Yves Lecarpentier

Elevated Blood Cyanide Concentrations in Victims of Smoke Inhalation

BACKGROUND The nature of the toxic gases that cause death from smoke inhalation is not known. In addition to carbon monoxide, hydrogen cyanide may be responsible, but its role is uncertain, because blood cyanide concentrations are often measured only long after exposure. METHODS We measured cyanide concentrations in blood samples obtained at the scene of residential fires from 109 fire victims before they received any treatment. We compared the results with those in 114 persons with drug intoxication (40 subjects), carbon monoxide intoxication (29 subjects), or trauma (45 subjects). The metabolic effect of smoke inhalation was assessed by measuring plasma lactate at the time of admission to the hospital in 39 patients who did not have severe burns. RESULTS The mean (+/-SD) blood cyanide concentrations in the 66 surviving fire victims (21.6 +/- 36.4 mumol per liter, P less than 0.001) and the 43 victims who died (116.4 +/- 89.6 mumol per liter, P less than 0.001) were significantly higher than those in the 114 control subjects (5.0 +/- 5.5 mumol per liter). Among the 43 victims who died, the blood cyanide concentrations were above 40 mumol per liter in 32 (74 percent), and above 100 mumol per liter in 20 of these (46 percent). There was a significant correlation between blood cyanide and carbon monoxide concentrations in the fire victims (P less than 0.001). Plasma lactate concentrations at the time of hospital admission correlated more closely with blood cyanide concentrations than with blood carbon monoxide concentrations. Plasma lactate concentrations above 10 mmol per liter were a sensitive indicator of cyanide intoxication, as defined by the presence of a blood cyanide concentration above 40 mumol per liter. CONCLUSIONS Residential fires may cause cyanide poisoning. At the time of a patients hospital admission, an elevated plasma lactate concentration is a useful indicator of cyanide toxicity in fire victims who do not have severe burns.

Total arterial compliance estimated by stroke volume-to-aortic pulse pressure ratio in humans

On the basis of the windkessel model, the stroke volume-to-aortic pulse pressure ratio (SV/PP) has been proposed as an estimate of total arterial compliance, but recent studies have questioned this approximation. Aortic pressure was obtained at rest in 31 adults undergoing cardiac catheterization (47 +/- 14 yr): controls (n = 7), patients with dilated cardiomyopathy (n = 10), and patients with other cardiac diseases (n = 14). We calculated PP, mean aortic pressure (MAoP), heart period (T), SV (thermodilution cardiac output/heart rate), total peripheral resistance (R), total arterial compliance estimated by area method (Carea), and the time constant of aortic pressure decay in diastole (RCarea). In the overall population (n = 31), there was no significant difference between SV/PP and Carea. SV/PP was linearly related to Carea (SV/PP = 0.99Carea + 0.05; r = 0.98; P < 0.001); the slope and intercept did not differ from unity and zero, respectively. Similar results were obtained in the three subgroups. These results implied that PP/MAoP and T/RCarea were proportionally related (T/RCarea = 1.18PP/MAoP - 0.07; r = 0.96; P < 0.001). We conclude that for humans at rest 1) SV/PP gave a reliable estimate of Carea, and 2) T normalized by the time constant of aortic pressure decay in diastole was proportionally related to PP/MAoP. This last relationship could be considered an aspect of the coupling between the left ventricle and its load.On the basis of the windkessel model, the stroke volume-to-aortic pulse pressure ratio (SV/PP) has been proposed as an estimate of total arterial compliance, but recent studies have questioned this approximation. Aortic pressure was obtained at rest in 31 adults undergoing cardiac catheterization (47 ± 14 yr): controls ( n = 7), patients with dilated cardiomyopathy ( n = 10), and patients with other cardiac diseases ( n = 14). We calculated PP, mean aortic pressure (MAoP), heart period ( T), SV (thermodilution cardiac output/heart rate), total peripheral resistance ( R), total arterial compliance estimated by area method ( C area), and the time constant of aortic pressure decay in diastole ( RC area). In the overall population ( n = 31), there was no significant difference between SV/PP and C area. SV/PP was linearly related to C area (SV/PP = 0.99 C area + 0.05; r = 0.98; P < 0.001); the slope and intercept did not differ from unity and zero, respectively. Similar results were obtained in the three subgroups. These results implied that PP/MAoP and T/ RC areawere proportionally related ( T/ RC area= 1.18PP/MAoP - 0.07; r = 0.96; P < 0.001). We conclude that for humans at rest 1) SV/PP gave a reliable estimate of C area, and 2) T normalized by the time constant of aortic pressure decay in diastole was proportionally related to PP/MAoP. This last relationship could be considered an aspect of the coupling between the left ventricle and its load.

