Gut barrier-microbiota imbalances in early life lead to higher sensitivity to inflammation in a murine model of C-section delivery.

BACKGROUND: Most interactions between the host and its microbiota occur at the gut barrier, and primary colonizers are essential in the gut barrier maturation in the early life. The mother-offspring transmission of microorganisms is the most important factor influencing microbial colonization in mammals, and C-section delivery (CSD) is an important disruptive factor of this transfer. Recently, the deregulation of symbiotic host-microbe interactions in early life has been shown to alter the maturation of the immune system, predisposing the host to gut barrier dysfunction and inflammation. The main goal of this study is to decipher the role of the early-life gut microbiota-barrier alterations and its links with later-life risks of intestinal inflammation in a murine model of CSD. RESULTS: The higher sensitivity to chemically induced inflammation in CSD mice is related to excessive exposure to a too diverse microbiota too early in life. This early microbial stimulus has short-term consequences on the host homeostasis. It switches the pup's immune response to an inflammatory context and alters the epithelium structure and the mucus-producing cells, disrupting gut homeostasis. This presence of a too diverse microbiota in the very early life involves a disproportionate short-chain fatty acids ratio and an excessive antigen exposure across the vulnerable gut barrier in the first days of life, before the gut closure. Besides, as shown by microbiota transfer experiments, the microbiota is causal in the high sensitivity of CSD mice to chemical-induced colitis and in most of the phenotypical parameters found altered in early life. Finally, supplementation with lactobacilli, the main bacterial group impacted by CSD in mice, reverts the higher sensitivity to inflammation in ex-germ-free mice colonized by CSD pups' microbiota. CONCLUSIONS: Early-life gut microbiota-host crosstalk alterations related to CSD could be the linchpin behind the phenotypic effects that lead to increased susceptibility to an induced inflammation later in life in mice. Video Abstract.

Usefulness of distinct activity thresholds according to baseline regional asynergy for predicting functional recovery in patients with chronic coronary artery disease and left ventricular dysfunction: a study with nitrate-enhanced sestamibi gated SPECT.

BACKGROUND: The role of gated single photon emission computed tomography (SPECT) in improving viability detection with the use of perfusion imaging is uncertain. This study aimed to verify whether the classification of baseline regional dysfunction with gated SPECT helps to predict functional recovery with the use of quantitative perfusion imaging. METHODS AND RESULTS: Resting nitrate-enhanced sestamibi gated SPECT was performed in 31 patients with left ventricular dysfunction, who later underwent coronary revascularization. With the use of a 16-segment model, tracer activity was quantified, and wall motion and thickening were estimated with a 4-point scoring scheme. Reversible dysfunction was assessed with follow-up gated SPECT. According to receiver operating characteristic curve analysis, the best overall cutoff for predicting reversible dysfunction in asynergic segments was 50% of peak activity or greater, with 83% sensitivity, 54% specificity, and 64% accuracy. When the segments were divided according to wall motion in resting gated SPECT, the optimal activity cutoff was greater than 68% for hypokinetic and 50% or greater for adyskinetic segments. With the use of 2 thresholds, the overall sensitivity remained good (76%), whereas specificity increased to 73% (P <.0005) and accuracy to 74% (P <.02). CONCLUSIONS: Regional dysfunction assessment directly on perfusion images permits use of different activity thresholds with an improvement over a single cutoff for all asynergic segments. Therefore combining perfusion and functional data with nitrate-enhanced gated SPECT at rest appears to be a promising approach for viability detection.

[The initial experience of the use of ReoPro in high-risk coronary angioplasty in Italy: the Italian Registry on the Conditions for the Use of ReoPro during Angioplasty (R.I.CO.R.D.A.)]. / Esperienza iniziale sull'impiego di ReoPro nell'angioplastica coronarica ad alto rischio in Italia: Registro Italiano sulle Condizioni d'Uso di ReoPro durante Angioplastica (R.I.CO.R.D.A.).

