Ecology of the cardiovascular system: A focus on air-related environmental factors.

Cardiology is a newcomer to environmental sciences. We aim to propose an original review of the scientific evidence regarding the effects of the environment on cardiovascular health. We report first influences of air-related environmental factors. Air temperature has a strong influence on cardiovascular mortality characterized by a V-like relationship confirming that both cold and hot periods have negative cardiovascular impacts. Furthermore, dynamic changes in temperature are likely more important than the absolute air temperature level. Cardiovascular reactions to air temperature are predominantly driven by increase in sympathetic tone. Indoor pollutants are mainly represented by smoke from cooking stoves and environmental tobacco smoke (ETS), and both are associated with increased cardiovascular mortality and morbidity. ETS is characterized by a curvilinear dose-effect relationship, showing already a significant effect even at low level of exposure and no threshold in effect appearance. Underlying ETS pathophysiology involves both effects of nicotinic stimulus on the sympathetic system and vascular oxidative stress. Smoking bans, as mitigation measures, were associated with a decrease in cardiovascular events. Long-term exposure to particulate air pollution was more recently recognized as an independent risk factor of cardiovascular mortality. Short-term increases in air pollution were also associated with an increased risk of myocardial infarction, stroke, and acute heart failure. Numerous experimental studies demonstrated that air pollution promotes a systemic vascular oxidative stress reaction followed by endothelial dysfunction, monocyte activation, and some proatherogenic changes of lipoproteins. Furthermore, air pollution favors thrombus formation as a result of increase in coagulation factors and platelet activation. Further studies are required to confirm that stricter air quality regulation or antioxidant regimen translate into some clinical benefits. In conclusion, ambient air temperature and pollution are major contributors to cardiovascular diseases. Improving air quality is now part of cardiovascular prevention.

[Recent progresses in the treatment of dyslipidemia]. / Actualités thérapeutiques en lipidologie.

There is a linear relationship between LDLcholesterol plasma concentration and coronary events, both in patients with stable angina pectoris and after an acute event. All medications that affect the lipid profile do not have a favorable effect on cardiovascular events (i.e. niacin, inhibitors of the cholesteryl ester transfer protein). Statins increase slightly the risk of type II diabetes in subjects at risk. We have also learnt that statins activate a transcription factor that increases LDL-cholesterol receptors, as well as a protein named " PCSK9 ". This latter protein reduces the number of LDL-cholesterol receptors on the hepatocyte and hampers thereby the LDLcholesterol lowering effects of statins. Spontaneous mutations that render PCSK9 ineffective reduce the LDL-cholesterol, and prevent coronary heart disease. Similar observations have been reproduced with numerous mutations that affect LDL-cholesterol levels. If a monoclonal antibody against PSCK9 is provided in addition to statin therapy, LDLcholesterol plasma concentration falls at unprecedented low concentrations of 30 mg/dl. 4.4% of these patients present a myocardial infarction, as compared to 6.3% in the placebo group. This new class of medication seems therefore promising for the secondary prevention in patients at risk of recurrent ischemic events.

Il y a une relation linéaire entre la concentration de LDL-cholestérol plasmatique et la survenue d'événements coronaires, tant après un événement coronaire aigu que dans la pathologie coronaire stable. Tous les agents pharmacologiques qui modifient le profil lipidique n'ont toutefois pas un effet positif sur les évènements cardiovasculaires (par exemple la niacine, les inhibiteurs de la " cholesteryl ester transfer protein "). Les statines augmentent discrètement le risque de diabète de type II chez des patients prédisposés. On sait aussi à présent que les statines accroissent l'expression d'un facteur de transcription qui augmente à la fois les récepteurs au LDL-cholestérol et une protéine dénommée " PCSK9 ". PCSK9 réduit le nombre de récepteurs au LDL-cholestérol sur l'hépatocyte, et limite par conséquent l'efficacité des statines. Les mutations qui rendent PCSK9 inopérant réduisent le LDL-cholestérol ainsi que le risque coronarien. Ceci a été reproduit avec un grand nombre de mutations qui affectent les concentrations du LDL-cholestérol plasmatique. Si on ajoute à une statine des anticorps monoclonaux qui inactivent PCSK9, le LDL cholestérol diminue considérablement à 30 mg/dl et seul 4,4 % des patients présentent un infarctus myocardique, contre 6,3 % dans le groupe placébo. Ces médicaments constituent par conséquent une nouvelle classe thérapeutique prometteuse pour la prévention secondaire d'évènements ischémiques chez des patients à risque.

