Lisa Kurland

Angiotensin converting enzyme gene polymorphism predicts blood pressure response to angiotensin II receptor type 1 antagonist treatment in hypertensive patients

Objectives To determine whether polymorphisms in the renin–angiotensin system can predict blood pressure-lowering response to antihypertensive treatment; more specifically, in response to treatment with irbesartan or atenolol. Design and methods Eighty-six patients with hypertension were randomized to double-blind treatment with either the angiotensin II type 1 receptor antagonist irbesartan or the β1 adrenergic receptor blocker atenolol and followed for 3 months. We analysed angiotensinogen T174M and M235T, angiotensin converting enzyme (ACE) I/D and angiotensin II type 1 receptor A1166C polymorphisms and related them to blood pressure reduction. Results The mean reductions in blood pressure were similar for both treatments. In the irbesartan group, individuals homozygous for the ACE gene I allele showed a greater reduction in diastolic blood pressure, exceeding those with the D allele (− 18 ± 11 SD versus − 7 ± 10 mmHg, P = 0.0096). This was not the case during treatment with atenolol, and the interaction term between type of treatment and ACE II genotype was significant (P = 0.0176). The angiotensinogen and angiotensin II type 1 receptor polymorhisms were not related to the response to treatment. Conclusions ACE genotyping predicted the blood pressure-lowering response to antihypertensive treatment with irbesartan but not atenolol. Thus, specific genotypes might predict the response to specific antihypertensive treatment.

Hydrochlorothiazide, but not Candesartan, aggravates insulin resistance and causes visceral and hepatic fat accumulation : the mechanisms for the diabetes preventing effect of Candesartan (MEDICA) Study

Treatment with angiotensin II receptor blockers is associated with lower risk for the development of type 2 diabetes mellitus compared with thiazide diuretics. The Mechanisms for the Diabetes Preventing Effect of Candesartan Study addressed insulin action and secretion and body fat distribution after treatment with candesartan, hydrochlorothiazide, and placebo. Twenty-six nondiabetic, abdominally obese, hypertensive patients were included in a multicenter 3-way crossover trial, and 22 completers (by predefined criteria; 10 men and 12 women) were included in the analyses. They underwent 12-week treatment periods with candesartan (C; 16 to 32 mg), hydrochlorothiazide (H; 25 to 50 mg), and placebo (P), respectively, and the treatment order was randomly assigned and double blinded. Intravenous glucose tolerance tests and euglycemic hyperinsulinemic (56 mU/m2 per minute) clamps were performed. Intrahepatic and intramyocellular and extramyocellular lipid content and subcutaneous and visceral abdominal adipose tissue were measured using proton magnetic resonance spectroscopy and MRI. Insulin sensitivity (M-value) was reduced following H versus C and P (6.07±2.05, 6.63±2.04, and 6.90±2.10 mg/kg of body weight per minute, mean±SD; P≤0.01). Liver fat content was higher (P<0.05) following H than both P and C. The subcutaneous to visceral abdominal adipose tissue ratio was reduced following H versus C and P (P<0.01). Glycosylated hemoglobin, alanine aminotransferase, aspartate aminotransferase, and high-sensitivity C-reactive protein levels were higher (P<0.05) after H, but not C, versus P. There were no changes in body fat, intramyocellular lipid, extramyocellular lipid, or first-phase insulin secretion. Blood pressure was reduced similarly by C and H versus P. In conclusion, visceral fat redistribution, liver fat accumulation, low-grade inflammation, and aggravated insulin resistance were demonstrated after hydrochlorothiazide but not candesartan treatment. These findings can partly explain the diabetogenic potential of thiazides.