Desmosomal gene analysis in arrhythmogenic right ventricular dysplasia/cardiomyopathy: spectrum of mutations and clinical impact in practice

AIMS Five desmosomal genes have been recently implicated in arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) but the clinical impact of genetics remains poorly understood. We wanted to address the potential impact of genotyping. METHODS AND RESULTS Direct sequencing of the five genes (JUP, DSP, PKP2, DSG2, and DSC2) was performed in 135 unrelated patients with ARVD/C. We identified 41 different disease-causing mutations, including 28 novel ones, in 62 patients (46%). In addition, a genetic variant of unknown significance was identified in nine additional patients (7%). Distribution of genes was 31% (PKP2), 10% (DSG2), 4.5% (DSP), 1.5% (DSC2), and 0% (JUP). The presence of desmosomal mutations was not associated with familial context but was associated with young age, symptoms, electrical substrate, and extensive structural damage. When compared with other genes, DSG2 mutations were associated with more frequent left ventricular involvement (P = 0.006). Finally, complex genetic status with multiple mutations was identified in 4% of patients and was associated with more frequent sudden death (P = 0.047). CONCLUSION This study supports the use of genetic testing as a new diagnostic tool in ARVC/D and also suggests a prognostic impact, as the severity of the disease appears different according to the underlying gene or the presence of multiple mutations.

Major alterations in relaxation during cardiac hypertrophy induced by aortic stenosis in guinea pig.

Left ventricular hypertrophy (LVH) was produced in guinea pigs after aortic stenosis (AS). The percentage of LVH in AS was determined by normalizing left ventricular (LV) weight by the mean LV weight of sham-operated controls (n = 12). After 3 weeks of cardiac overload, a mild LVH (30 +/- 3%) was induced in 17 animals and a relatively severe LVH (56 +/- 3%) was induced in 7 animals. LV papillary muscles were rapidly excised for mechanical studies. No significant differences were observed between control and mild hypertrophy groups. In contrast, a marked decrease in myocardial performance was seen in the more severe cardiac hypertrophy group and was expressed as a percentage of sham-operated levels (Vmax, 22%; active isometric force/mm2, 23%; +dF/dt max/mm2, 26%). Relaxation in this group was still more impaired than contraction (peak lengthening velocity, 14%; -dF/dt max/mm2, 19%). Moreover, the load sensitivity of relaxation was present in both sham-operated controls and mild hypertrophy but almost disappeared in more severe hypertrophy. Isometric relaxation was delayed in the latter group, as shown by the 15% increase of the half-time of the decline of isometric relaxation (t 1/2). On the other hand, acute hypoxia (95% N2-5% CO2 for 20 minutes) also induced a fall in contractility and the disappearance of the load sensitivity of relaxation but with a 67% decrease of t 1/2. Thus, the mechanical analysis of relaxation allows the effects of chronic overload in relatively severe cardiac hypertrophy to be separated from those of acute hypoxia. Moreover, in severe cardiac hypertrophy, the impairment of the load sensitivity of relaxation with increased t 1/2 strongly suggests alterations of the sarcoplasmic reticulum, especially since the moderate decrease in the myofibrillar ATPase activity, which has been observed previously in guinea pig pressure overload, cannot account completely for the marked fall in myocardial performance.

