Simone Vanni

Cardiac Growth Factors in Human Hypertrophy Relations With Myocardial Contractility and Wall Stress

The aim of the present study was to investigate whether and which cardiac growth factors are involved in human hypertrophy, whether growth factor synthesis is influenced by overload type and/or by the adequacy of the hypertrophy, and the relationships between cardiac growth factor formation and ventricular function. Cardiac growth factor formation was assessed by measuring aorta-coronary sinus concentration gradient in patients with isolated aortic stenosis (n=26) or regurgitation (n=15) and controls (n=12). Gene expression and cellular localization was investigated in ventricular biopsies using reverse transcriptase-polymerase chain reaction and in situ hybridization. Cardiac hypertrophy with end-systolic wall stress <90 kdyne/cm2 was associated with a selective increased formation of insulin-like growth factor (IGF)-I in aortic regurgitation and of IGF-I and endothelin (ET)-1 in aortic stenosis. mRNA levels for IGF-I and preproET-1 were elevated and mainly expressed in cardiomyocytes. At stepwise analysis, IGF-I formation was correlated to the mean velocity of circumferential fiber shortening (r=0.86, P<0.001) and ET-1 formation to relative wall thickness (r=0.82, P<0. 001). When end-systolic wall stress was >90 kdyne/cm2, IGF-I and ET-1 synthesis by cardiomyocytes was no longer detectable, and only angiotensin (Ang) II was generated, regardless of the type of overload. The mRNA level for angiotensinogen was high, and the mRNA was exclusively expressed in the interstitial cells. Ang II formation was positively correlated to end-systolic stress (r=0.89, P<0.001) and end-diastolic stress (r=0.84, P<0.001). Multivariate stepwise analysis selected end-systolic stress as the most predictive variable and left ventricular end-diastolic pressure as the independent variable for Ang II formation (r=0.93, P<0.001). In conclusion, the present results indicate that the course of human left ventricular hypertrophy is characterized by the participation of different cardiac growth factors that are selectively related both to the type of hemodynamic overload and to ventricular function.

Role of Endothelin-1 in Exposure to High Altitude Acute Mountain Sickness and Endothelin-1 (ACME-1) Study

Background— The degree of pulmonary hypertension in healthy subjects exposed to acute hypobaric hypoxia at high altitude was found to be related to increased plasma endothelin (ET)-1. The aim of the present study was to investigate the effects of ET-1 antagonism on pulmonary hypertension, renal water, and sodium balance under acute and prolonged exposure to high-altitude–associated hypoxia. Methods and Results— In a double-blind fashion, healthy volunteers were randomly assigned to receive bosentan (62.5 mg for 1 day and 125 mg for the following 2 days; n=10) or placebo (n=10) at sea level and after rapid ascent to high altitude (4559 m). At sea level, bosentan did not induce any significant changes in hemodynamic or renal parameters. At altitude, bosentan induced a significant reduction of systolic pulmonary artery pressure (21±7 versus 31±7 mm Hg, P<0.03) and a mild increase in arterial oxygen saturation versus placebo after just 1 day of treatment. However, both urinary volume and free water clearance (H2OCl/glomerular filtration rate) were significantly reduced versus placebo after 2 days of ET-1 antagonism (1100±200 versus 1610±590 mL; −6.7±3.5 versus −1.8±4.8 mL/min, P<0.05 versus placebo for both). Sodium clearance and segmental tubular function were not significantly affected by bosentan administration. Conclusions— The present results indicate that the early beneficial effect of ET-1 antagonism on pulmonary blood pressure is followed by an impairment in volume adaptation. These findings must be considered for the prevention and treatment of acute mountain sickness.

