Jean-Marie Moalic

On-Pump, Beating-Heart Coronary Artery Operations in High-Risk Patients: An Acceptable Trade-off?

BACKGROUND Current cardioplegic techniques do not consistently avoid myocardial ischemic damage in high-risk patients undergoing coronary artery bypass grafting. Alternatively, revascularization without cardiopulmonary bypass is not always technically feasible. We investigated whether an intermediary approach based on maintenance of a beating heart with cardiopulmonary bypass support but without aortic cross-clamping might be an acceptable trade-off. METHODS Thirty-seven consecutive patients underwent coronary artery bypass grafting (with an average of two grafts per patient) in a pump-supported, non-cross-clamped beating heart. Inclusion criteria were poor left ventricular function (18 patients; mean ejection fraction, 0.25), evolving myocardial ischemia or infarction (11 patients, 5 of whom were in cardiogenic shock), and advanced age (3 patients; mean age 79.5 years) with comorbidities. Results were assessed primarily on the basis of clinical outcome. In addition, measurements of plasma levels of markers of myocardial damage (troponin Ic) and systemic inflammation (interleukin-6, interleukin-10, elastase) were done in 9 patients before and after bypass. In 6 patients, right atrial biopsy specimens were taken before and after bypass and processed by Northern blotting for the expression of messenger ribonucleic acid coding for the cardioprotective heat-shock protein 70. These biologic data were compared with those from control patients who underwent warm cardioplegic arrest within the same time span. RESULTS There was one cardiac-related death (2.7%), one Q-wave myocardial infarction, and no strokes. Four other deaths occurred from noncardiac causes, yielding an overall mortality rate of 13.5%. Limitation of myocardial injury was demonstrated by the minimal increase in postoperative troponin Ic levels (3.3 +/- 1.0 micrograms/L versus 6.6 +/- 1.5 micrograms/L in controls; p < 0.05) and the finding that heat-shock protein 70 messenger ribonucleic acid levels (expressed as a percentage of an internal standard) were significantly increased after bypass compared with pre-bypass values (279% +/- 80% versus 97% +/- 21%; p < 0.05). In the control group (cardioplegia), end-arrest values of heat-shock protein 70 messenger ribonucleic acid were not significantly changed from baseline (148% +/- 49% versus 91% +/- 29%), a finding suggesting a defective adaptive response to surgical stress. Conversely, peak levels of inflammatory mediators were not significantly different between the two groups. The eight grafts to the left anterior descending coronary artery that were assessed angiographically, by transthoracic Doppler echocardiography, or both methods were patent with satisfactory anastomoses. CONCLUSIONS In select high-risk patients, on-pump, beating-heart coronary artery bypass grafting may be an acceptable trade-off between conventional cardioplegia and off-pump operations. It is still associated with the potentially detrimental effects of cardiopulmonary bypass but eliminates intraoperative global myocardial ischemia.

Genetics of dopamine receptors and drug addiction.

Dopamine plays a key role in reward behavior, yet the association of drug dependence as a chronic, relapsing disorder with the genes encoding the various dopaminergic receptor subtypes remains difficult to delineate. In the context of subsequent genome-wide association (GWAS) research and post-GWAS investigations, we summarize the novel data that link genes encoding molecules involved in the dopaminergic system (dopamine receptors, transporter and enzymes in charge of its metabolism) to drug addiction. Recent reports indicate that the heritability of drug addiction should be high enough to allow a significant role for a specific set of genes, and the available genetic studies, which might not be already conclusive because of the heterogeneity of designs, methods and recruited samples, should support the idea of a significant role of at least one gene related to dopaminergic system. Evolutionary changes in primates and non-primate animals of genes coding for molecules involved in dopaminergic system highlight why addictive disorders are mainly limited to humans. Restricting the analyses to more specific intermediate phenotypes (or endophenotypes) such as attention allocation, stress reactivity, novelty seeking, behavioral disinhibition and impulsivity, instead of the broad addictive disorder concept can be instrumental to identify novel genes associated with these traits in the context of genome-wide studies.

Molecular and cellular biology of the senescent hypertrophied and failing heart

During aging, experimental studies have revealed various cellular changes, principal among which is myocyte hypertrophy, which compensates for the loss of myocytes and is associated with fibrosis. The expression of alpha-myosin heavy chain is replaced by that of the isogene beta-myosin, which leads to decreased myosin adenosine triphosphatase (ATPase) activity. In consequence, contraction is slower and more energetically economical. The Ca(2+)-ATPase of the sarcoplasmic reticulum and Na+/Ca2+ exchange activity are decreased, which probably explains the reduced velocity of relaxation. Membrane receptors are also modified, since the density of both the total beta-adrenergic and muscarinic receptors is decreased. The senescent heart is able to hypertrophy in response to overload and to adapt to the new requirements. Similar alterations are observed both in the senescent heart and in the overloaded heart, in clinical as well as in experimental studies; however, differences do exist, especially in terms of fibrosis and arrhythmias.