BACKGROUND: The R.I.CO.R.D.A. Registry was created with the aim of monitoring early Italian experience on the use of abciximab (ReoPro) in the setting of high-risk coronary angioplasty (PTCA). Indication for enrollment included abciximab administration either on an elective basis (i.e. preprocedural or planned) or as bailout for complicated PTCA (i.e. intraprocedural, as a rescue treatment). METHODS: From June 1996 to January 1998, 359 patients undergoing PTCA on 443 lesions were enrolled in 24 Italian catheterization laboratories. In 91/359 patients (25%) abciximab was administered as bailout, and in the remaining cases on an elective basis as a pre-PTCA treatment. RESULTS: The incidence of death, coronary artery bypass grafting, Q wave and large non-Q wave myocardial infarction, small non-Q wave myocardial infarction and recurrent ischemia in the elective group were 1.9, 1.9, 2.6, 6.7 and 3.4%, respectively. In the bailout group corresponding figures were 4.4 (p = NS), 3.3 (p = NS), 16.5 (p < 0.01), 16.5 (p < 0.01) and 12.1% (p < 0.01), respectively. The heparin dose during PTCA was quite variable, particularly in the very early stages. Overall, 46% of patients received a heparin dose of < or = 5000 IU, and the remaining a higher dose, more often 10,000 IU. The latter group showed a significantly higher incidence of bleeding complications (25 vs 10%, p < 0.01). The incidence of bleeding was almost double in patients treated with bailout abciximab as compared with the elective group (29 vs 15%, p < 0.01), according to the higher heparin dose administered (9253 +/- 3341 vs 6649 +/- 3156 IU, p < 0.01). Overall, the incidence of red blood cell transfusions was 5.8%. CONCLUSIONS: The results of this Registry shed light on the actual use of abciximab in the setting of high-risk PTCA in Italy. The incidence of cardiac events and bleeding complications in the group of patients treated on an elective basis is comparable to that reported in the main large-scale international trials. The bailout abciximab group showed a higher incidence of both cardiac events and bleeding complications.

[Clinical use of glycoprotein IIb/IIIa inhibitors]. / Impiego clinico degli inibitori della glicoproteina IIb/IIIa.

Glycoprotein IIb/IIIa inhibitors are a new class of very powerful antiplatelet agents that act by inhibiting fibrinogen interplatelet bridges. Abciximab, tirofiban, lamifiban, and integrelin, all intravenous formulations, have been evaluated in phase II and phase III clinical trials. Although there seem to be relevant differences among drugs, their efficacy in treating acute ischemic syndromes and preventing acute complications of coronary angioplasty has been demonstrated. The major side effect has been an increase in bleeding complications. Future studies will be aimed at optimizing results and improving safety through more accurate assessment of optimal dosage and duration of infusion.

Comparative effects of enalapril and verapamil on myocardial blood flow in systemic hypertension.

BACKGROUND: The comparative effects of calcium channel blockers and ACE inhibitors on myocardial blood flow (MBF) in hypertensive patients after long-term treatment are still unknown. METHODS AND RESULTS: Twenty hypertensive subjects with normal coronary arteries were randomly assigned to verapamil 240 to 480 mg/d or enalapril 10 to 40 mg/d. MBF was quantified at rest, during pacing tachycardia, and after dipyridamole by positron emission tomography and 13N-ammonia before and 6 months after treatment after 1 week of pharmacological washout. In both groups, blood pressure and heart rate during flow measurements were not different before and after therapy. Before treatment, mean MBF at rest, during pacing tachycardia, and after dipyridamole infusion was similar in the two groups; however, pacing and dipyridamole flows were significantly lower than those obtained in a control group of normotensive subjects. After treatment, in the enalapril-treated patients, MBF did not change in the three study conditions. In the verapamil-treated patients, MBF did not change at rest and significantly increased during pacing and after dipyridamole. The inhomogeneity of regional MBF distribution, evaluated from the coefficient of variation, decreased at rest after both treatments and, in the enalapril group, also during pacing. No relation was found between changes in MBF and changes in left ventricular mass. CONCLUSIONS: In arterial hypertension, MBF during pacing tachycardia and after dipyridamole is impaired. Successful therapy with verapamil increases MBF response to these stimuli, independent of changes in perfusion pressure and left ventricular mass. These results suggest that verapamil directly improves coronary microcirculatory function in hypertension. Enalapril does not significantly change MBF but reduces the inhomogeneity of regional flow distribution.

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.