Selective Upregulation of Cardiac Endothelin System in Patients With Ischemic but Not Idiopathic Dilated Cardiomyopathy: Endothelin-1 System in the Human Failing Heart

Only scarce information is available on the activity and modifications of the cardiac endothelin (ET)-1 system in heart failure due to ischemic (ICM) or idiopathic dilated (DCM) cardiomyopathy. The activity of the ET-1 system was investigated by measuring cardiac ET-1 and big ET-1 formation and quantifying cardiac mRNA for prepro-ET-1 (ppET-1), ET-converting enzyme-1, and ET(A) and ET(B) receptors both in myocardium and in isolated myocytes using Northern blot, reverse transcription-polymerase chain reaction, and in situ hybridization in 22 patients with DCM and 20 with ICM who underwent cardiac transplantation and in 7 potential heart transplant donors (nonfailing hearts). Notwithstanding a similar increase of plasma ET-1 in the 2 groups, cardiac ET formation, mRNA levels for ppET-1, and ET(A) and ET(B) receptors were higher on both the myocardium and isolated myocytes from ICM than on those from DCM hearts (P<0.001 for all). ppET-1 and ET-converting enzyme-1 mRNAs were expressed on myocytes and endothelial and interstitial cells in ICM, whereas in DCM and nonfailing hearts they were mainly expressed on nonmyocyte cells. In both ICM and DCM, the ET(A) mRNA signal was expressed on both myocytes and nonmyocyte cells, whereas ET(B) mRNA was almost exclusively localized on nonmyocyte cells. ET(A)- and ET(B)-specific receptor binding was increased on both myocytes and cardiac membranes, showing a positive correlation with left ventricular ejection fraction in ICM (r=0.78 and 0.70) but not in DCM patients. The present results show that human ventricular myocytes express all of the components of the ET-1 system, which is selectively upregulated in ICM patients and appears to be functionally important in the maintenance of cardiac function.

Accuracy of Point-of-Care Multiorgan Ultrasonography for the Diagnosis of Pulmonary Embolism

BACKGROUND Presenting signs and symptoms of pulmonary embolism (PE) are nonspecific, favoring a large use of second-line diagnostic tests such as multidetector CT pulmonary angiography (MCTPA), thus exposing patients to high-dose radiation and to potential serious complications. We investigated the diagnostic performance of multiorgan ultrasonography (lung, heart, and leg vein ultrasonography) and whether multiorgan ultrasonography combined to Wells score and D-dimer could safely reduce MCTPA tests. METHODS Consecutive adult patients suspected of PE and with a Wells score > 4 or a positive D-dimer result were prospectively enrolled in three EDs. Final diagnosis was obtained with MCTPA. Multiorgan ultrasonography was performed before MCTPA and considered diagnostic for PE if one or more subpleural infarcts, right ventricular dilatation, or DVT was detected. If multiorgan ultrasonography was negative for PE, an alternative ultrasonography diagnosis was sought. Accuracies of each single-organ and multiorgan ultrasonography were calculated. RESULTS PE was diagnosed in 110 of 357 enrolled patients (30.8%). Multiorgan ultrasonography yielded a sensitivity of 90% and a specificity of 86.2%, lung ultrasonography 60.9% and 95.9%, heart ultrasonography 32.7% and 90.9%, and vein ultrasonography 52.7% and 97.6%, respectively. Among the 132 patients (37%) with multiorgan ultrasonography negative for PE plus an alternative ultrasonographic diagnosis or plus a negative D-dimer result, no patients received PE as a final diagnosis. CONCLUSIONS Multiorgan ultrasonography is more sensitive than single-organ ultrasonography, increases the accuracy of clinical pretest probability estimation in patients with suspected PE, and may safely reduce the MCTPA burden. TRIAL REGISTRY ClinicalTrials.gov; No.: NCT01635257; URL: www.clinicaltrials.gov.

Identification of intermediate-risk patients with acute symptomatic pulmonary embolism

The identification of normotensive patients with acute pulmonary embolism (PE) at high risk of adverse PE-related clinical events (i.e. intermediate-risk group) is a major challenge. We combined individual patient data from six studies involving 2874 normotensive patients with PE. We developed a prognostic model for intermediate-risk PE based on the clinical presentation and the assessment of right ventricular dysfunction and myocardial injury. We used a composite of PE-related death, haemodynamic collapse or recurrent PE within 30 days of follow-up as the main outcome measure. The primary outcome occurred in 198 (6.9%) patients. Predictors of complications included systolic blood pressure 90–100 mmHg (adjusted odds ratio (aOR) 2.45, 95% CI 1.50–3.99), heart rate ≥110 beats per min (aOR 1.87, 95% CI 1.31–2.69), elevated cardiac troponin (aOR 2.49, 95% CI 1.71–3.69) and right ventricular dysfunction (aOR 2.28, 95% CI 1.58–3.29). We used these variables to construct a multidimensional seven-point risk index; the odds ratio for complications per one-point increase in the score was 1.55 (95% CI 1.43–1.68; p<0.001). The model identified three stages (I, II and III) with 30-day PE-related complication rates of 4.2%, 10.8% and 29.2%, respectively. In conclusion, a simple grading system may assist clinicians in identifying intermediate-risk PE. A simple grading system to identify intermediate-risk pulmonary embolism http://ow.ly/uItnL

