment elevation AMI were randomized to either anakinra 100 mg/day subcutaneously for 14 days or placebo in a double-blind fashion. Two cardiac magnetic resonance (CMR) imaging and echocardiographic studies were performed during a 10- to 14-week period. The primary end point was the difference in the interval change in the LV end-systolic volume index (LVESVi) between the 2 groups on CMR imaging. The secondary end points included differences in the interval changes in the LV end-diastolic volume index, and C-reactive protein levels. A +2.0 ml/m(2) median increase (interquartile range +1.0, +11.5) in the LVESVi on CMR imaging was seen in the placebo group and a -3.2 ml/m(2) median decrease (interquartile range -4.5, -1.6) was seen in the anakinra group (p = 0.033). The median difference was 5.2 ml/m(2). On echocardiography, the median difference in the LVESVi change was 13.4 ml/m(2) (p = 0.006). Similar differences were observed in the LV end-diastolic volume index on CMR imaging (7.6 ml/m(2), p = 0.033) and echocardiography (9.4 ml/m(2), p = 0.008). The change in C-reactive protein levels between admission and 72 hours after admission correlated with the change in the LVESVi (R = +0.71, p = 0.022). In conclusion, in the present pilot study of patients with ST-segment elevation AMI, IL-1 blockade with anakinra was safe and favorably affected by LV remodeling. If confirmed in larger trials, IL-1 blockade might represent a novel therapeutic strategy to prevent heart failure after AMI.

Myocardial Blood Flow Response to Pacing Tachycardia and to Dipyridamole Infusion in Patients With Dilated Cardiomyopathy Without Overt Heart Failure A Quantitative Assessment by Positron Emission Tomography

BACKGROUND Myocardial blood flow (MBF) impairment has been documented in advanced dilated cardiomyopathy (DCM) in which hemodynamic factors, secondary to severe ventricular dysfunction, may limit myocardial perfusion. To assess whether MBF impairment in DCM may also be present independent of hemodynamic factors, the present study was designed to quantify myocardial perfusion in patients with mild disease without overt heart failure. METHODS AND RESULTS Absolute regional MBF (milliliters per minute per gram) was measured by positron emission tomography and 13N-ammonia in resting conditions, during pacing-induced tachycardia, and after dipyridamole infusion (0.56 mg/kg over 4 minutes) in 22 DCM patients and in 13 healthy subjects. Patients were in New York Heart Association functional class I-II and showed depressed left ventricular (LV) ejection fraction by radionuclide angiography (35 +/- 8%; range, 21% to 48%), normal coronary angiography, and normal or moderately increased LV end-diastolic pressure (9.2 +/- 5.5 mm Hg; range, 2 to 20 mm Hg). There were no differences in arterial blood pressure, heart rate, and rate-pressure product between patients and control subjects in the three study conditions. Compared with control subjects, DCM patients had lower mean MBF at rest (0.80 +/- 0.25 versus 1.08 +/- 0.20 mL.min-1.g-1, P < .01), during atrial pacing tachycardia (1.21 +/- 0.59 versus 2.03 +/- 0.64 mL.min-1.g-1, P < .01), and after dipyridamole infusion (1.91 +/- 0.76 versus 3.78 +/- 0.86 mL.min-1.g-1, P < .01). LV MBF values were related to baseline LV end-diastolic pressure at rest (r = -.57, P < .01) and during pacing (r = -.67, P < .01) but not after dipyridamole infusion (r = .19, P = .40). Five patients had LV end-diastolic pressure > 12 mm Hg; in 4, myocardial perfusion was severely depressed both at baseline and in response to stress. CONCLUSIONS In patients with DCM without overt heart failure, myocardial perfusion is impaired both at rest and in response to vasodilating stimuli. The abnormalities in vasodilating capability can be present despite normal hemodynamics; progression of the disease is associated with more depressed myocardial perfusion.