[Hypertension and cardiovascular prevention: what has changed in 2014]. / Hypertension artérielle et prévention cardiovasculaire: ce qui a changé en 2014.

During the two past years, several recommendations regarding the management of the hypertensive patient and cardiovascular risk have been published. This article is focused on the main changes which are important for the general practitioner.

[Atrial fibrillation: recent progress]. / Fibrillation auriculaire: progrès récents.

Atrial fibrillation is the most common cardiac arrhythmia. Pharmacological treatment plays still an important role in the management of this disease. However, pulmonary vein isolation techniques are more and more important due to the high rate of recurrences and many side effects associated with antiarrhythmic drugs. This article is focused on the main changes that are important for the general practitioner in his daily clinical practice.

Three dimensional Ballistocardiogram and Seismocardiogram: what do they have in common?

3D-body accelerations, i.e. Ballistocardiograms (BCG) and Seismocardiograms (SCG), ECG and Impedance-cardiograms (ICG) were recorded on healthy volunteers participating to the European Space Agency (ESA) 59th parabolic flight campaign. In the present paper we document the similarities and differences that can be seen in the seismo- and ballisto-cardiogram signals in different positions (standing and supine) under normal gravity condition as well as during the weightlessness phases (0G) of a parabolic flight. Our results demonstrate that SCG and BCG both present a similar three dimensional (3D) nature, with components of the BCG having lower frequency content than the SCG. The recordings performed in the 0G environment are the one with the smoothest shape and largest maximum magnitude of the Force vector. The differences seen between SCG and BCG stress further the importance for the need of using different nomenclature for the identification of peaks in both signals.

[Renal denervation: new treatment for refractory hypertension?]. / Dénervation rénale: nouveau traitement de l'hypertension artérielle résistante?

Sympathetic renal hyperactivity is involved hypertension and in its progression towards organ damages. Using femoral access, a dedicated ablation catheter can be inserted into the renal vessels to deliver high frequency energy in the arterial wall. This therapy leads to a focal heating, which ablates the renal nerve fibers running in the adventitia. First clinical results (Simplicity HTN 1 and HTN 2 trials) have demonstrated a significant and sustained decrease in office blood pressure. The response rate to this therapy was about 85 to 90%. This procedure did not cause serious adverse event and seems to have also positive impact on glucose metabolism and exercise capacity. Based on these first results, renal denervation appears as a new interesting therapy, which requires further studies to better define its place in the antihypertensive therapeutic arsenal. Actually, it should not be considered as an alternative to pharmacological therapy and renal denervation should be only proposed to patients with resistant hypertension. Prior to renal denervation, an upstream work has to be done to ensure an adequate patient selection. The mandatory point is to ensure that patient scheduled for this therapy respond to the definition of arterial resistant hypertension. Because of the narrowed limit between the very common situation of "uncontrolled" hypertension and the "true resistant" group, we proposed a 3 steps algorithm that can help for patient selection.

[A new, spontaneous method for assessing sympathetic baroreflex function in humans]. / Une nouvelle méthode spontanée pour l'évaluation du baroréflexe sympathique chez l'Homme.