Prognostic Value of ECG Among Patients with Acute Pulmonary Embolism and Normal Blood Pressure

OBJECTIVE To investigate the prognostic value of electrocardiography (ECG) alone or in combination with echocardiography in patients with acute pulmonary embolism and normal blood pressure. METHODS Consecutive adult patients presenting to the emergency department at Azienda Ospedaliero-Universitaria Careggi with the first episode of pulmonary embolism were included. Patients with systolic blood pressure less than 100 mm Hg were excluded. ECG and echocardiography were performed within 1 hour from diagnosis and evaluated in a blinded fashion. Right ventricular strain was diagnosed in the presence of one or more of the following ECG findings: complete or incomplete right ventricular branch block, S1Q3T3, and negative T wave in V1-V4. The main outcome measurement was clinical deterioration or death during in-hospital stay. The association of variables with the main outcome was evaluated by multivariate Cox survival analysis. RESULTS A total of 386 patients with proved pulmonary embolism were included in the study; 201 patients (52%) had right ventricular dysfunction according to echocardiography, and 130 patients (34%) showed right ventricular strain. Twenty-three patients (6%) had clinical deterioration or died. At multivariate survival analysis, right ventricular strain was associated with adverse outcome (hazard ratio 2.58; 95% confidence interval, 1.05-6.36) independently of echocardiographic findings. Patients with both right ventricular strain and right ventricular dysfunction (26%) showed an 8-fold elevated risk of adverse outcome (hazard ratio 8.47; 95% confidence interval, 2.43-29.47). CONCLUSION Right ventricular strain pattern on ECG is associated with adverse short-term outcome and adds incremental prognostic value to echocardiographic evidence of right ventricular dysfunction in patients with acute pulmonary embolism and normal blood pressure.

Accuracy of lung ultrasound for the diagnosis of consolidations when compared to chest computed tomography

OBJECTIVES Despite emerging evidences on the clinical usefulness of lung ultrasound (LUS), international guidelines still do not recommend the use of sonography for the diagnosis of pneumonia. Our study assesses the accuracy of LUS for the diagnosis of lung consolidations when compared to chest computed tomography (CT). METHODS This was a prospective study on an emergency department population complaining of respiratory symptoms of unexplained origin. All patients who had a chest CT scan performed for clinical reasons were consecutively recruited. LUS was targeted to evaluate lung consolidations with the morphologic characteristics of pneumonia, and then compared to CT. RESULTS We analyzed 285 patients. CT was positive for at least one consolidation in 87 patients. LUS was feasible in all patients and in 81 showed at least one consolidation, with a good inter-observer agreement (k = 0.83), sensitivity 82.8% (95% CI 73.2%-90%) and specificity 95.5% (95% CI 91.5%-97.9%). Sensitivity raised to 91.7% (95% CI 61.5%-98.6%) and specificity to 97.4% (95% CI 86.5%-99.6%) in patients complaining of pleuritic chest pain. In a subgroup of 190 patients who underwent also chest radiography (CXR), the sensitivity of LUS (81.4%, 95% CI 70.7%-89.7%) was significantly superior to CXR (64.3%, 95% CI 51.9%-75.4%) (P<.05), whereas specificity remained similar (94.2%, 95% CI 88.4%-97.6% vs. 90%, 95% CI 83.2%-94.7%). CONCLUSIONS LUS represents a reliable diagnostic tool, alternative to CXR, for the bedside diagnosis of lung consolidations in patients with respiratory complains.

