Fabio Salvi

Renin-angiotensin system, natriuretic peptides, obesity, metabolic syndrome, and hypertension: An integrated view in humans

The obesity pandemic is closely related to hypertension and metabolic syndrome. Visceral adipose tissue plays a key role in the metabolic and cardiovascular complications of being overweight. The pathophysiological link between visceral adiposity and cardiometabolic complications focuses on insulin sensitivity, sympathetic nervous system, renin–angiotensin–aldosterone system (RAAS) and, only recently, on cardiac natriuretic peptide system (CNPS). RAAS and CNPS are endogenous antagonistic systems on sodium balance, cardiovascular system, and metabolism. The circulating RAAS is dysregulated in obese patients, and adipose tissue has a full local renin–angiotensin system that is active at local and systemic level. Adipocyte biology and metabolism are influenced by local renin–angiotensin system, with angiotensin II acting as a ‘growth factor’ for adipocytes. CNPS induces natriuresis and diuresis, reduces blood pressure, and, moreover, has powerful lipolytic and lipomobilizing activity in humans but not in rodents. In obesity, lower plasmatic natriuretic peptides levels with increasing BMI, waist circumference, and metabolic syndrome have been documented. Thus, reduced CNPS effects coupled with increased RAAS activity have a central role in obesity and its deadly complications. We propose herein an integrated view of the dysregulation of these two antagonistic systems in human obesity complicated with hypertension, metabolic syndrome, and increased cardiovascular risk.

Adverse Drug Events as a Cause of Hospitalization in Older Adults

Older adults are about four to seven times more likely than younger persons to experience adverse drug events (ADEs) that cause hospitalization, especially if they are women and take multiple medications. The prevalence of drug-related hospitalizations has been reported to be as high as 31%, with large heterogeneity between different studies, depending on study setting (all hospital admissions or only acute hospital admissions), study population (entire hospital, specific wards, selected population and/or age groups), type of drug-related problem measured (adverse drug reaction or ADE), method of data collection (chart review, spontaneous reporting or database research) and method and definition used to detect ADEs. The higher risk of drug-related hospitalizations in older adults is mainly caused by age-related pharmacokinetic and pharmacodynamic changes, a higher number of chronic conditions and polypharmacy, which is often associated with the use of potentially inappropriate drugs. Other factors that have been involved are errors related to prescription or administration of drugs, medication non-adherence and inadequate monitoring of pharmacological therapies. A few commonly used drugs are responsible for the majority of emergency hospitalizations in older subjects, i.e. warfarin, oral antiplatelet agents, insulin and oral hypoglycaemic agents, central nervous system agents.The aims of the present review are to summarize recent evidence concerning drug-related hospitalization in older adults, to assess the contribution of specific medications, and to identify potential interventions able to reduce the occurrence of these drug-related events, as they are, at least partly, potentially preventable.

Screening for frailty in elderly emergency department patients by using the Identification of Seniors At Risk (ISAR).

ObjectivesFrail older adults are at an increased risk for adverse outcomes after an Emergency Department (ED) visit. Comprehensive geriatric assessment (CGA) has been proposed to screen for frailty in the ED, but it is difficult to carry out. We tested whether a CGA-based approach using the Identification of Seniors At Risk (ISAR) screening tool was associated with the brief deficit accumulation index (DAI) of frailty.DesignProspective observational study.SettingTwo urban EDs in Italy.ParticipantsA cohort of 200 elderly (≥65 years) ED patients.MeasurementsIdentifiers, triage, clinical and social data along with the administration of ISAR. CGA was performed using: Charlson Index, Short Portable Mental Status Questionnaire and Katz’s ADL. Follow-up data at 30 and 180 days included: mortality, ED revisit, hospital admission, and.functional decline. Frailty was defined according to a brief DAI. Logistic regression evaluated the consistency of the frailty definition; ROC curves evaluated ISAR ability in identifying frailty.ResultsFrailty was present in 117 (58.5%) subjects and predicted ED revisit and frequent ED return, hospitalization and 6-month mortality. ISAR had an AUC of 0.92 (95%CI 0.88–0.96, p<0.0001) in identifying frail elders in the ED and using a cut-off of 2 showed 94% sensitivity and 63% specificity.ConclusionISAR is a useful screening tool for frailty and identifies elderly patients at risk of adverse outcomes after an ED visit. ISAR can also be used to select high-risk patients more likely to benefit from a geriatric approach or intervention, independently of admission or discharge.

