Jean-Philippe Baguet

Obstructive Sleep Apnea and Atherosclerosis

Obstructive sleep apnea (OSA) is associated with significant cardiovascular morbidity and excess in mortality. Atherosclerosis has been shown to occur in OSA patients free of any other significant risk factors. In particular, intima media thickness, an early marker of atherosclerosis, may be increased at the carotid level in OSA. Thus, early atherosclerosis could be one of the intermediary mechanisms supporting the link between OSA and cardiovascular morbidity. The current concept is that the development of atherosclerotic lesions results from a dynamic interplay between the native cells of the vasculature and different proinflammatory leukocytes issued from the general circulation. Immunoinflammatory cells dominate early atherosclerotic processes, with the secretion of several proinflammatory molecules aggravating lesion progression. There is now substantial evidence that intermittent hypoxia in rodents, as a partial model of sleep apnea, triggers atherogenesis. Blood pressure alterations and hemodynamic strains on the vascular wall, impairment in vascular reactivity, lipid metabolism dysregulation, and activation of proinflammatory transcription factors at the vascular wall level are among the key factors promoting atherosclerosis. Specifically, increases in leukocyte rolling and adhesion molecule expression at the endothelial cell level have been shown to occur in the first 2 weeks after intermittent hypoxia exposure initiation. Early changes at the vascular wall level have been shown in OSA patients and its reversibility under continuous positive airway pressure has also been suggested. Several biological markers potentially linked with early atherosclerosis development are under study in OSA patients. Further studies are needed to identify at-risk subjects prone to develop vascular changes because OSA treatment may either be initiated earlier or combined with specific drug treatments.

Adherence to Antihypertensive Treatment and the Blood Pressure-Lowering Effects of Renal Denervation in the Renal Denervation for Hypertension (DENERHTN) Trial.

Background: The DENERHTN trial (Renal Denervation for Hypertension) confirmed the blood pressure–lowering efficacy of renal denervation added to a standardized stepped-care antihypertensive treatment for resistant hypertension at 6 months. We report the influence of adherence to antihypertensive treatment on blood pressure control. Methods: One hundred six patients with hypertension resistant to 4 weeks of treatment with indapamide 1.5 mg/d, ramipril 10 mg/d (or irbesartan 300 mg/d), and amlodipine 10 mg/d were randomly assigned to renal denervation plus standardized stepped-care antihypertensive treatment, or the same antihypertensive treatment alone. For standardized stepped-care antihypertensive treatment, spironolactone 25 mg/d, bisoprolol 10 mg/d, prazosin 5 mg/d, and rilmenidine 1 mg/d were sequentially added at monthly visits if home blood pressure was ≥135/85 mmu2009Hg after randomization. We assessed adherence to antihypertensive treatment at 6 months by drug screening in urine/plasma samples from 85 patients. Results: The numbers of fully adherent (20/40 versus 21/45), partially nonadherent (13/40 versus 20/45), or completely nonadherent patients (7/40 versus 4/45) to antihypertensive treatment were not different in the renal denervation and the control groups, respectively (P=0.3605). The difference in the change in daytime ambulatory systolic blood pressure from baseline to 6 months between the 2 groups was –6.7 mmu2009Hg (P=0.0461) in fully adherent and –7.8 mmu2009Hg (P=0.0996) in nonadherent (partially nonadherent plus completely nonadherent) patients. The between-patient variability of daytime ambulatory systolic blood pressure was greater for nonadherent than for fully adherent patients. Conclusions: In the DENERHTN trial, the prevalence of nonadherence to antihypertensive drugs at 6 months was high (≈50%) but not different in the renal denervation and control groups. Regardless of adherence to treatment, renal denervation plus standardized stepped-care antihypertensive treatment resulted in a greater decrease in blood pressure than standardized stepped-care antihypertensive treatment alone. Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01570777.

Cathepsin G is associated with atheroma formation in human carotid artery.

