Increased salt retention and hypertension from non-steroidal agents in the elderly

We studied blood pressure and natriuretic responses to acute salt loading, and the effect of non-steroidal anti-inflammatory agents on these responses, in five healthy normotensive women aged 65 to 71 years. Five women aged 25 to 31 years acted as controls. Intravenous saline loading, with and without prior ingestion of ibuprofen, was 15 ml/kg/h for 3 h. Baseline blood pressures were higher in the elderly. Saline infusion without ibuprofen raised systolic blood pressure (SBP) by about 25 mmHg in the older group only. Ibuprofen increased baseline SBP in the elderly (129 +/- 6 vs. 116 +/- 5 mmHg, p < 0.05). Saline loading after ibuprofen again raised blood pressure by about 25 mmHg in the elderly only. The elderly group showed markedly increased sodium excretion during saline loading, but this was reduced by ibuprofen. Ibuprofen had no effect on SBP or sodium excretion in controls. Ageing appears to increase susceptibility to salt retention and hypertension from non-steroidal anti-inflammatory agents.      

Imaging of thoracic aortic dissection

Acute thoracic aortic dissection has a high mortality if untreated, so the diagnosis must be rapidly made if mortality is to be lowered significantly. Multiple imaging techniques are often used. This retrospective study from 1988 to 1993 assesses the usefulness in diagnosis of chest X-rays, computed tomography (CT) scanning, aortography, magnetic resonance imaging (MRI), trans-thoracic (TTE) and trans-oesophageal (TOE) echocardiography. Forty-two patients with a final clinical diagnosis of dissection were studied. The diagnosis was confirmed in 16 (13 at surgery and three at autopsy). Three died with dissection given as the only cause for death. Chest X-ray abnormalities were seen in all 19 patients with surgery or death from dissection, with a widened mediastinum and/or dilated aorta being present in 17. In the group of 16 patients with surgery or autopsy proof, CT scans found dissections in 9 of 12 patients studied and correctly classified the type in only five. Aortography was performed in five, with accurate depiction of dissection and type in all. TTE found dissections in three of eight patients imaged by this method. MRI and TOE were performed each on two patients, with accurate depiction of dissection and type in each. Because of the relatively low sensitivity of CT scanning in defining aortic dissections Westmead Hospital is currently assessing the use of TOE as the prime imaging modality prior to surgical intervention.     

Ambulatory blood pressure monitoring: practical considerations

Ambulatory blood pressure monitoring (ABPM) allows one to evaluate the blood pressure (BP) profile over a 24-hour period in the patient's natural environment. Casual pressure measurements in the physician's office can be affected by alarm reactions, thus causing "white coat" hypertension. ABPM allows one to evaluate these reactions and determine the average pressure and variability of BP along with the effects of physical activity and emotional arousal on BP patterns while at work, at home, and during sleep. Average pressures determined by ABPM are more predictive of target organ involvement and cardiovascular complications of hypertension than casual monitoring of BP in the clinic. The absence of physiologic decline in arterial pressure during sleep is associated with increased prevalence of atherosclerotic complications and left ventricular hypertrophy as well as impairment of the autonomic nervous system. Although further prospective studies are needed to confirm the benefits of home pressure readings and ABPM, ABPM can be helpful in the diagnosis and determination of prognosis and therapeutic responses in a select group of patients.     

A double mutant [N543H+2393del9] allele in the LDL receptor gene in familial hypercholesterolemia: effect on plasma cholesterol levels and cardiovascular disease

Familial hypercholesterolemia is a genetic disorder caused by mutations in the LDL receptor gene. During a survey of mutations of LDL receptor gene in Spanish FH patients we found two mutations in the same allele: a missense N543H mutation in exon 11 and a 9bp inframe deletion (2393del9) located in exon 17. This double mutant allele was founded in 10 out of 458 unrelated patients: one homozygous FH [N543H+2393del9] + [N543H+2393del9], one compound heterozygote [N543H+2393del9] + [W-18X+E256K] and 8 heterozygotes. Flow cytometric analysis showed a defective LDL binding (20% of normal value) and internalization (23%) in lymphocytes from the homozygous patient; furthermore, studies of mitogen-stimulated lymphocytes demonstrated that the ability of LDL to support cell proliferation was impaired. Unexpectedly, not all carriers of the double mutant allele develop hypercholesterolemia and, furthermore, cholesterol-lowering treatment of the homozygous patient resulted in a 58% LDL cholesterol reduction. In conclusion, the phenotypic expression in the homozygous and heterozygous patients presented here, as well as the LDL-receptor residual activity, allowed the classification of this mutation as mild extending the group of mild mutations found at homozygosity.     

Distribution of mutations in the PEX gene in families with X-linked hypophosphataemic rickets (HYP)

Mutations in the PEX gene at Xp22.1 (phosphate-regulating gene with homologies to endopeptidases, on the X-chromosome), are responsible for X-linked hypophosphataemic rickets (HYP). Homology of PEX to the M13 family of Zn2+ metallopeptidases which include neprilysin (NEP) as prototype, has raised important questions regarding PEX function at the molecular level. The aim of this study was to analyse 99 HYP families for PEX gene mutations, and to correlate predicted changes in the protein structure with Zn2+ metallopeptidase gene function. Primers flanking 22 characterised exons were used to amplify DNA by PCR, and SSCP was then used to screen for mutations. Deletions, insertions, nonsense mutations, stop codons and splice mutations occurred in 83% of families screened for in all 22 exons, and 51% of a separate set of families screened in 17 PEX gene exons. Missense mutations in four regions of the gene were informative regarding function, with one mutation in the Zn2+-binding site predicted to alter substrate enzyme interaction and catalysis. Computer analysis of the remaining mutations predicted changes in secondary structure, N-glycosylation, protein phosphorylation and catalytic site molecular structure. The wide range of mutations that align with regions required for protease activity in NEP suggests that PEX also functions as a protease, and may act by processing factor(s) involved in bone mineral metabolism.      

Fitness in the fit: does physical conditioning affect cardiovascular risk factors in middle-aged marathon runners?

OBJECTIVE: The study was designed to assess cardiovascular risk factorsin marathon runners with different degrees of fitness. DESIGN: A total of 30 male middle-aged marathon runners were dividedaccording to their marathon running time into fit (265 ±8 min), fitter (222 ± 5 min) and fittest (178 ±12 min). The three groups of 10 runners each were comparablein age, weight, and body surface area. Cardiovascular risk factorswere assessed by measuring arterial pressure before and duringexercise (150 watts) and determination of plasma lipoproteins,uric acid, glucose and white blood cell count before and aftera marathon run. RESULTS: All measured laboratory values such as high-density lipoproteincholesterol (P<0.05), low-density lipoprotein cholesterol(P <0.05), total cholesterol (non-significant), triglycerides(non-significant), blood sugar (non-significant), uric acid(P <0.05), and white blood cell count (P <0.05) indicateda lower cardiovascular risk in the fastest when compared withthe slowest runners. Resting blood pressure was similar in thethree groups but consistently lower at all levels of exercisein the fittest when compared with the less fit runners. Thefittest runners also showed greater increases in high-densitylipoprotein cholesterol after the marathon run (14% vs 8% inthe slowest runners, P<0.05). CONCLUSIONS: We conclude that even at the extreme end of a continuum suchas represented by well-conditioned, middle-aged marathon runners,cardiovascular risk factors are related to the degree of fitness,as measured by the marathon running time.