Darwinian evolution and cardiovascular remodeling.

Mechanotransduction, MT, is an ancient evolutionary legacy existing in every living species and involving complex rearrangements of multiple proteins in response to a mechanical stress. MT includes three different interrelated processes: mechanosensation, mechanotransmission, and mechanoresponse. Each process is specifically adapted to a given tissue and stress. Both cardiac and arterial remodeling involve MT. Physiological or pathological cardiac remodeling, CR, is firstly a beneficial mechanoresponse, MR, which allows the heart to recover to a normal economy, better adapted to the new working conditions. Nevertheless, exercise-induced cardiac remodeling is more a coming-back to normal conditions than a superimposed event. On the longer term, the MR creates fibrosis which accounts, in part, for the reduced cardiac output in the CR. In the hypertension-induced arterial remodeling, arterial MR allows the vessels to maintain a normal circumferential constraint before an augmented arterial pressure. In atherogenesis: (i) The presence of atheroma in several animal species and atherosclerosis in ancient civilizations suggests more basic predispositions. (ii) The atherosclerotic plaques preferably develop at predictable arterial sites of disturbed blood flow showing that MT is involved in the initial steps of atherogenesis.

[Health consequences of environmental temperature and climate variations]. / Consequences médicales des variations de la température ambiante et des variations climatiques.

Recent climate change is a consequence of the greenhouse effect and human activity, and is directly responsible for extreme events such as heatwaves (see report of the French Académie des Sciences). Human thermoregulation depends more on behavior than on biology Air conditioning and building structure play an essential role. The 2003 heatwave was not a unique event. Preventive measures reduced mortality during subsequent heatwaves. Most deaths were due to heat stroke associated with dehydration. During strenuous exercise, especially during military training, heat stroke requires specific treatment. Temperature/ global mortality and temperature/cardiovascular mortality curves are both U-shaped. Usually, global mortality increases winter and is linked to temperature. During summer, global mortality increases only when heatwaves occur. Climate change participates in the spread of infectious diseases. Nevertheless, in continental France, for the moment, climate change is not a major factor in the incidence of infectious diseases, despite the fact that several bacteria, viruses and vectors are temperature-sensitive. The situation in Reunion, French Polynesia and French Departments of America is more complicated, due to their geographic heterogeneity. Some areas are more exposed to the climatic risk and could act as a gateway for new infections and mutations. The dramatic loss of biodiversity is partly a consequence of climate change. It increases the transmissibility of some pathogens and can also potentially lead to an increase in autoimmune diseases and obesity. Climate change plays a important role in allergic diseases, through changes in the diffusion and composition of pollens. These modifications are being monitored by several observatories. Six different veterinary diseases, including several zoonoses, are of particular concern.

Molecular mechanisms in evolutionary cardiology failure.

Integration of the relevant evolutionary paradigm in cardiology has not yet been fully achieved: In the past, heart failure (HF) was mainly ascribed to infections, and the origins of cardiac hypertrophy (CH) were regarded as mechanical. Recent changes in lifestyle have both reduced the incidence of infections and increased lifespan, and HF is now seen as a complex disease--one that is still caused by mechanical disorder, but also associated with ischemia and senescence. The long-held view that CH serves to restore myocardial economy back to normal is still valid. The adaptive process is characterized by a quantitative and a qualitative fetal gene reprogramming, which is now being confirmed by recent advances in microRNA research. It underscores the fact CH is the physiologic reaction of the heart to a pathologic stimulus. The goal for therapy is economic, not inotropic. Another major issue is myocardial fibrosis, a major determinant of diastolic function and arrhythmias. Recent changes in lifestyle have crucially modified the context in which HF occurs.

[Evolutionary medicine: an introduction. Evolutionary biology, a missing element in medical teaching]. / Une introduction à la médecine évolutionniste. L'évolution biologique, grande absente de l'enseignement médical.