Objective To elucidate the organization of the tissue angiotensin system, we investigated the expression and cellular localization of angiotensin system components and cathepsins D and G, potentially involved in intraparietal angiotensin II formation and atheroma. Methods Total RNA was extracted from atheroma plaque, fatty streaks and macroscopically intact tissue obtained during carotid endarterectomy in 21 hypertensive patients. mRNA levels were compared between these tissues using a semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR). In situ hybridization and immunohistochemistry were used to define the cellular localization of the transcripts and their respective proteins. Results Apart from renin and angiotensin type 2 (AT2) receptors, which were never detected, the studied mRNAs could be measured in all patients. Angiotensin-converting enzyme (ACE) mRNA was increased five-fold in atheroma, and angiotensin type 1 receptor (AT1) mRNA decreased 2.5-fold in atheroma and 1.4-fold in fatty streaks compared to intact tissue. A two-fold increase in cathepsin G mRNA was observed in atheroma plaque. In atheroma and intact tissue, significant positive correlations were found between cathepsin G and angiotensinogen, AT1 receptor and ACE mRNAs. Angiotensinogen and cathepsin mRNAs and proteins were detected in both arterial layers. AT1 immunoreactivity was mainly associated with α-actin-positive cells. Conclusion All components required for angiotensin II formation are expressed locally in the arterial wall, where, in the absence of renin, cathepsin G could be a major angiotensin-generating enzyme. Overexpression of ACE and cathepsin G may lead to angiotensin II overproduction and contribute, with decreased number of differentiated smooth muscle cells, to the lower amount of AT1 receptor in atheroma.

Increased aortic root size is associated with nocturnal hypoxia and diastolic blood pressure in obstructive sleep apnea.

STUDY OBJECTIVESnObstructive sleep apnea (OSA) is known as a major cardiovascular risk factor, and high prevalence of OSA has been reported in patients with thoracic aortic dissection. The aim of our study was to assess the relationship between OSA, its vascular consequences, and aortic root size.nnnDESIGN/PATIENTSn156 newly diagnosed apneic patients free of cardiovascular disease and medication were included. Patients underwent cardiac ultrasound for measuring aortic root diameter, polysomnography, office and 24-h ambulatory blood pressure (BP) measurements, baroreflex sensitivity (BRS), and arterial stiffness evaluation by carotid-to-femoral pulse wave velocity (PWV).nnnMEASUREMENTS AND RESULTSnIn univariate analysis, greater aortic root size was associated with older age (P = 0.03) and severity of OSA as expressed by mean nocturnal oxygen saturation (SpO2) (P = 0.015). Moreover, greater aortic root size was associated with higher diastolic BP, measured both clinically (P = 0.0005) or by 24-h ambulatory BP monitoring (P = 0.02), and PWV (P = 0.03). Mean nocturnal SpO(2) was correlated with BRS (P = 0.0008), thus potentially influencing BP values and arterial stiffness. In multivariate stepwise regression analysis, diastolic BP was the only significant factor for aortic root size (P = 0.0003).nnnCONCLUSIONSnIn OSA patients, nocturnal hypoxemia decreased BRS and increased diastolic BP, which was the main factor influencing aortic root size.

Effect of Acute Increase in Blood Pressure on Intraocular Pressure in Pigs and Humans

PURPOSEnTo study the effect on intraocular pressure (IOP) of a sudden increase in blood pressure (BP) and of changes in partial pressure of CO(2) (pCO(2)).nnnMETHODSnTwo experimental studies were conducted: in pigs (n = 7), where BP was reduced by intravenous injection of sodium nitroprusside and increased by injection of angiotensin II; and in humans (n = 17 healthy subjects), where BP was increased by two types of isometric exercise (squatting and handgripping) performed for 2 minutes; IOP and pCO(2) were measured every 30 seconds during separate tests (rest, hyperventilation, isometric exercise) and then after 1, 3, 6, and 10 minutes of rest.nnnRESULTSnIn pigs, there is a linear relationship between BP and IOP variations: DeltaIOP = 1.21 DeltaBP - 0.14 (P < 0.001). In humans, this linear relationship is as follows: DeltaIOP = 0.40 DeltaBP + 0.85 (P < 0.001) for squatting and DeltaIOP = 0.54 DeltaBP + 0.55 (P = 0.02) for handgripping. BP and IOP increases are greater with squatting than with handgripping (53% vs. 46%, P = 0.05 and 46% vs. 35%, P = 0.03, respectively). Handgripping causes a greater fall in capnia than squatting does (P = 0.02). Capnia and IOP are positively correlated (P < 0.001).nnnCONCLUSIONSnThe pharmacological approach in animals and the study of isometric exercise in humans show that IOP rises significantly and rapidly with kinetics close to those of BP, and the two values are linearly related. The absence of variation in capnia and the greater increase in BP during squatting may explain the greater increase in IOP during this exercise compared to handgripping.