Allelic variants of natriuretic peptide receptor genes are associated with family history of hypertension and cardiovascular phenotype

Objective Abnormalities in the natriuretic peptide system could play a key role in the genesis of hypertension. We evaluated the associations between a family history of hypertension, cardiovascular phenotype and allelic variants of Npr1 and Npr3, two candidate genes that codify for natriuretic peptide receptors. Methods We genotyped 45 young normotensive subjects (19 males, 26.8 ± 3.7 years) with accurately assessed family history of hypertension (FH+) and 52 (26 males, 26.1 ± 3.1 years) without (FH−) for the known variants of Npr1 and Npr3 genes, and for a novel length difference (3C/4C) polymorphism at position 15129 in the 3′-untranslated region of the Npr1 gene. Blood pressure, echocardiography and plasma brain natriuretic peptide were assessed. Results Both the novel Npr1 3C allele (59 versus 33%, P < 0.001) and the 3C/3C genotype (31 versus 8%; P < 0.001) were significantly more frequent in FH+ than in FH−. The inverse distribution of the 4C/4C genotype suggested that a casual association was very unlikely. Moreover, the 3C/3C homozygous had significantly higher systolic blood pressure (121.1 ± 6.3 versus 115.6 ± 7.8 mmHg in 4C/4C; P < 0.05) and a longer left ventricular isovolumic relaxation time (67 ± 10 versus 61 ± 9 ms; P < 0.05). The Npr3 C(−55) allele variant was also more frequent in FH+ (88 versus 76%, P < 0.05), but was not associated with the cardiovascular phenotype. Conclusions The novel Npr1 gene 3C variant and the Npr3 gene C(−55) allele are associated with hypertensive family history. Moreover, the functional Npr1 3C variant, when homozygous, is also associated with higher systolic blood pressure and prolonged ventricular relaxation.

Predictive validity of the Identification of Seniors At Risk (ISAR) screening tool in elderly patients presenting to two Italian Emergency Departments

Background and aims: Elderly patients presenting to Emergency Departments (ED) have complex health problems and often undergo adverse outcomes after an ED visit. In Canadian ED, the Identification of Seniors At Risk (ISAR) is useful in screening for these aspects. This study evaluated the predictive validity of ISAR for elderly patients presenting to Italian ED. Methods: Prospective observational study of a cohort of 200 elderly patients presenting to two urban ED in Ancona (Italy). Identifiers and triage, clinical and social data were collected, and the ISAR was administered. The following single outcomes were considered: early (30-day) and late (6-month) ED revisit, frequent ED return, hospital admission, and functional decline. Composite outcomes were: [1] death, long-term care (LTC) placement, functional decline; [2] the same as [1] plus any ED revisit or hospitalization. Odds ratios (OR) and 95% confidence intervals (CI) were calculated. Results: ISAR was positive for 141 (70.5%) subjects, who had high comorbidity, disability and cognitive impairment. ISAR-positive atients hadan OR of 4.77(95% CI, 2.19–10.42) to undergo composite outcome [1] and of 3.46 (95% CI, 1.68–7.15) to experience composite outcome [2]. ISAR also predicted ED revisit and frequent use, hospitalization and functional decline at 6 months. ISAR was also an independent predictor of 6-month mortality (Hazard Ratio 6.9, 95%, CI 1.65–29, p=0.008). Conclusions: ISAR can be used as a screening test to identify Italian elderly ED patients who have an increased 6-month risk of death, LTC placement, functional decline, ED revisit, or hospitalization.