The CYP2C9 genotype predicts the blood pressure response to irbesartan: results from the Swedish Irbesartan Left Ventricular Hypertrophy Investigation vs Atenolol (SILVHIA) trial

Background The cytochrome P450 CYP2C9 enzyme (CYP2C9) metabolizes many clinically important drugs, for example, phenytoin, warfarin and the angiotensin II type 1 (AT1) receptor antagonists, losartan and irbesartan. Single nucleotide polymorphisms in the CYP2C9 gene result in the expression of three important variants, CYP2C9*1 (wild-type), CYP2C9*2 and CYP2C9*3, the last two exhibiting reduced catalytic activity compared with the wild-type. The CYP2C9 genotype is known to determine sensitivity to and dose requirements for both warfarin and phenytoin, and also the rate of metabolism of losartan. However, its influence on clinical response to treatment with the AT1 receptor antagonist, irbesartan, has not been investigated. Objective To determine whether the CYP2C9 genotype influences the blood pressure-decreasing response to antihypertensive treatment with irbesartan. Design and methods One hundred and two patients with essential hypertension and left ventricular hypertrophy were allocated randomly to groups to receive double-blind treatment with either irbesartan (n = 49) or the β1-adrenergic receptor blocker, atenolol (n = 53). Blood pressure was measured before and after 12 weeks of treatment. CYP2C9 genotyping was performed using solid-phase minisequencing. Results The diastolic blood pressure (DBP) response differed in relation to the CYP2C9 genotype in patients given irbesartan: the reduction in patients with genotype CYP2C9*1/ CYP2C9*1 (n = 33) was 7.5% and that with CYP2C9*1/ CYP2C9*2 (n = 12) was 14.4% (P = 0.036). A similar trend was seen for systolic blood pressure. In contrast, no relation was seen between the CYP2C9 genotype and blood pressure response to atenolol, a drug not metabolized via CYP2C9. Conclusions The CYP2C9 genotype seems to predict the DBP response to irbesartan, but not to atenolol, in patients with essential hypertension.

Polymorphisms in the angiotensinogen and angiotensin II type 1 receptor gene are related to change in left ventricular mass during antihypertensive treatment: results from the Swedish Irbesartan Left Ventricular Hypertrophy Investigation versus Atenolol (SILVHIA) trial.

Background Our aim was to determine if gene polymorphisms in the renin–angiotensin–aldosterone system (RAAS) were related to the degree of change in left ventricular hypertrophy (LVH) during antihypertensive treatment. Methods and results Patients with essential hypertension and echocardiographically diagnosed LVH were included in a double-blind study to receive treatment with either the angiotensin II type 1 receptor (AT1-receptor) antagonist irbesartan (n = 41), or the beta-1 adrenergic receptor blocker atenolol (n = 43) as monotherapy for 3 months. The angiotensinogen T174M and M235T, the angiotensin-converting enzyme I/D, the AT1-receptor A1166C and the aldosterone synthase (CYP11B2) -344 C/T polymorphisms were analysed and related to the change in left ventricular mass (LVM). Patients with the angiotensinogen 174 TM genotype treated with irbesartan responded with the greatest reduction in LVM (−23 ± 31SD g/m2 for TM and +0.5 ± 18 g/m2 for TT, P = 0.005), independent of blood pressure reduction. Both the angiotensinogen 235 T-allele (P = 0.02) and the AT1-receptor 1166 AC genotype responded with the greatest reduction in LVM when treated with irbesartan (−0.1 ± 19 g/m2 for AA and –18 ± 30 g/m2 for AC, P = 0.02), independent of blood pressure reduction. These polymorphisms were not associated with the change in LVM during treatment with atenolol. Discussion The angiotensinogen T174M and M235T and the AT1-receptor A1166C polymorphisms were related to the change in LVH during antihypertensive treatment with an AT1-receptor antagonist; of these angiotensinogen T174M was the most powerful. This highlights the role of the RAAS for left ventricular hypertrophy and the potential of pharmacogenetics as a tool for guidance of antihypertensive therapy.

Aldosterone synthase (CYP11B2) -344 C/T polymorphism is related to antihypertensive response : Results from the Swedish Irbesartan left ventricular hypertrophy investigation versus atenolol (SILVHIA) trial