Development and validation of a method using supported liquid extraction for aldosterone determination in human plasma by LC-MS/MS.

BACKGROUNDnAccurate quantitation of aldosterone is essential for screening, diagnosis and subtype classification in primary aldosteronism. A simple, sensitive method for aldosterone in human plasma using supported liquid extraction (SLE) in combination with liquid chromatography tandem mass spectrometry (LC-MS/MS) was developed and validated.nnnMETHODSnPlasma samples were diluted with water containing d7-aldosterone as internal standard. The samples were extracted with methyl-tert-butyl-ether (MTBE) on SLE cartridges. Separation was carried out on a Luna C18 (2) column using a methanol-water gradient. Detection was performed in the negative electrospray multiple reaction monitoring (MRM) quantitation. The use of water-based calibrators was evaluated against calibrators prepared in steroid-free serum.nnnRESULTSnThe assay was linear up to 3265pmol/L with an LOQ of approximately 40pmol/L. Within-run and between-run precision for plasma aldosterone were less than 10% except at low level near LOQ but were still less than 14.7% (Westgards desirable specification). The mean recovery of the analyte added to plasma was greater than 97.7% and matrix effects were less than 4%. Comparison with another LC-MS/MS method was performed on a more sensitive instrument (ABSciex TQ 5500) and gave the equation API 3000=0.957×TQ 5500+12.6, linear regression r(2)=0.974 (n=43). An estimation of the reference interval for adults was established on a group of healthy volunteers (n=53). Calibration with water-based calibrators was validated and can be used for measurement of aldosterone by LC-MS/MS.nnnCONCLUSIONSnThis method is reliable, easy to perform on plasma specimens in a clinical environment and is attractive because of its simplicity.

Choroidal blood flow regulation after posture change or isometric exercise in men with obstructive sleep apnea syndrome.

PURPOSEnObstructive sleep apnea (OSA) syndrome generates hypertension, atherosclerosis, and endothelial and autonomic dysfunction, which may mutually interact with ocular vascular regulation. Exercise and posture changes can be used to manipulate blood pressure, ocular perfusion pressure (OPP), or both. It was hypothesized that choroidal vascular reactivity in response to isometric exercise and posture changes could be altered in OSA patients.nnnMETHODSnHealthy men were matched 1:1 for body mass index, sex, and age with patients with newly diagnosed OSA without cardiovascular comorbidities. All subjects underwent sleep studies and cardiovascular phenotyping (24-hour blood pressure monitoring, arterial stiffness measurements, and cardiac and carotid echography). Choroidal reactivity was assessed by laser Doppler flowmetry, which measured subfoveal choroidal blood flow.nnnRESULTSnDuring exercise, blood pressure parameters increased significantly within the same range, with a similar profile over time in OSA patients and control subjects. A significant linear relationship (P = 0.0003) was noted between choroidal vascular resistance and the OPP changes during exercise in OSA patients and control subjects. From the sitting to the supine position, a significant decrease in mean arterial pressure occurred in both groups (10.9%-13.4%; P < 0.001). In both populations, no significant change in choroidal blood flow or vascular resistance was found during the posture change. Choroidal blood flow responses to exercise and posture changes were unchanged after 6 to 9 months of continuous positive airway pressure treatment.nnnCONCLUSIONSnThis study strongly suggests that the regulation of choroidal blood flow, which depends on the orthosympathetic and parasympathetic systems, is unaltered in men with OSA who have no comorbidities.