A Geriatric Emergency Service for Acutely Ill Elderly Patients : Pattern of Use and Comparison with a Conventional Emergency Department in Italy

The current disease‐oriented, episodic model of emergency care does not adequately address the complex needs of older adults presenting to emergency departments (EDs). Dedicated ED facilities with a specific organization (e.g., geriatric EDs (GEDs)) have been advocated. One of the few GED experiences in the world is described and its outcomes compared with those of a conventional ED (CED). In a secondary analysis of a prospective observational cohort of 200 acutely ill elderly patients presenting to two urban EDs in Ancona, Italy, identifiers and triage, clinical, and social data were collected and the following outcomes considered: early (30‐day) and late (6‐month) ED revisit, frequent ED return, hospital admission, and functional decline. Death, functional decline, any ED revisit and any hospital admission were also considered as a composite outcome. Odds ratios and 95% confidence intervals (CIs) were calculated. Overall, GED patients were older and frailer than CED patients. The two EDs did not differ in terms of early, late, or frequent ED return or in 6‐month hospital admission or functional decline. The mortality rate was slightly but significantly lower in the GED patients (hazard ratio=0.47, 95% CI=0.22–0.99, P=.047). The data suggest noninferiority and, indirectly, a slight superiority for the GED system in the acute care of elderly people, supporting the hypothesis that ED facilities specially designed for older adults may provide better care.

Mini Nutritional Assessment (short form) and functional decline in older patients admitted to an acute medical ward

Background and aims: Protein and/or energy malnutrition is common in hospitalized older patients and is associated with poor outcomes. Among recommended nutritional screening tools, contrasting data exist about the usefulness of the Mini Nutritional Assessment Short-Form (MNA-SF). We evaluated whether the MNA-SF, alone or integrated with serum albumin levels, is a reliable predictor of functional decline in older patients. Methods: We studied 275 elderly patients (mean age 76.5, 60.7% males) admitted to an acute medical ward of a tertiary-care teaching hospital over a 12-month period. In this observational study, we evaluated nutritional status, with the MNA-SF alone or integrated with albumin. Data were collected at admission and related to laboratory and geriatric assessment features, and length of stay (LOS). Functional decline (defined as a loss ≥10% in terms of Barthel Index score at discharge compared with 2 weeks before admission) was considered as outcome. Results: The MNA-SF estimated 46% patients at risk of malnutrition. These subjects had worse clinical features (lower total cholesterol and albumin levels), longer LOS (13.3 vs 11.2 days, p=0.014) and considerable functional decline (OR 4.25, 95% CI 1.83–9.9, p=0.001). Integrating the MNA-SF with albumin values, we obtained an effective instrument to detect older inpatients with protein-energy malnutrition, at higher risk of undergoing functional decline (OR 16.19, 95% CI 4.68–56.03, p<0.0001). Conclusions: The MNA-SF is a useful screening tool for hospitalized elders at risk of malnutrition. It is associated with poor clinical outcomes and is able to predict functional decline. Together with hypoalbuminemia, it better identifies patients with true protein-energy malnutrition.

Prognostic Stratification of Elderly Patients in the Emergency Department: A Comparison Between the “Identification of Seniors at Risk” and the “Silver Code”

BACKGROUND The increasing number of elderly patients accessing emergency departments (EDs) requires use of validated assessment tools. We compared the Identification of Seniors at Risk (ISAR), using direct patient evaluation, with the Silver Code (SC), based on administrative data. METHODS Subjects aged 75+ years accessing a geriatric ED over an 8-month period were enrolled. Outcomes were need for hospital admission and mortality at the index ED access, ED return visit, hospitalization, and death at 6 months. RESULTS Of 1,632 participants (mean age 84 ± 5.5 years), 75% were ISAR positive, and the sample was homogeneously distributed across the four SC risk categories (cutoffs of 0-3, 4-6, 7-10, and 11+). The two scores were mildly correlated (r = .350, p < .001) and had a similar area under the receiver-operating characteristic curve in predicting hospital admission (ISAR: 0.65, SC: 0.63) and mortality (ISAR: 0.72, SC: 0.70). ISAR-positive subjects were at greater risk of hospitalization and death (odds ratio 2.68 and 5.23, respectively, p < .001); the risk increased across SC classes (p < .001). In the 6-month follow-up of discharged patients, the tools predicted similarly ED return visit, hospital admission, and mortality. The SC predicted these outcomes even in participants not hospitalized at the index ED access. CONCLUSIONS Prognostic stratification of elderly ED patients with the SC is comparable with that obtained with direct patient evaluation. The SC, previously validated in hospitalized patients, predicts ED readmissions and future hospitalizations even in patients discharged directly from the ED.