BACKGROUND Our aim was to determine whether the aldosterone synthase (CYP11B2) -344 C/T polymorphism was associated with the blood pressure (BP)-lowering response to antihypertensive treatment. METHODS Patients with mild-to-moderate primary hypertension and left ventricular hypertrophy were randomized in a double-blind study to receive treatment with either the angiotensin II type 1 (AT1) receptor antagonist irbesartan (n = 43), or the beta1-adrenergic receptor blocker atenolol (n = 43). The aldosterone synthase (CYP11B2) -344 C/T polymorphism was analyzed using solid-phase minisequencing and related to BP reduction after 3 months treatment. Serum aldosterone levels were measured. RESULTS After 3 months treatment the mean reductions in BP were similar for both treatment groups. When assessing the systolic BP reduction in the irbesartan group, patients with the TT variant had a more pronounced reduction (-21 +/- 19 SD mm Hg, n = 17) than both the TC (-14 +/- 18 mm Hg, n= 18) and CC (0 +/- 17 mm Hg, n = 8) genotypes (P = .04). There was no association between this polymorphism and the diastolic BP response. The -344 C/T polymorphism was not associated with the BP response to atenolol. Nor was it related to the baseline serum aldosterone level. CONCLUSIONS The aldosterone synthase -344 C/T polymorphism was related to the BP-lowering response in hypertensive patients treated with the AT1-receptor antagonist irbesartan.

Comparison of the SALT and Smart triage systems using a virtual reality simulator with paramedic students.

Objectives Virtual reality systems may allow for organized study of mass casualty triage systems by allowing investigators to replicate the same mass casualty incident, with the same victims, for a large number of rescuers. The study objectives were to develop such a virtual reality system, and use it to assess the ability of trained paramedic students to triage simulated victims using two triage systems. Methods Investigators created 25 patient scenarios for a highway bus crash in a virtual reality simulation system. Paramedic students were trained to proficiency on the new ‘Sort, Assess, Life saving interventions, Treat and Transport (SALT)’ triage system, and 22 students ran the simulation, applying the SALT algorithm to each victim. After a 3-month washout period, the students were retrained on the ‘Smart’ triage system, and each student ran the same crash simulation using the Smart system. Data inputs were recorded by the simulation software and analyzed with the paired t-tests. Results The students had a mean triage accuracy of 70.0% with SALT versus 93.0% with Smart (P=0.0001). Mean overtriage was 6.8% with SALT versus 1.8% with Smart (P=0.0015), and mean undertriage was 23.2% with SALT versus 5.1% with Smart (P=0.0001). The average time for a student to triage the scene was 21 min 3 s for SALT versus 11 min 59 s for Smart (P=0.0001). Conclusion The virtual reality platform seems to be a viable research tool for examining mass casualty triage. A small sample of trained paramedic students using the virtual reality system was able to triage simulated patients faster and with greater accuracy with ‘Smart’ triage than with ‘SALT’ triage.

Hospital incident command system (HICS) performance in Iran; decision making during disasters

BackgroundHospitals are cornerstones for health care in a community and must continue to function in the face of a disaster. The Hospital Incident Command System (HICS) is a method by which the hospital operates when an emergency is declared. Hospitals are often ill equipped to evaluate the strengths and vulnerabilities of their own management systems before the occurrence of an actual disaster. The main objective of this study was to measure the decision making performance according to HICS job actions sheets using tabletop exercises.MethodsThis observational study was conducted between May 1st 2008 and August 31st 2009. Twenty three Iranian hospitals were included. A tabletop exercise was developed for each hospital which in turn was based on the highest probable risk. The job action sheets of the HICS were used as measurements of performance. Each indicator was considered as 1, 2 or 3 in accordance with the HICS. Fair performance was determined as < 40%; intermediate as 41-70%; high as 71-100% of the maximum score of 192. Descriptive statistics, T-test, and Univariate Analysis of Variance were used.ResultsNone of the participating hospitals had a hospital disaster management plan. The performance according to HICS was intermediate for 83% (n = 19) of the participating hospitals. No hospital had a high level of performance. The performance level for the individual sections was intermediate or fair, except for the logistic and finance sections which demonstrated a higher level of performance. The public hospitals had overall higher performances than university hospitals (P = 0.04).ConclusionsThe decision making performance in the Iranian hospitals, as measured during table top exercises and using the indicators proposed by HICS was intermediate to poor. In addition, this study demonstrates that the HICS job action sheets can be used as a template for measuring the hospital response. Simulations can be used to assess preparedness, but the correlation with outcome remains to be studied.

Identification of adult septic patients in the prehospital setting: a comparison of two screening tools and clinical judgment.