In humans, assessment of the sympathetic component of the arterial baroreceptor reflex (sBRS) is usually based on microneurographic recordings of muscle sympathetic nerve activity (MSNA), while inducing reflex changes with intravenous administration of vasoactive drugs (modified Oxford method). This method has several limitations, among which its poor temporal resolution. Some studies have proposed alternative methods by using spontaneous changes in arterial pressure (AP) and MSNA, usually collected under baroreflex closed-loop conditions (AP alters MSNA while MSNA alters AP), which makes the results difficult to interpret. In rats, a method has been developed and validated (Kanbar et al., 2007 [1]), which uses oscillations of renal SNA at the frequency of the heart beat. At this frequency, the baroreflex operates under open-loop conditions because of the low-pass filter properties of the resistance vasculature. The goal of the present study was to examine whether this method is applicable in humans. Data were previously collected by Gujic et al. (2007) [2]. Briefly, MSNA and AP were recorded in 16 young healthy subjects during a 5-minute baseline resting period then during a modified Oxford test (sodium nitroprusside and phenylephrine administrations). Using the 5-minute baseline recordings, spontaneous sBRS was assessed through empirical mode decomposition over consecutive 20-second periods. Spontaneous sBRS was significantly related to pharmacological sBRS (R=0.67, n=16, P=0.004). During the 5-minute period, spontaneous sBRS exhibited variations (CV=21.7±1.7%) that were negatively correlated with AP in five subjects (R=-0.61±0.03, P<0.05) and positively correlated with MSNA in ten subjects (R=0.73±0.03, P<0.05). The new method is able to correctly estimate sBRS, and reveals the existence of previously unrecognized fast fluctuations of sBRS.

Effects of ß2-adrenergic stimulation on exercise capacity in normal subjects.

ß2-Adrenergic receptor agonists are believed to present with ergogenic properties. However, how combined respiratory, cardiovascular and muscular effects of these drugs might affect exercise capacity remain incompletely understood. The effects of salbutamol were investigated in 23 healthy subjects. The study was randomised, placebo-controlled in double-blind and followed a cross-over design. Salbutamol was given at the dose of 10 µg/min in 11 subjects and 20 µg/min iv in the other 12 subjects. Measurements included muscle sympathetic nerve activity (MSNA), ventilatory responses to hyperoxic hypercapnia (7% CO(2) in O(2,) central chemoreflex), isocapnic hypoxia (10% O(2) in N(2), peripheral chemoreflex) and isometric muscle contraction followed by a local circulatory arrest (metaboreflex), cardiopulmonary exercise test (CPET) variables and isokinetic muscle strength. Salbutamol 10 µg/min increased heart rate and blood pressure, while MSNA burst frequency remained unchanged. Peripheral chemosensitivity increased, as evidenced by an increased ventilatory response to hypoxia, but ventilatory responses to hypercapnia or muscle ischaemia remained unchanged. The effects of salbutamol 20 µg/min were similar. Both doses of salbutamol did not affect CPET. Only the higher dose of salbutamol decreased the anaerobic threshold, but this was not associated with a change in VO(2) max. Salbutamol increased the slopes of ventilation as a function of VO(2) (P < 0.05) and VCO(2) (P < 0.001) during CPET. Maximal isokinetic muscle strength was not affected by salbutamol. In conclusion, the acute administration of either low or high dose salbutamol does not affect exercise capacity in normal subjects, in spite of an earlier anaerobic threshold and increased chemosensitivity.

Altered interaction between cardiac vagal influence and delta sleep EEG suggests an altered neuroplasticity in patients suffering from major depressive disorder.

OBJECTIVE: Major depressive disorder (MDD), which is associated with altered neuroplasticity and increased relative cardiac sympathic activity, enhances the risk of cardiovascular pathologies. Interaction between cardiac sympatho-vagal indexes and delta sleep power is probably altered in MDD. METHOD: Sleep characteristics and cardiac sympatho-vagal indexes of 10 depressive patients were compared to 10 control men across the first three non-rapid eye movement (NREM)-REM cycles. Interaction between normalized high frequency (HF) and delta power bands was studied using coherence analysis. RESULTS: Patients showed increased sleep latency, stage 1 and wake durations. No differences in heart rate variabilities were observed: Total power, HF and RR-interval decreased from NREM to REM sleep and wakefulness in both groups. Gain value was lower in patients while coherence and phase shift were similar between groups. Modifications in HF appear 8 min before modifications in delta. CONCLUSION: Major depressive disorder is related to an altered link between cardiac vagal influence and delta sleep, suggesting disorders in cardiovascular controls and an altered neuroplasticity.

Digoxin increases peripheral chemosensitivity and the ventilatory response to exercise in normal subjects.