The aim of this brief review article is to help to reconcile medicine with evolutionary biology, a subject that should be taught in medical school. Evolutionary medicine takes the view that contemporary ills are related to an incompatibility between the environment in which humans currently live and their genomes, which have been shaped by diferent environmental conditions during biological evolution. Human activity has recently induced acute environmental modifications that have profoundly changed the medical landscape. Evolutionary biology is an irreversible, ongoing and discontinuous process characterized by periods of stasis followed by accelerations. Evolutionary biology is determined by genetic mutations, which are selected either by Darwinian selective pressure or randomly by genetic drift. Most medical events result from a genome/environment conflict. Some may be purely genetic, as in monogenic diseases, and others purely environmental, such as traffic accidents. Nevertheless, in most common diseases the clinical landscape is determined by the conflict between these two factors, the genetic elements of which are gradually being unraveled Three examples are examined in depth:--The medical consequences of the greenhouse effect. The absence of excess mortality during recent heat waves suggests that the main determinant of mortality in the 2003 heatwave was heatstroke and old age. The projected long-term effects of global warming call for research on thermolysis, a forgotten branch of physiology.--The hygiene hypothesis postulates that the exponential rise in autoimmune and allergic diseases is linked to lesser exposure to infectious agents, possibly involving counter-regulatory factors such as IL-10.--The recent rise in the incidence of obesity and type 2 diabetes in rich countries can be considered to result from a conflict between a calorie-rich environment and gene variants that control appetite. These variants are currently being identified by genome-wide analysis. Biological evolution should be taken into account in future holistic health policies.

Exercise training improves functional post-ischemic recovery in senescent heart.

The incidence of ischemic cardiac diseases increases with age and elderly subjects are more vulnerable to myocardial infarction. Endurance exercise (e.g. treadmill training) provides cardioprotection against an ischemia and reperfusion (IR) event in adult heart but such a potential beneficial effect of regular exercise has never been evaluated during aging. Therefore, this study investigated the effects of moderate running training on post-ischemic recovery of contractile function and coronary perfusion in senescent myocardium. Isolated hearts of sedentary (24 mo-sedentary; n=10) and trained senescent (24 mo-trained; n=11; moderate running: 1h/day, 5 days/week for 12 weeks) rats were submitted to 45min low-flow ischemia (15% of initial coronary flow (CF)) followed by 30min reperfusion. Active tension (AT) and CF were recorded at baseline and after 1, 3, 5, 10, 15, 20, 25 and 30min of reperfusion. Left ventricular protein carbonylation, and both heat-shock-protein 70 (HSP70) and endothelial nitric oxide synthase (eNOS) contents were determined by Oxyblotting and Western blotting, respectively. Regular physical exercise improves impairment of functional post-ischemic recovery (AT and CF) of aged hearts during reperfusion and this cardioprotection is associated to limited protein oxidation and increased HSP70 and eNOS myocardial contents.

[Medical consequences of global warming]. / Conséquences médicales du réchauffement climatique.

INTRODUCTION: The global warming of the planet and its anthropogenic origin are no longer debatable. Nevertheless, from a medical point of view, while the epidemiological consequences of the warming are rather well-known, the biological consequences are still poorly documented. This is a good example of evolutionary (or darwinian) medicine. METHODS: The research strategy of this systematic review is based on both PubMed during the period of 2000-2007 and several reviews articles for the period >2000. RESULTS: From a medical point of view, there are four types of consequences. 1-The simple elevation of the average external temperature is accompanied by an increased global mortality and morbidity, the mortality/external temperature is a J curve, with the warm branch more pronounced than the cold one. A recent study on 50 different cities had confirmed that global, and more specifically cardiovascular mortalities were enhanced at the two extreme of the temperatures. 2-The acute heatwaves, such as that which happened in France in August 2003, have been studied in detail by several groups. The mortality which was observed during the recent heatwaves was not compensated by harvesting, strongly suggesting that we were dealing with heat stroke, and that such an increased mortality was more reflecting the limits of our adaptational capacities than aggravation of a previously altered health status. 3-Climate changes have modified the repartition and virulence of pathogenic agents (dengue, malaria...) and above all their vectors. Such modifications were exponential and are likely to reflect the biological properties of parasites. 4-Indirect consequences of global warming include variations in the hydraulic cycle, the new form of tropical hurricanes and many different changes affecting both biodiversity and ecosystems. They will likely result in an increased level of poverty. DISCUSSION: These finding gave rise to several basic biological questions, rarely evoked, and that concern the limits of the adaptational capacities of human genome. Our genome has indeed been shaped in the past by a rather cold environment which has acutely been modified. The immediate physiological regulation includes sweating and skin vasodilatation. The latter may strongly enhance the cardiac output which explains the heat-induced cardiac decompensation. Long term regulation depends upon the numerous mechanisms of uncoupling of the mitochondrial respiration. For the moment, the thermolytic mechanisms and their regulation were rather poorly documented.