Coronary flow as a determinant of c-myc and c-fos proto-oncogene expression in an isolated adult rat heart

Chronic cardiac overload induces quantitative and qualitative changes of the phenotype which finally adapt the myocardium to its new functional requirements (Swynghedauw, 1986). It has been proposed that both stretch and enhanced isometric tension could trigger these modifications (Peterson and Lesch, 1972), but until now no real messenger has been found. In a search for signals which may account for these changes, we decided to investigate the expression of two proto-oncogenes, c-fos and c-myc, coding for nuclear proteins (review in Adamson, 1987) because several of their properties are consistent with their possessing a role in the transduction of extracellular growth signals to the cell interior. We report here that, in adult rat heart, expression of the c-fos and c-myc proto-oncogene was both sequentially and transitorily increased when, in a beating heart but not in an arrested heart, the coronary flow (and/or pressure) was augmented. This was studied in an isolated, coronary perfused heart preparation, a model in which the initial conditions of a cardiac overload may be mimicked in such a way that protein synthesis is stimulated by increasing the coronary perfusion pressure (Kira et al., 1984).

Is the senescent heart overloaded and already failing

SummaryHeart failure mainly occurs during the last decades of life, and it is important to know if the senescent heart is not an already failing heart. During aging, both contraction and relaxation of papillary muscle are impaired. Such an impairment is compensated in vivo and the cardiac output remains normal. In spite of a loss in myocytes, the heart weight/body weight ratio is unchanged, but the myocytes are bigger. Arrhythmias are permanent and are accompanied by a loss of the normal heart rate variability. Changes in specific mRNAs include: a shift in myosin heavy chain (MHC) isogene expression leading to an increased βMHC content; decreased densities of Ca2+ ATPase of the sarcoplasmic reticulum, β1-adrenergic receptor, and muscarinic receptors; and attenuation of the Na+/Ca2+ exchange activity. Most of these changes, but not all, resemble those observed during cardiac overload and are accompanied by an increased duration of both the action potential and the intracellular calcium transient. However, the senescent heart is still able to further modify its phenotype in response to mechanical overload. The senescent heart is a diseased heart, and the origin of the “disease” is multifactorial and includes the general process of senescence, hormonal changes, and the myocardial consequences of senescence of the vessels.

Decrease in β1-adrenergic and M2-muscarinic receptor mRNA levels and unchanged accumulation of mRNAs coding for Gαi‒2 and Gαs proteins in rat cardiac hypertrophy

During compensatory cardiac hypertrophy in the rat, hemodynamic overload induces a parallel decrease in the densities of both beta 1-adrenergic (beta 1-AR) and M2-muscarinic (M2-MR) receptors in the left ventricle, but the total number of receptors remains unchanged. It is not known whether this reduction is transcriptionally or translationally regulated, or if the functionally closely linked alpha-subunits of G protein (G alpha s and G alpha i-2) partake in this regulation. In order to resolve these questions, the absolute concentrations of mRNAs for both receptors and for G alpha s and G alpha i-2 were quantified by slot blot analysis of the left ventricles of adult rats 5 weeks after aortic banding. The results showed a significant decrease of both receptor mRNA levels in hypertrophied left ventricle (beta 1-AR: -48%; M2-MR: -42%) that paralleled the reduction in receptor protein densities and was negatively correlated with the left ventricular weight/body weight ratio (LVW/BW). By contrast, the relative levels of G alpha s and G alpha i-2 mRNAs remained unchanged, and both accumulated proportionally to the increase in LVW/BW. These results show that the beta 1-AR and the M2-MR were pretranslationally regulated. This suggests the hypothesis that the corresponding genes do not follow the general increase in transcriptional activity. By contrast, the genes coding for G alpha s and G alpha i-2 may follow the general pattern of activation during hypertrophy. Receptors and coupling proteins belong to two different groups of genes that are controlled by distinct mechanisms of regulation.

Myosin heavy chain and actin fractional rates of synthesis in normal and overload rat heart ventricles.

The rates of synthesis (in per cent per day) of the total protein (ks) and myosin heavy chains (ke HC) and actin (ke A), isolated by preparative electrophoresis from myofibrils prepared in a relaxing medium, have been measured in rat heart ventricles after a continuous infusion of 50 microCi of (14C) Tyrosine (0.5 ml/h during 6 h). Normal values, in the sham-operated group, were for ks 19%, ke HC 23% and ke A 11%. Two to 4 days after an abdominal aortic stenosis there was an increase in the specific radioactivity of free plasma and intra-cellular tyrosine and of protein-bound tyrosine. The rate of synthesis also increased up to 37% for ks, 41% for ke HC and 21% for ke A but the ratio ke HC/ke A remained unchanged. We conclude that the normal heterogeneity of the rate of synthesis of the two main contractile proteins, at least when measured on myofibrils free from easily releasable myofilaments, was unmodified by cardiac overload, although both of these rates of synthesis were stimulated.