1. The contribution of peripheral chemoreceptors to the regulation of ventilation during exercise remains incompletely understood. Digoxin has been reported to increase chemoreflex sensitivity in humans. In the present randomized, cross-over, double-blind study, we tested the hypothesis that this increases the ventilatory response to exercise in normal subjects, as assessed by changes in minute ventilation (V(E)) in response to the rate of CO(2) production (VCO(2)). 2. Minute ventilation, end-tidal PCO(2), pulse oximetric O(2) saturation (S(p)O(2)), heart rate and blood pressure (BP) were measured in 11 healthy young male untrained subjects after intravenous infusion of digoxin (0.01 mg/kg) or placebo during normoxia, isocapnic hypoxia and hyperoxic hypercapnoea. All participants underwent a maximum cardiopulmonary exercise test. 3. During normoxia, digoxin increased systolic BP only. During hypoxia, digoxin increased V(E) compared with placebo (P = 0.009) for the same fall in S(p)O(2) (P = NS). Moreover, no significant effects on ventilation and haemodynamic responses were recorded during hypercapnoea. Digoxin increased the V(E) /VCO(2) slope above the anaerobic threshold from 30.4 +/- 2.9 to 32.8 +/- 3.7 (P < 0.05), but did not affect VO(2max). 4. In conclusion, enhanced peripheral chemosensitivity with digoxin increases the ventilatory response to CO(2) production above the anaerobic threshold, but does not affect exercise capacity in healthy humans.

Differential effects of oral beta blockade on cardiovascular and sympathetic regulation.

In patients with hypertension, beta blockade decreases muscle sympathetic nerve activity (MSNA; micrographic technique) expressed in burst frequency (burst/min) but does not affect MSNA expressed in burst incidence (burst/100 heart beats), because reductions in blood pressure (BP) upon each diastole continue to deactivate the arterial baroreceptors, but at a slower heart rate (HR). We studied the effects of oral beta blockade on MSNA and baroreflex sensitivity (BRS) in normal participants. Bisoprolol (5 mg, 1 week) was administered in 10 healthy young adults, using a double-blind, placebo-controlled, randomized cross-over study design. The beat-to-beat mean RR interval (RR) and systolic blood pressure (SBP) series were analyzed by power spectral analysis and power computation over the very low frequency (VLF), low frequency, and high frequency (HF) bands. Baroreflex sensitivity was computed from SBP and RR cross-analysis, using time and frequency domain methods. Bisoprolol increased RR (P < .0005), decreased mean SBP and diastolic blood pressure values (P < .01), did not change the SBP and RR powers, except for RR power in VLF (P < .02) and SBP power in HF (P < .03). The MSNA variability (P > .13) and respiratory pattern (P = .84) did not change from placebo to bisoprolol condition. The bisoprolol-induced bradycardia was associated with higher burst/100 heart beats (P < .05) and bisoprolol did not affect burst/min (P = .80). Time domain BRS estimates were increased after bisoprolol (P < .05), while frequency domain ones did not change (P > .1). Oral bisoprolol induces differential effects on sympathetic burst frequency and incidence in normal participants. Peripheral sympathetic outflow over time is preserved as a result of an increased burst incidence, in the presence of a slower HR. Unchanged BP and HR and MSNA variability suggests that the larger burst incidence is not due to sympathetic activation.

Decreased ventilatory response to exercise by dopamine-induced inhibition of peripheral chemosensitivity.

The contribution of the peripheral chemoreflex to the ventilatory response to exercise and aerobic exercise capacity remains incompletely understood. Low-dose dopamine has been reported to specifically inhibit the peripheral chemoreceptors. We therefore investigated the effects of intravenous dopamine (3 microg kg(-1)min(-1)) on cardiopulmonary exercise test (CPET) variables in 13 healthy young male subjects. The study was prospective, placebo-controlled, and randomized with more than 24h between placebo and dopamine administrations. During the CPET, dopamine decreased the .V(E)/.V(CO2) output slope (24.61+/-1.84 vs. 23.09+/-1.81, placebo vs. Dopamine respectively, p=0.025), without affecting maximum workload, .V(E) and O(2) uptake. In conclusion, our study reveals that inhibition of peripheral chemoreflex function with dopamine decreases the .V(E)/.V(CO2) slope during dynamic exercise, with no change in aerobic exercise capacity.

