Aldosterone synthase gene polymorphism, stroke volume and age-related changes in aortic pulse wave velocity in subjects with hypertension.

PURPOSE: In rats, chronic aldosterone administration with high diet intake increases aortic stiffness independent of mechanical stress. In hypertensive humans, enhanced plasma aldosterone and arterial stiffness are positively associated. Whether the aldosterone synthase gene polymorphism (ASGP) CYP11B2 influences the age-related changes in blood pressure (BP) and arterial stiffness in hypertensive subjects has never been investigated. METHODS: In 425 untreated hypertensive men and women, ASGP was evaluated together with aortic pulse wave velocity (PWV). In 191 of these subjects, cardiac haemodynamics were measured using echo-Doppler techniques. RESULTS: In the overall population, independently of sex, the TC and CC genotypes of ASPG had significantly higher heart rate (HR) (P < 0.05) and lower stroke index (P < 0.01) than the TT genotype, but did not affect BP. In men, the adjusted slopes of the curves relating age to PWV and HR were significantly steeper (P = 0.04; P = 0.002) for the TC and CC than for the TT genotype. Such gene-related differences were not observed for the age-systolic BP relationship. CONCLUSION: In hypertensive subjects, the TC and CC genotypes of ASGP involve, by comparison with the TT genotype, significantly higher HR and reduced stroke index. In men with the C allele, the reduced stroke index (cardiac effect) compensates for the steep increase of PWV with age (arterial effect), thus modulating the cardiovascular phenotype and explaining the lack of increased incidence of systolic hypertension. The results are consistent with a local role of endogenous aldosterone on both heart and vessels.

Angiotensin-converting enzyme D/I gene polymorphism and age-related changes in pulse pressure in subjects with hypertension.

UNLABELLED: Background- Few studies have examined the possible influence of gene polymorphisms on the increase of systolic blood pressure (SBP) and pulse pressure (PP) with age, although in older populations, SBP>160 mm Hg or PP>60 mm Hg are strong mechanical factors predicting cardiovascular mortality. METHODS AND RESULTS: This cross-sectional study involved 315 men and 154 women with either systolic-diastolic or isolated systolic hypertension. Using polymerase chain reaction, the angiotensin-converting enzyme (ACE) D/I gene polymorphism was investigated separately in men and women, enabling us to determine the relationships between age and PP, SBP, and diastolic blood pressure (DBP) for each genotype in each population. In men, most of which were under 50 years of age, the slope of the age-PP and age-SBP (but not age-DBP) relationships differed significantly between genotypes (P=0.0096 and 0.0175). The interslope difference was unmodified after adjustments involving all of the following factors together: plasma glucose, cholesterol, creatinine, potassium, body weight, tobacco consumption, mean blood pressure, and previous antihypertensive therapy. Adjustment of the two latter parameters alone significantly attenuated the interslope difference. Based on logistic regressions, the DD genotype was shown to independently predict a PP>60 mm Hg but not a SBP>160 mm Hg. CONCLUSIONS: In men, the ACE D/I gene polymorphism independently modulates age-related increase of PP, and potentially modulates the resulting cardiovascular risk. This finding requires the development of long-term follow-up.

Gene polymorphisms of the renin-angiotensin system and age-related changes in systolic and diastolic blood pressure in subjects with hypertension.

BACKGROUND: Few studies have examined to what extent genes might modulate the changes of systolic and diastolic blood pressure (BP) with age although, in older populations, systolic BP and diastolic BP vary with age in opposite directions. METHODS: This study involved 205 men and 99 women with either systolic-diastolic or isolated systolic hypertension. Age was > 50 years. Using polymerase chain reaction, four gene polymorphisms related to the renin-angiotensin system were independently investigated in men and women. Adjustments to cardiovascular and renal risk factors as well to the sodium/potassium extracellular space ratio were performed. RESULTS: Regarding the angiotensin-converting enzyme (ACE) gene polymorphism, in men > 50 years of age, the slope (mm Hg per unit of age) of the age-diastolic BP (and not age-systolic BP) relationships significantly (P = .0092) differed between genotypes: - 0.79 +/- 0.15 (P < .0001) for the DD genotype, -0.53 +/- 0.10 for the ID genotype (P < .0001), and -0.23 +/- 0.11 for II genotypes (P = NS). Such findings were not observed in the female population in which the age-diastolic BP curves were substantially flatter than in men. No comparable results were observed for gene polymorphisms related either to angiotensinogen or to angiotensin II type 1 receptor. CONCLUSIONS: In men > 50 years of age, the ACE gene polymorphism modulates the physiologic age-induced reduction of diastolic BP. The D allele might contribute to enhance this reduction, a finding that needs confirmation using prospective studies.

Age-related increase of pulse pressure and gene polymorphisms in essential hypertension: a preliminary study.

Genes may modulate the changes of blood pressure (BP) with age; this possibility has never been studied for the age-related increase of pulse pressure (PP), although in older populations, PP is considered the stronger mechanical factor predicting cardiovascular mortality. In humans, the presence of the mutant allele C of the angiotensin II (Ang II) AT(1)-receptor or of the mutant allele T of the eNOS G(298) T gene polymorphisms is associated with enhanced contractile properties of conduit arteries in response to vasoconstrictive agents. In this study, we evaluated, in subjects with untreated essential hypertension, whether the presence of these mutant alleles or their combination might influence the age-related increase of PP. Three main findings emerged from the study and were particularly observed in women: 1) the presence of the C and/or of the T mutant alleles or their combination were associated with a steeper slope of the age versus PP curve, compared with subjects without the mutant allele; 2) the slope was more significantly enhanced when the two mutant alleles were associated in the same genotype; and 3) no comparable age- and gender-related changes in systolic, diastolic or mean BP were found according to this genetic classification. In subjects with essential hypertension, genes may modulate the age-mediated increase of PP. This finding gives new insights in the interactions between genes, mechanical factors and cardiovascular risk.

Deciphering cellular states of innate tumor drug responses.

BACKGROUND: The molecular mechanisms underlying innate tumor drug resistance, a major obstacle to successful cancer therapy, remain poorly understood. In colorectal cancer (CRC), molecular studies have focused on drug-selected tumor cell lines or individual candidate genes using samples derived from patients already treated with drugs, so that very little data are available prior to drug treatment. RESULTS: Transcriptional profiles of clinical samples collected from CRC patients prior to their exposure to a combined chemotherapy of folinic acid, 5-fluorouracil and irinotecan were established using microarrays. Vigilant experimental design, power simulations and robust statistics were used to restrain the rates of false negative and false positive hybridizations, allowing successful discrimination between drug resistance and sensitivity states with restricted sampling. A list of 679 genes was established that intrinsically differentiates, for the first time prior to drug exposure, subsequently diagnosed chemo-sensitive and resistant patients. Independent biological validation performed through quantitative PCR confirmed the expression pattern on two additional patients. Careful annotation of interconnected functional networks provided a unique representation of the cellular states underlying drug responses. CONCLUSION: Molecular interaction networks are described that provide a solid foundation on which to anchor working hypotheses about mechanisms underlying in vivo innate tumor drug responses. These broad-spectrum cellular signatures represent a starting point from which by-pass chemotherapy schemes, targeting simultaneously several of the molecular mechanisms involved, may be developed for critical therapeutic intervention in CRC patients. The demonstrated power of this research strategy makes it generally applicable to other physiological and pathological situations.