Background Timely identification and treatment of sepsis is crucial for patient outcome. The aim of this study was to compare two previously unvalidated prehospital sepsis screening tools with clinical judgment by emergency medical services (EMS) personnel with respect to identification of septic patients. Patients and methods We carried out a retrospective cross-sectional study of 353 adult patients, transported by the EMS, with a hospital discharge International Classification of Diseases code consistent with sepsis. We analyzed EMS records for the identification of sepsis according to two screening tools and clinical judgment by EMS providers. The Robson screening tool includes temperature, heart rate, respiratory rate, altered mental status, plasma glucose, and a history suggestive of a new infection. BAS 90-30-90 refers to the vital signs: oxygen saturation, respiratory rate, and systolic blood pressure. McNemar’s two related samples test was used to compare the sensitivity of the two screening tools with the sensitivity of clinical judgment. Results The Robson screening tool had a sensitivity of 75% (18 out of 24 patients for whom all parameters were documented, P<0.001, as compared with clinical judgment). BAS 90-30-90 had a sensitivity of 43% (76 out of 175 patients, P<0.001). EMS personnel documented suspected sepsis in 42 out of 353 (12%) patients with sepsis. Conclusion The Robson screening tool had a sensitivity superior to both BAS 90-30-90 and clinical judgment. This supports our hypothesis that the implementation of a screening tool could lead to increased prehospital identification of sepsis, which may enable a more timely treatment of these patients.

Facilitators and obstacles in pre-hospital medical response to earthquakes: a qualitative study

BackgroundEarthquakes are renowned as being amongst the most dangerous and destructive types of natural disasters. Iran, a developing country in Asia, is prone to earthquakes and is ranked as one of the most vulnerable countries in the world in this respect. The medical response in disasters is accompanied by managerial, logistic, technical, and medical challenges being also the case in the Bam earthquake in Iran. Our objective was to explore the medical response to the Bam earthquake with specific emphasis on pre-hospital medical management during the first days.MethodsThe study was performed in 2008; an interview based qualitative study using content analysis. We conducted nineteen interviews with experts and managers responsible for responding to the Bam earthquake, including pre-hospital emergency medical services, the Red Crescent, and Universities of Medical Sciences. The selection of participants was determined by using a purposeful sampling method. Sample size was given by data saturation.ResultsThe pre-hospital medical service was divided into three categories; triage, emergency medical care and transportation, each category in turn was identified into facilitators and obstacles. The obstacles identified were absence of a structured disaster plan, absence of standardized medical teams, and shortage of resources. The army and skilled medical volunteers were identified as facilitators.ConclusionsThe most compelling, and at the same time amenable obstacle, was the lack of a disaster management plan. It was evident that implementing a comprehensive plan would not only save lives but decrease suffering and enable an effective praxis of the available resources at pre-hospital and hospital levels.

Single nucleotide polymorphisms predict the change in left ventricular mass in response to antihypertensive treatment

Background Our aim was to determine whether the change in left ventricular (LV) mass in response to antihypertensive treatment could be predicted by multivariate analysis of single nucleotide polymorphisms (SNPs) in candidate genes reflecting pathways likely to be involved in blood pressure control. Methods Patients with mild to moderate primary hypertension and LV hypertrophy were randomized in a double-blind fashion to treatment with either the angiotensin II type 1 receptor antagonist irbesartan (n = 48) or the β1 adrenoreceptor blocker atenolol (n = 49). A microarray-based minisequencing system was used for genotyping 74 SNPs in 25 genes. These genotypes were related to the change in LV mass index by echocardiography, after 12 weeks treatment as monotherapy, using stepwise multiple regression analysis. Results The blood pressure reductions were similar and significant in both treatment groups. Two SNPs in two separate genes (the angiotensinogen T1198C polymorphism, corrsponding to the M235T variant and the apolipoprotein B G10108A polymorphism) for those treated with irbesartan, and the adrenoreceptor α2A A1817G for those treated with atenolol, significantly predicted the change in LV mass. The predictive power of these SNPs was independent of the degree of blood pressure reduction. Conclusion SNPs in the angiotensinogen, apolipoprotein B, and the α2 adrenoreceptor gene predicted the change in LV mass during antihypertensive therapy. These results illustrate the potential of using microarray-based technology for SNP genotyping in predicting individual drug responses.