The impact of chronic primary insomnia on the heart rate--EEG variability link.

OBJECTIVE: To determine if chronic insomnia alters the relationship between heart rate variability and delta sleep determined at the EEG. METHODS: After one night of accommodation, polysomnography was performed in 14 male patients with chronic primary insomnia matched with 14 healthy men. ECG and EEG recordings allowed the determination of High Frequency (HF) power of RR-interval and delta sleep EEG power across the first three Non Rapid Eye Movement (NREM)-REM cycles. Interaction between normalized HF RR-interval variability and normalized delta sleep EEG power was studied by coherency analysis. RESULTS: Patients showed increased total number of awakenings, longer sleep latency and wake durations and shorter sleep efficiency and REM duration than controls (p<.01). Heart rate variability across first three NREM-REM cycles and sleep stages (NREM, REM and awake) were similar between both groups. In each group, normalized HF variability of RR-interval decreased from NREM to both REM and awake. Patients showed decreased linear relationship between normalized HF RR-interval variability and delta EEG power, expressed by decreased coherence, in comparison to controls (p<.05). Gain and phase shift between these signals were similar between both groups. CONCLUSIONS: Interaction between changes in cardiac autonomic activity and delta power is altered in chronic primary insomniac patients, even in the absence of modifications in heart rate variability and cardiovascular diseases. SIGNIFICANCE: This altered interaction could reflect the first step to cardiovascular disorders.

[What are the alternatives to betablockers in 2009?]. / Quelles alternatives aux bêtabloquants en 2009?

Betablockers reduce mortality by 30% after a myocardial infarction. The anti anginal effects of betablockers are also very well established. They improve survival after a non cardiac surgery in patients at high cardiovascular risk. Atenolol should nevertheless be avoided for primary cardiovascular protection in patients with hypertension older than 55 yrs. This may not apply to more selective betablockers, or betablockers with vasodilator effects. We also now have another bradycardic agent, ivabradine, which may prove very useful in heart failure patients who cannot tolerate a betablocker.

Acute effect of sidestream cigarette smoke extract on vascular endothelial function.

Acute exposure to passive smoking adversely affects vascular function by promoting oxidative stress and endothelial dysfunction. However, it is not known whether tobacco sidestream (SS) smoke has a greater deleterious effect on the endothelium than non-tobacco SS smoke and whether these effects are related to nicotinic endothelial stimulation. To test these hypotheses, endothelial-dependent relaxation and superoxide anion production were assessed in isolated rat aortas incubated with tobacco SS smoke, non-tobacco SS smoke, or pure nicotine. Tobacco SS smoke decreased the maximal relaxation to acetylcholine (Ach) from 79 +/- 6% to 57 +/- 7.3% (% inhibition of phenylephrine-induced plateau, P < 0.001) and increased superoxide anion production from 31 +/- 9.7 to 116 +/- 24 count/10 sec/mg (P < 0.01, lucigenin-enhanced chemiluminescence technique). The non-tobacco SS smoke extract had no significant effect on the response to Ach but increased superoxide anion production in the aortic wall to 133 +/- 2 count/10 sec/mg (P < 0.001). Furthermore, concentration-response curves to Ach and superoxide production remained unaltered with nicotine (0.001, 0.01, or 0.1 mM). In conclusion, despite similar increases in vascular wall superoxide production with tobacco and non-tobacco SS smoke, only the tobacco SS smoke extracts affected endothelium-dependent vasorelaxation. Nicotine alone does not reproduce the effects seen with tobacco SS smoke, suggesting that the acute endothelial toxicity of passive smoking cannot simply be ascribed to a nicotine-dependent mechanism.

Facial cooling and peripheral chemoreflex mechanisms in humans.