Induction of tissue kallikrein in human carotid atheroma does not lead to kallikrein-kinins pathway activation.

Objective The impairment of the tissue kallikrein-kinin system (KKS) may result in atheroma development. To determine the involvement of KKS in pathophysiology of human atherosclerosis, we examined the expression of all components of this system as well as angiotensinogen (another tissue kallikrein (TK) substrate), at messenger ribonucleic acid (mRNA) and protein levels in the human carotid artery with and without atheroma. Methods mRNA levels were compared with semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) between atheroma plaque and intact tissue obtained during carotid endarterectomy in 15 patients. The cellular localization of the transcripts and proteins was analyzed with in situ hybridization and immunohistochemistry. TK activity was measured using chromogenic substrate. Results The kininogen mRNA was not detected in carotid wall. The TK mRNA was increased four-fold and TK activity 23-fold in atheroma plaque compared with intact tissue. No difference was observed for B1, B2 receptors, kallistatin, angiotensinogen and protein-kinase G type 1α (PK-G) mRNAs. The TK and angiotensinogen transcripts as well as kininogen and angiotensinogen proteins were present in both intimal and medial cells. The kininogen immunoreactivity was weaker in atheroma. Conclusions All KKS components were synthesized in arterial wall except kininogen probably coming from plasma. The absence of PK-G mRNA down-regulation in atheroma suggests that the kallikrein induction does not lead to KKS activation.

Hypertension diagnosis in obstructive sleep apnea: Self or 24-hour ambulatory blood pressure monitoring?

blood pressure monitoring? Jean-Philippe Baguet ⁎, Isabelle Boutin , Gilles Barone-Rochette , Patrick Levy , Renaud Tamisier , Hélène Pierre , Laetitia Boggetto-Graham , Jean-Louis Pépin d,e a Department of Cardiology, University Hospital, Grenoble, France b Bioclinic Radiopharmaceutics Laboratory, INSERM U1039, Joseph Fourier University, Grenoble, France c Respiratory and Sleep Medicine, Laval University, Quebec City, Canada d HP2 Laboratory (Hypoxia: Pathophysiology), INSERM U1042, Joseph Fourier University, Grenoble, France e Sleep Laboratory, EFCR, University Hospital, Grenoble, France

Direct Admission to the Operating Room: An Efficient Strategy for Patients With Diagnosed or Highly Suspected Acute Type A Aortic Dissection

BACKGROUNDnAcute type A aortic dissection (ATAAD) is a life-threatening condition with a poor acute prognosis, which requires rapid and effective surgical management. The aim of this study is to assess our strategy with regard to this condition.nnnMETHODSnAccording to a regional emergency protocol, patients with diagnosed or highly suspected ATAAD are directly transferred to the cardiac operating room. Transesophageal echocardiography is performed under anaesthesia, and the patient then undergoes surgery if the diagnosis is confirmed. The present retrospective study examines the implementation of this management strategy between January 1, 1990 and December 31, 2009.nnnRESULTSnOut of 380 patients, 245 were directly admitted to the operating room. Three hundred twelve cases of ATAAD, 15 cases of aneurysm of the ascending aorta, 9 cases of acute type B dissection, 4 cases of chronic dissection, 4 cases of hemopericardium, and 7 other diagnoses were observed. In 10 cases, no etiology was found. Nineteen patients died before surgery could be performed. Out of the 307 cases of ATAAD undergoing surgery, 15 patients were operated with cardiac massage (14 cases of aortic rupture). This management strategy was justified in 93.1% of patients (228/245) directly admitted to the operating room, because of the need for surgery or aortic rupture.nnnCONCLUSIONSnOur management strategy enabled patients with ATAAD to receive effective and unselective treatment. Despite appropriate management, the large number of patients still dying before surgery, or undergoing surgery with cardiac massage, justifies and consolidates the need for immediate treatment of this condition.