Genomics in cardiac metabolism.

Cell biology is in transition from reductionism to a more integrated science. Large-scale analysis of genome structure, gene expression, and metabolites are new technologies available for studying cardiac metabolism in diseases known to modify cardiac function. These technologies have several limitations and this review aims both to assess and take a critical look at some important results obtained in genomics restricted to molecular genetics, transcriptomics and metabolomics of cardiac metabolism in pathophysiological processes known to alter myocardial function. Therefore, our goal was to delineate new signalling pathways and new areas of research from the vast amount of data already published on genomics as applied to cardiac metabolism in diseases such as coronary heart disease, heart failure, and ischaemic reperfusion.

[The nineteenth century roots of the contemporary biological revolution]. / Les racines dix-neuvièmistes de la revolution biologique contemporaine.

The recent publication of the human genomic sequence is the most important progress in biology. It originates from four major watersheds between 1860-1865, namely the biological evolution by Darwin in 1858, the Mendel laws of heredity in 1865, the basis of physiology established by Claude Bernard also in 1865, and the discoveries of microbacteria by Louis Pasteur around 1857. Before 1860, biology did not exist as a science. After 1860, the Darwin's theory progressively became a law after the discovery of the DNA polymorphism and that of the mechanisms of genetic mixing. So far the Mendel's laws were confirmed in parallel with the development of molecular genetics after the discovery of DNA structure and genetic code. The discovery of hormones is one example, amongst several on how integrative physiology applies to Claude Bernard's basis. Finally, based on Pasteur's discovery and Pasteur Institutes, microbiology became a tool for molecular biologists.

Phenotypic plasticity of adult myocardium: molecular mechanisms.

Cardiac phenotypic plasticity (so-called cardiac remodelling, CR) is characterized by changes in myocardial structure that happen in response to either mechanical overload or a loss of substance such as that occurring after myocardial infarction. Mechanosensation is a widespread biological process and is inextricably mixed with other transduction systems from hormones and vasopeptides, which ultimately produce post-translational modifications of transcription factors. The expression of the four main transcription factors during cardiogenesis is also enhanced as a link to foetal reprogramming. CR results from re-expression of the foetal programme, which is mostly adaptive, but also from several other phenotypic modifications that are not usually adaptive, such as fibrosis. (i) The initial determinant is mechanical, and re-expression of the foetal programme includes a global increase in genetic expression with cardiac hypertrophy, re-expression of genes that are normally not expressed in the adult ventricles, repression of genes not expressed during the foetal life, and activation of pre-exisiting stem cells. Microarray technology has revealed a coordinated change in expression of genes pertaining to signal transduction, metabolic function, structure and motility, and cell organism defence. The physiological consequence is a better adapted muscle. (ii) During clinical conditions, the effects of mechanics are modified by several interfering determinants that modify CR, including senescence, obesity, diabetes, ischemia and the neurohormonal reaction. Each of these factors can alter myocardial gene expression and modify molecular remodelling of mechanical origin. Finally, as compared to evolutionary phenotypic plasticity described in plants and insects in response to variations in environmental conditions, in CR, the environmental factor is internal, plasticity is primarily adaptive, and it involves coordinated changes in over 1400 genes. Study of reaction norms showed that the genotypes from different animal species are similarly plastic, but there are transgenic models in which adaptation to mechanics is not caused by hypertrophy but by qualitative changes in gene expression.

Effects of autonomic blockade on non-linear cardiovascular variability indices in rats.