AIM: Reductions in arterial oxygen partial pressure activate the peripheral chemoreceptors which increase ventilation, and, after cessation of breathing, reduce heart rate. We tested the hypothesis that facial cooling facilitates these peripheral chemoreflex mechanisms. METHODS: Chemoreflex control was assessed by the ventilatory response to hypoxia (10% O2 in N2) and the bradycardic response to voluntary end-expiratory apnoeas of maximal duration in 12 young, healthy subjects. We recorded minute ventilation, haemoglobin O2 saturation, RR interval (the time between two R waves of the QRS complex) and the standard deviation of the RR interval (SDNN), a marker of cardiac vagal activity throughout the study. Measurements were performed with the subject's face exposed to air flow at 23 and 4 degrees C. RESULTS: Cold air decreased facial temperature by 11 degrees C (P < 0.0001) but did not affect minute ventilation during normoxia. However, facial cooling increased the ventilatory response to hypoxia (P < 0.05). The RR interval increased by 31 +/- 8% of the mean RR preceding the apnoea during the hypoxic apnoeas in the presence of cold air, compared to 17 +/- 5% of the mean RR preceding the apnoea in the absence of facial cooling (P < 0.05). This increase occurred despite identical apnoea durations and reductions in oxygen saturation. Finally, facial cooling increased SDNN during normoxia and hypoxia, as well as during the apnoeas performed in hypoxic conditions (all P < 0.05). CONCLUSION: The larger ventilatory response to hypoxia suggests that facial cooling facilitates peripheral chemoreflex mechanisms in normal humans. Moreover, simultaneous diving reflex and peripheral chemoreflex activation enhances cardiac vagal activation, and favours further bradycardia upon cessation of breathing.

The link between cardiac autonomic activity and sleep delta power is altered in men with sleep apnea-hypopnea syndrome.

We hypothesize that sleep apnea-hypopnea alters interaction between cardiac vagal modulation and sleep delta EEG. Sleep apnea-hypopnea syndrome (SAHS) is related to cardiovascular complications in men. SAHS patients show higher sympathetic activity than normal subjects. In healthy men, non-rapid eye movement (NREM) sleep is associated with cardiac vagal influence, whereas rapid eye movement (REM) sleep is linked to cardiac sympathetic activity. Interaction between cardiac autonomic modulation and delta sleep EEG is not altered across a life span nor is the delay between appearances of modifications in both signals. Healthy controls, moderate SAHS, and severe SAHS patients were compared across the first three NREM-REM cycles. Spectral analysis was applied to ECG and EEG signals. High frequency (HF) and low frequency (LF) of heart rate variability (HRV), ratio of LF/HF, and normalized (nu) delta power were obtained. A coherency analysis between HF(nu) and delta was performed, as well as a correlation analysis between obstructive apnea index (AI) or hypopnea index (HI) and gain, coherence, or phase shift. HRV components were similar between groups. In each group, HF(nu) was larger during NREM, while LF(nu) predominated across REM and wake stages. Coherence and gain between HF(nu) and delta decreased from controls to severe SAHS patients. In SAHS patients, the delay between modifications in HF(nu) and delta did not differ from zero. AI and HI correlated negatively with coherence, while HI correlated negatively with gain only. Apneas-hypopneas affect the link between cardiac sympathetic and vagal modulation and delta EEG demonstrated by the loss of cardiac autonomic activity fluctuations across shifts in sleep stages. Obstructive apneas and hypopneas alter the interaction between both signals differently.

[Physiopathology of heart failure: experimental model and therapeutic effects]. / Physiopathologie de l'insuffisance cardiaque : modèle expérimental et effets thérapeutiques.

Studies have shown the importance of heart rate variability alterations as a marker of neurohumoral dysregulation and haemodynamic derangements in experimental heart failure. Other studies have also revealed the importance of enhanced sympathetic nerve traffic and chemoreflex dysregulation in patients with pulmonary hypertension. Furthermore, the lack of favorable effects of beta mimetic agents on long term survival in heart failure patients may implicate an absence of sympathoinhibition, possibly related to a sensitization of the peripheral chemoreceptors. Sympathetic hyperactivity is however reduced by cardiac resynchronisation therapy. Last, a comparison of sympathetic nerve traffic during normoxia and hyperoxia in heart transplant recipients, essential hypertensive patients and control subjects has revealed that transplantation does not normalize peripheral chemoreflex hyperactivity and hypersensitivity. This mechanism contributes to blood pressure elevation and exercise hyperpnea in cardiac transplant recipients.