Risk Stratification of Older Patients in the Emergency Department: Comparison Between the Identification of Seniors At Risk and Triage Risk Screening Tool

BACKGROUND AND OBJECTIVES The increasing number of elderly patients accessing emergency departments (ED) requires use of validated, rapid assessment instruments. The aim of this study was to compare the Identification of Seniors at Risk (ISAR) and Triage Risk Screening Tool (TRST), based on direct patient evaluation. RESEARCH DESIGN AND SUBJECTS This study was a prospective observational study with 6 months follow-up. Subjects were 2,057 residents in the Marche Region, aged 65 or more years, accessing the first-level ED of a geriatric hospital in Ancona, Italy, over a 6-month period. METHODS ISAR and TRST were administered at triage by nurse. Outcomes were in need of hospital admission and mortality at the index ED access, early (within 30 days) and late ED revisit, hospitalization, and death in 6 months. RESULTS ISAR (cutoff of≥2) was positive in 68% of patients, whereas 64% were TRST-positive. The two scores were significantly correlated and had similar areas under the receiver operating characteristic (ROC) curves in predicting hospital admission (ISAR, 0.68; TRST, 0.66) and mortality (ISAR, 0.74; TRST, 0.68), as well as early ED revisit (ISAR, 0.63; TRST, 0.61). In the 6-month follow-up of patients discharged alive, the tools predicted comparably ED return visit (ISAR, 0.60; TRST, 0.59), hospital admission (ISAR, 0.63; TRST, 0.60), and mortality (ISAR, 0.74; TRST, 0.73). A similar performance was observed in the subgroup of participants discharged directly from the ED. CONCLUSIONS Risk stratification of elderly ED patients with ISAR or TRST is substantially comparable for selecting elderly ED patients who could benefit from geriatric interventions. ISAR had slightly higher sensitivity and lower specificity than TRST.

Cardiovascular phenotype of young adults and angiotensinogen alleles.

Objectives and Design Angiotensinogen (AGT) gene variants influence angiotensinogen plasma levels in children and young adults. The angiotensinogen promoter (-6)A variant facilitates gene transcription in human tissues and it has been associated with high blood pressure in older adults. A young adult population can be used as a model to study genotype/phenotype associations between AGT (-6) variants and cardiovascular variables. Methods and Results Anthropometric measurements, blood pressure and heart rate were taken in 422 white Caucasian students (mean age 23.5 years, SD 2.5 years). Family history for hypertension, physical activity and smoking history were evaluated. Left ventricular variables were measured by echocardiography. Carotid artery wall intimal-media thickness (IMT) was measured by high resolution sonography and digitalized morphometry. The AGT G(-6)A alleles were evaluated by mutagenically separated polymerase chain reaction controlled by direct sequencing. No significant associations were found between angiotensinogen genotype and blood pressure, cardiac variables [except for deceleration time in females which increased with the number of (-6)A alleles] and IMT. Allele frequencies were similar between the first and third tertile of blood pressure and left ventricular mass, and were also similar between negative or positive family history for hypertension (the last group having significantly higher systolic blood pressure in males, P = 0.04 and diastolic blood pressure in females, P < 0.01). Moreover, no relevant interaction on the cardiovascular variables was found between AGT genotype and body mass index. Conclusions The angiotensinogen G(-6)A variants do not affect cardiovascular parameters in young adults, but an effect of this polymorphism on cardiovascular phenotype (and hypertension) in older adults cannot be excluded. Additional factors, associated with ageing, should be present to unleash the supposed unfavourable potential of the (-6)A angiotensinogen variant.