1. The present study assesses the effects of autonomic blockade (alpha- and beta-adrenoceptor and cholinergic) on cardiovascular function studied by heart rate variability (HRV), blood pressure variability (BPV) and baroreflex sensitivity in rats using non-linear dynamics. Little is known about the influence of pharmacological autonomic nervous system interventions on non-linear cardiovascular regulatory indices. 2. In 13 conscious rats, heart rate and aortic blood pressure were measured continuously before, during and after autonomic blockade with atropine, phentolamine and propranolol. Non-linear scaling properties were studied using 1/f slope, fractal dimension and long- and short-term correlation. Non-linear complexity was described with correlation dimension, Lyapunov exponent and approximate entropy. Non-linear indices were compared with linear time and frequency domain indices. 3. Beta-adrenoceptor blockade did not alter the non-linear characteristics of HRV and BPV, although low-frequency power of HRV was depressed. Alpha-adrenoceptor blockade decreased the scaling behaviour of HRV, whereas cholinergic blockade decreased the complexity of the non-linear system of HRV. For BPV, the scaling behaviour was increased during alpha-adrenoceptor blockade and the complexity was increased during cholinergic blockade. The linear indices of HRV and BPV were decreased. 4. The present results indicate that the beta-adrenoceptor system has little involvement in the generation of non-linear HRV and BPV in rats. 5. Alpha-adrenoceptor blockade mostly influenced the scaling properties of the time series, whereas cholinergic blockade induced changes in the complexity measures. 6. The absence of the baroreflex mechanism can trigger a compensatory feed-forward system increasing the complexity of BPV.

Severe impairment of ventricular compliance accounts for advanced age-associated hemodynamic dysfunction in rats.

Advanced aging is associated with hemodynamic dysfunction in rats as in humans. The aim of this study was to assess the mechanisms of development of left ventricular (LV) dysfunction in the rat model of aging. In vivo hemodynamics and ex vivo LV papillary muscle mechanics, myofilaments sensitivity to calcium in skinned fibers and pressure/volume curves in isolated perfused hearts were performed in 3, 24 and 28 month old (mo) male Wistar rats. Hemodynamic dysfunction occurs in 28 mo rats and is characterized by both a systolic and diastolic dysfunction and a LV hypertrophy (+34.7% of LV weight). In papillary muscle, normalized active developed force and myofilament sensitivity to calcium were unchanged between 24 and 28 months of age. In contrast, both resting force/total force ratio in papillary muscle and the slope of the pressure/volume curves in isolated heart are increased between 3 and 24 mo but also between 24 and 28 mo, indicating a progression of the impairment of both papillary muscle stiffness and LV compliance in advanced aging. Hemodynamic dysfunction occurring at advanced age, i.e. 28 mo in rats mainly results from impairment of ventricular compliance resulting from fibrosis.

Protection of endothelial-derived vasorelaxation with cariporide, a sodium-proton exchanger inhibitor, after prolonged hypoxia and hypoxia-reoxygenation: effect of age.

Calcium overload during hypoxia and reoxygenation exerts deleterious effects in endothelial and smooth muscle cells but potential effects of sodium-proton exchanger (NHE) inhibitors have never been investigated in both adult and senescent vessels. Isolated aortic rings from adult and senescent rats were submitted to hypoxia (50 min) or to hypoxia/reoxygenation (20/30 min) without or with cariporide (10(-6) M) and aortic vasoreactivity was recorded. After hypoxia, relaxation to acetylcholine was preserved in adult rings treated with cariporide (-22.3% vs. -9.3% of baseline value in control and treated groups respectively, P<0.05) but not in senescents. Cariporide treatment restored relaxation to acetylcholine after hypoxia-reoxygenation in adult rings (-32.04% vs. -0.03% of baseline value in control and treated groups respectively, P<0.01) and to a lesser extent, in senescent rings (-30.8% vs. -24.4% of baseline value in control and treated groups respectively, P<0.01). These results suggested that hypoxia induced lower acidosis and/or involved other mechanisms of proton extrusion than NHE in senescent aorta. Improvement of endothelial function with cariporide after reoxygenation in senescent aorta, but in a lesser extent than in adult aorta, suggests a lower role of NHE in pH regulation and subsequent calcium overload during aging.