β-Adrenergic and muscarinic receptor mRNA accumulation in the sinoatrial node area of adult and senescent rat hearts

The sinoatrial (SA) node is the cardiac pacemaker and changes in its adrenergic-muscarinic phenotype have been postulated as a determinant of age-associated modifications in heart rate variability. To address this question, right atria were microdissected, the SA node area was identified by acetylcholinesterase staining, and, using a RT-PCR method, the accumulation of mRNA molecules encoding beta1- and beta2-adrenergic (beta1- and beta2-AR) and muscarinic (M2-R) receptor was quantified to define the proportion between beta-AR and M2-R mRNAs within the sinoatrial area of adult (3 months) and senescent (24 months) individual rat hearts. In adult hearts, the highest M2-R/beta-AR mRNA ratio was observed within the sinoatrial area compared with adjacent atrial myocardium, while in the senescent hearts, no difference was observed between sinoatrial and adjacent areas. This change was specific of the sinoatrial area since adult and senescent whole atrial or ventricular myocardium did not differ in their M2-R/beta-AR mRNA ratio, and was associated with a fragmentation of acetylcholinesterase staining of the senescent SA node. Quantitative changes in the expression of genes encoding proteins involved in heart rate regulation specifically affect the sinoatrial area of the senescent heart.

Decreased accumulation of β1-adrenergic receptor, Gαs and total myosin heavy chain messenger RNAs in the left ventricle of senescent rat heart

Abstract The expression of genes coding for the β1-adrenergic receptor (β1-AR), the α subunit of Gs and total myosin heavy chain (MHC) was compared between left ventricles (LVs) from young (6–7 weeks old) and old (22 months old) rats. The mRNA levels were quantitated by Northern or Slot blots analyses using specific DNA probes. Ageing was found to be associated with a reduction in β1-AR (77%), Gαs (33%) and total MHC (51%) mRNA levels with no concomitant change in 18S RNA and poly(A+) mRNA levels. These results indicate that transcriptional and/or post-transcriptional mechanisms participate in the control of β-adrenergic receptor density during ageing. As in the senescent LV, β1-AR mRNA level is reduced in the hypertrophied LV, whereas the level of Gαs mRNA is reduced in the senescent but not in the hypertrophied LV. From our data we conclude (1) that a dual mechanism may operate during ageing, mechanical factors indirectly regulating β1-AR mRNA level, while changes in Gαs mRNA level do not depend on hemodynamic load and (2) that the re-expression of β-MHC mRNA does not compensate for the decreased accumulation of α-MHC mRNA which results in a large decrease in the level of total MHC mRNA in the senescent LV.

Heart rate and heart rate variability, a pharmacological target

SummaryHeart rate varies with respiration, blood pressure, emotion, etc., and heart rate variability (HRV) is presently one of the best indices to predict fatal issues in cardiac failure and after myocardial infarction. HRV depends on various reflexes. In addition, parallel studies of HRV and the myocardial adrenergic and muscarinic transduction system in experimental models of cardiac hypertrophy (CH) have suggested that the myocardial phenotype at the sinus-node level may also play a role. A transgenic strain of mice with atrial overexpression of the 677-1 receptors was generated with attenuated HRV, which demonstrates that the phenotype itself is a determinant of HRV. HRV is explored by noninvasive techniques, including simple determination of the standard error of the mean, time-domain analysis, and Fourier transformation. We recently developed a time and frequency domain method of analysis, the smoothed pseudo-Wigner-Ville transformation, which allows better exploration of nonstationarity. Nonlinear methods have also been applied due to the extreme complexity of the biological determinants, and have provided evidence of a chaotic attractor in certain conditions. It is proposed that in steady state a very simple process, which is not completely deterministic, could better explain intermit interval regulations than chaotic behavior. In contrast, under extreme circumstances the regulation proceeds using chaotic behavior. Arrhythmias and HRV can be quantitated in 16-month-old unanesthetized spontaneously hypertensive rats (SHR). Ventricular premature beats are more frequent in SHR than in age-matched controls; they disappear after converting enzyme inhibition (CEI) relative to the reduction of both cardiac hypertrophy and ventricular fibrosis. HRV is attenuated in SHR, as it is in compensatory CH in humans. When CH is prevented, HRV returns to normal. CEI is therefore antiarrhythmic. Another pharmacological application of this concept concerns the bradycardic agents that may improve HRV.