Adrenergic Receptor Blockade Reverses Right Heart Remodeling and Dysfunction in Pulmonary Hypertensive Rats

RATIONALE Most patients with pulmonary arterial hypertension (PAH) die from right heart failure. Beta-adrenergic receptor blockade reduces mortality by about 30% in patients with left-sided systolic heart failure, but is not used in PAH. OBJECTIVES To assess the effect of the adrenergic receptor blocker carvedilol on the pulmonary circulation and right heart in experimental pulmonary hypertension in rats. METHODS Angioproliferative pulmonary hypertension was induced in rats by combined exposure to the vascular endothelial growth factor-receptor antagonist SU5416 and hypoxia. Carvedilol treatment was started after establishment of pulmonary hypertension and right heart dysfunction. MEASUREMENTS AND MAIN RESULTS Compared with vehicle-treated animals, treatment with carvedilol resulted in increased exercise endurance; improved right ventricular (RV) function (increased tricuspid annular plane systolic excursion and decreased RV dilatation); and an increased cardiac output. The morphology of the pulmonary vessels and the RV afterload were not affected by carvedilol. Carvedilol treatment was associated with enhancement of RV fetal gene reactivation, increased protein kinase G (PKG) activity, and a reduction in capillary rarefaction and fibrosis. Metoprolol had similar but less pronounced effects in the SU5416 and hypoxia model. Cardioprotective effects were noted of both carvedilol and metoprolol in the monocrotaline model. In the case of carvedilol, but not metoprolol, part of these effects resulted from a prevention of monocrotaline-induced lung remodeling. CONCLUSIONS Adrenergic receptor blockade reverses RV remodeling and improves RV function in experimental pulmonary hypertension. Beta-adrenergic receptor blockers are not recommended in humans with PAH before their safety and efficacy are assessed in well-designed clinical trials.

A collaborative systematic review and meta-analysis on 1278 patients undergoing percutaneous drug-eluting stenting for unprotected left main coronary artery disease ☆

BACKGROUND Cardiac surgery is the standard treatment for unprotected left main disease (ULM). Drug-eluting stent (DES) implantation has been recently reported in patients with ULM but with unclear results. We systematically reviewed outcomes of percutaneous DES implantation in ULM. METHODS Several databases were searched for clinical studies reporting on > or = 20 patients and > or = 6-month follow-up. The primary end point was major adverse cardiovascular events (MACEs; ie, death, myocardial infarction, or target vessel revascularization [TVR]) at the longest follow-up. Incidence and adjusted risk estimates were pooled with generic inverse variance random-effect methods (95% CIs). RESULTS From 823 initial citations, 16 studies were included (1278 patients, median follow-up 10 months). Eight were uncontrolled registries, 5 nonrandomized comparisons between DES and bare-metal stents and 3 nonrandomized comparisons between DES and CABG, with no properly randomized trial. Meta-analysis for DES-based PCI showed, at the longest follow-up, rates of 16.5% (11.7%-21.3%) MACE, 5.5% (3.4%-7.7%) death, and 6.5% (3.7%-9.2%) TVR. Comparison of DES versus bare-metal stent disclosed adjusted odds ratios for MACE of 0.34 (0.16-0.71), and DES versus CABG showed adjusted odds ratios for MACE plus stroke of 0.46 (0.24-0.90). Meta-regression showed that disease location predicted MACE (P = .001) and TVR (P = .020), whereas high-risk features predicted death (P = .027). CONCLUSIONS Clinical studies report apparently favorable early and midterm results in selected patients with ULM. However, given their limitations in validity and the inherent risk for DES thrombosis, results from randomized trials are still needed to definitely establish the role of DES implantation instead of the reference treatment, surgery.

Pathobiology of pulmonary arterial hypertension and right ventricular failure

Pulmonary arterial hypertension (PAH) is no longer an orphan disease. There are three different classes of drugs for the treatment of PAH that are currently being used and an increasing number of patients are being treated with a single drug or combination therapy. During the last 25 yrs, new insights into the pathobiology of PAH have been gained. The classical mechanical concepts of pressure, flow, shear stress, right ventricle wall stress and impedance have been complemented with the new concepts of cell injury and repair and interactions of complex multicellular systems. Integrating these concepts will become critical as we design new medical therapies in order to change the prognosis of patients with these fatal diseases. This review intends to summarise recent pathobiological concepts of PAH and right ventricle failure mainly derived from human studies, which reflect the progress made in the understanding of this complex group of pulmonary vascular diseases.