In Vitro Effects of Propofol on Rat Myocardium

Propofol is a short-acting intravenous induction agent that induces cardiovascular depression. However, the effects of propofol on intrinsic myocardial contractility remain debatable. Thus, we studied the effects of three concentrations of propofol (1, 3, and 10 micrograms.ml-1, respectively) and its solvent on the mechanics and energetics of isolated rat left ventricular papillary muscles. Propofol and its solvent did not induce any significant inotropic effect as shown by the lack of significant changes in maximum unloaded shortening velocity and in active isometric force. Nevertheless, propofol induced a slight decrease in isometric force (92 +/- 6%, 95 +/- 5%, and 95 +/- 4%, respectively, all P less than 0.01) under certain experimental conditions (i.e., after isometric stabilization). Using various afterloaded twitches, the peak power output and the curvature of the force-velocity curve were calculated. Propofol and its solvent did not significantly modify these two energetic parameters, indicating that it did not change myothermal economy and cross-bridge kinetics. Propofol impaired isotonic relaxation, suggesting that it decreased calcium uptake by the sarcoplasmic reticulum, whereas its solvent alone did not. However, alteration of sarcoplasmic reticulum function was moderate, since postrest potentiation and postrest recovery were unmodified after propofol. It was concluded that propofol induces moderate changes on intrinsic myocardial contractility. These results suggest that cardiovascular depression observed with propofol in vivo is not related to intrinsic myocardial depression.

Interaction of Halothane with α- and β-Adrenoceptor Stimulations in Rat Myocardium

BackgroundHalothane induces negative inotropic and lusitropic effects in myocardium. It has been suggested that halothane potentiates beta-adrenoceptor stimulation. However, its effects on the inotropic response to alpha-adrenoceptor stimulation and its effects on the lusitropic effects of alpha- an

Myosin molecular motor dysfunction in dystrophic mouse diaphragm.

Cross-bridge properties and myosin heavy chain (MHC) composition were investigated in isolated diaphragm from 6-mo-old control ( n = 12) and mdx( n = 12) mice. Compared with control, peak tetanic tension fell by 50% in mdx mice ( P < 0.001). The total number of cross bridges per square millimeter (×109), the elementary force per cross bridge, and the peak mechanical efficiency were lower in mdx than in control mice (each P < 0.001). The duration of the cycle and the rate constant for cross-bridge detachment were significantly lower in mdx than in control mice. In the overall population, there was a linear relationship between peak tetanic tension and either total number of cross bridges per square millimeter or elementary force per cross bridge ( r = 0.996 and r = 0.667, respectively, each P < 0.001). The mdx mice presented a higher proportion of type IIA MHC ( P < 0.001) than control mice and a reduction in type IIX MHC ( P < 0.001) and slow myosin isoforms ( P < 0.01) compared with control mice. We concluded that, in mdx mice, impaired diaphragm strength was associated with qualitative and quantitative changes in myosin molecular motors. It is proposed that reduced force generated per cross bridge contributed to diaphragm weakness in mdx mice.Cross-bridge properties and myosin heavy chain (MHC) composition were investigated in isolated diaphragm from 6-mo-old control (n = 12) and mdx (n = 12) mice. Compared with control, peak tetanic tension fell by 50% in mdx mice (P < 0.001). The total number of cross bridges per square millimeter (x10(9)), the elementary force per cross bridge, and the peak mechanical efficiency were lower in mdx than in control mice (each P < 0.001). The duration of the cycle and the rate constant for cross-bridge detachment were significantly lower in mdx than in control mice. In the overall population, there was a linear relationship between peak tetanic tension and either total number of cross bridges per square millimeter or elementary force per cross bridge (r = 0.996 and r = 0.667, respectively, each P < 0.001). The mdx mice presented a higher proportion of type IIA MHC (P < 0.001) than control mice and a reduction in type IIX MHC (P < 0.001) and slow myosin isoforms (P < 0.01) compared with control mice. We concluded that, in mdx mice, impaired diaphragm strength was associated with qualitative and quantitative changes in myosin molecular motors. It is proposed that reduced force generated per cross bridge contributed to diaphragm weakness in mdx mice.