[Biology of cardiac and vascular senescence]. / Biologie du vieillissement cardiaque et vasculaire.

None of the many theories of senescence can account for the aging process in its entirety. These theories include the evolutionary theory of aging and its EvoDevo corollary, the replicative senescence and free radicals theory, theories based on large-scale analyses (proteomics, etc.), and systemic theories. Cardiovascular senescence is first and foremost due to vascular senescence. Aging is associated with enhanced aortic characteristic impedance, which is mainly due to glycation of vessel wall proteins. This increased impedance overloads the left ventricle and causes compensatory left ventricular hypertrophy, usually associated with fibrosis. Extreme aging (> 80 years in humans, > 30 months in rats) is associated with age-related heart failure. Senescence favors heart failure, atrial fibrillation and cardiac hypertrophy. It is also associated with increased systolic pressure and decreased diastolic pressure. The most characteristic features are enhanced pulse pressure and arterial compliance.

[The acquired long QT during cardiac hypertrophy. Origin, incidence and significance]. / L'allongement acquis de l'espace QT dans l'hypertrophie ventriculaire. Origine, fréquence, signification.

Long QT is not only inherited or drug-induced. It reflects the degree of myocardial adaptation to mechanical overload In normal conditions, in isolated cells, the action potential (AP) duration depends on the activity of several ion channels. On body-surface ECG, the QT interval depends on two additional factors, namely transmural gradients and the spatial 3D projection of the electrical wave vectors. AP lengthening is a well-documented feature of cardiac hypertrophy and failure. The ion current most frequently involved, especially in humans, is an outward potassium current, I(tO), whose density is reduced as a consequence of a reduction in the corresponding gene density. In vivo, cardiac hypertrophy can modify and even reverse the transmural gradients. In humans and rats, hypertensive cardiopathy is associated with a reversible prolongation of the QT interval. The reduction in the density of l(tO )is adaptative, participates in the slowing of the cardiac cycle, and reflects fetal reprogramming. The ECG counterpart of this cellular mechanism is frequently attenuated or even masked by associated myocardial ischemia or by remodelling of the cardiac anatomic structure. Prolongation of the QT interval is a crucial component of the adaptative response to mechanical overload. As such, it has prognostic significance in heart failure of purely mechanical origin, such as hypertensive cardiopathy.

[Myocardial effects of nitric oxide, NO. Clinical and experimental evidence]. / Les effets myocardiques du monoxyde d'azote, NO. Données cliniques et expérimentales.

The vasodilatory properties of nitric oxide (NO) are well documented, but its direct effects on myocardial contractility are somewhat controversial. The present report follows a series of articles in which we reported the translocation of NO synthase isoforms both after myocardial infarction in aged rats and in human heart failure (HF). This redistribution is due to nNOS1 translocation from the sarcoplasmic reticulum to the caveolae in the outer membranes. Translocation is determined by strong interactions between the enzyme and caveoline-3 (a marker of caveolae). It suggests a regulatory role of nNOS1 in both normal inotropism and HF. The physiological consequences of this translocation were studied in a well-documented experimental model of myocardial infarction with HF in adult rats. Myocardial function was analyzed before and after adrenergic activation, both ex vivo on isolated hearts and in vivo with a Millar probe.--In rats, as in humans, the level of nNOS1 is enhanced, and this is associated with translocation to the caveolae. Such a process is seen in both humans and rats with HF.--In HF, ventricular elastance (E(s), in mmHg/microL: a load-independent measure of contractility) is reduced, and the time constant of relaxation, tau, is prolonged. In basal conditions, in non HF controls, specific nNOS1 inhibition by L-VNIO induces a 33% increase in E(s) and a 17% increase in the time constant of relaxation. The response to an adrenergic stimulation is attenuated in HF. The main result of this work is that pharmacological inhibition of nNOS1, either ex vivo with L-VNIO, or in vivo with SMTC, normalizes the adrenergic response of failing hearts. nNOS1 translocation is thus a major contributor to the autocrine regulation of contractility in HF, and is probably responsible for hampering the adrenergic response in HF.