Decreased regional blood flow in patients with acromegaly

One‐third of acromegalic patients have hypertension. Acromegaly is also associated with intrinsic cardiac abnormalities known collectively as a hyperkinetic heart syndrome, which is characterized by an increased cardiac index and decreased systemic vascular resistance. As a result, blood flow should be increased in the regional vascular beds of acromegalic patients. The aim of the study was to measure, using direct methods, blood flow and vascular resistance at the level of the brachial artery in acromegalic patients with a confirmed hyperkinetic heart syndrome.

Circadian rhythms, Wnt/beta-catenin pathway and PPAR alpha/gamma profiles in diseases with primary or secondary cardiac dysfunction.

Circadian clock mechanisms are far-from-equilibrium dissipative structures. Peroxisome proliferator-activated receptors (PPAR alpha, beta/delta, and gamma) play a key role in metabolic regulatory processes, particularly in heart muscle. Links between circadian rhythms (CRs) and PPARs have been established. Mammalian CRs involve at least two critical transcription factors, CLOCK and BMAL1 (Gekakis et al., 1998; Hogenesch et al., 1998). PPAR gamma plays a major role in both glucose and lipid metabolisms and presents circadian properties which coordinate the interplay between metabolism and CRs. PPAR gamma is a major component of the vascular clock. Vascular PPAR gamma is a peripheral regulator of cardiovascular rhythms controlling circadian variations in blood pressure and heart rate through BMAL1. We focused our review on diseases with abnormalities of CRs and with primary or secondary cardiac dysfunction. Moreover, these diseases presented changes in the Wnt/beta-catenin pathway and PPARs, according to two opposed profiles. Profile 1 was defined as follows: inactivation of the Wnt/beta-catenin pathway with increased expression of PPAR gamma. Profile 2 was defined as follows: activation of the Wnt/beta-catenin pathway with decreased expression of PPAR gamma. A typical profile 1 disease is arrhythmogenic right ventricular cardiomyopathy, a genetic cardiac disease which presents mutations of the desmosomal proteins and is mainly characterized by fatty acid accumulation in adult cardiomyocytes mainly in the right ventricle. The link between PPAR gamma dysfunction and desmosomal genetic mutations occurs via inactivation of the Wnt/beta-catenin pathway presenting oscillatory properties. A typical profile 2 disease is type 2 diabetes, with activation of the Wnt/beta-catenin pathway and decreased expression of PPAR gamma. CRs abnormalities are present in numerous pathologies such as cardiovascular diseases, sympathetic/parasympathetic dysfunction, hypertension, diabetes, neurodegenerative diseases, cancer which are often closely inter-related.

Use of arginine–glycine–aspartic acid adhesion peptides coupled with a new collagen scaffold to engineer a myocardium-like tissue graft

Background Cardiac tissue engineering might be useful in treatment of diseased myocardium or cardiac malformations. The creation of functional, biocompatible contractile tissues, however, remains challenging. We hypothesized that coupling of arginine–glycine–aspartic acid–serine (RGD+) adhesion peptides would improve cardiomyocyte viability and differentiation and contractile performance of collagen-cell scaffolds.Methods Clinically approved collagen scaffolds were functionalized with RGD+ cells and seeded with cardiomyocytes. Contractile performance, cardiomyocyte viability and differentiation were analyzed at days 1 and 8 and/or after culture for 1 month.Results The method used for the RGD+ cell–collagen scaffold coupling enabled the following features: high coupling yields and complete washout of excess reagent and by-products with no need for chromatography; spectroscopic quantification of RGD+ coupling; a spacer arm of 36Å, a length reported as optimal for RGD+-peptide presentation and favorable for integrin-receptor clustering and subsequent activation. Isotonic and isometric mechanical parameters, either spontaneous or electrostimulated, exhibited good performance in RGD+ constructs. Cell number and viability was increased in RGD+ scaffolds, and we saw good organization of cell contractile apparatus with occurrence of cross-striation.Conclusions We report a novel method of engineering a highly effective collagen-cell scaffold based on RGD+ peptides cross-linked to a clinically approved collagen matrix. The main advantages were cell contractile performance, cardiomyocyte viability and differentiation.