Different Growth Factor Activation in the Right and Left Ventricles in Experimental Volume Overload

Abstract—Mechanical factors play a key role in activation of cardiac growth factor response in hemodynamic overload, and both cooperate in myocardial remodeling. The present study was performed to investigate whether a different growth factor response is activated in the right and left ventricles in aortocaval fistula and its effects on regional myocardial adaptation. Relations between regional growth factor expression (angiotensin II, insulin-like growth factor-I, and endothelin-1), myocyte shape changes, and collagen deposition were investigated at mRNA and peptide levels in adult pigs after the creation of an aortocaval fistula distal to the renal arteries (n=15) and in sham-operated animals (n=15). The role of angiotensin II was investigated by the administration of angiotensin-converting enzyme inhibitor or angiotensin II receptor antagonist. In the left ventricle, pure volume overload was accompanied by persistent increase of insulin-like growth factor-I mRNA expression, peptide concentration (2.2-fold versus sham at 3 months, P <0.05), and significant increase of myocyte length (+29% at 3 months, P <0.05). Conversely, the mixed pressure-volume overload faced by the right ventricle resulted in significant regional overexpression of all growth factors investigated (angiotensin II, insulin-like growth factor-I, and endothelin-1), with corresponding increase of myocyte diameter and length and collagen deposition (+117% at 3 months). Collagen accumulation in the right ventricle as well as the increase in right ventricular end-diastolic pressure at the 3-month observation were inhibited by angiotensin II antagonism. The left and right ventricles respond differently to aortocaval fistula, and local growth factor expression is closely related to the regional myocardial adaptation.

Characterization of endothelin-1 receptor subtypes in isolated human cardiomyocytes.

On cardiac membranes and isolated cardiomyocytes from the human heart, cell-type distribution and functional activities of endothelin-1 (ET-1) receptor subtypes were investigated by using binding methods and messenger RNA (mRNA) in situ hybridization. The ET-receptor antagonist BMS-182874 selectively and competitively inhibits ET(A) receptors both on isolated myocytes and ventricular membranes with approximately 1,300 times greater affinity for ET(A) than ET(B) subtypes. The [125I]-ET-1 specific binding revealed 42.851+/-2,546 receptors/myocyte with a prevalent proportion of ET(A)-receptor subtypes on both myocytes (84+/-2%) and ventricular membranes (66+/-3%). In situ hybridization studies revealed that mRNA for ET(A) receptors was expressed on both myocytes and nonmyocyte cells, whereas mRNA for ET(B) receptors was almost exclusively expressed on fibroblasts and endothelial cells. Specific binding of [125I]-ET-1 to both myocytes and ventricular membranes in the presence of specific ET(A) (BMS-182874) and ET(B) (BQ-788)-receptor antagonists showed a displacement of [125I]-ET-1 by unlabeled ET-1, which were significantly faster from ET(B) than from ET(A). This suggests a clearance function of ventricular ET(B) receptors.

Delayed neuropsychological sequelae after carbon monoxide poisoning: predictive risk factors in the Emergency Department. A retrospective study

BackgroundDelayed neuropsychological sequelae (DNS) commonly occur after recovery from acute carbon monoxide (CO) poisoning. The preventive role and the indications for hyperbaric oxygen therapy in the acute setting are still controversial. Early identification of patients at risk in the Emergency Department might permit an improvement in quality of care. We conducted a retrospective study to identify predictive risk factors for DNS development in the Emergency Department.MethodsWe retrospectively considered all CO-poisoned patients admitted to the Emergency Department of Careggi University General Hospital (Florence, Italy) from 1992 to 2007. Patients were invited to participate in three follow-up visits at one, six and twelve months from hospital discharge. Clinical and biohumoral data were collected; univariate and multivariate analysis were performed to identify predictive risk factors for DNS.ResultsThree hundred forty seven patients were admitted to the Emergency Department for acute CO poisoning from 1992 to 2007; 141/347 patients participated in the follow-up visit at one month from hospital discharge. Thirty four/141 patients were diagnosed with DNS (24.1%). Five/34 patients previously diagnosed as having DNS presented to the follow-up visit at six months, reporting a complete recovery. The following variables (collected before or upon Emergency Department admission) were associated to DNS development at one month from hospital discharge in the univariate analysis: CO exposure duration >6 hours, a Glasgow Coma Scale (GCS) score <9, seizures, systolic blood pressure <90 mmHg, elevated creatine phosphokinase concentration and leukocytosis. There was no significant correlation with age, sex, voluntary exposure, headache, transient loss of consciousness, GCS between 14 and 9, arterial lactate and carboxyhemoglobin concentration. The multivariate analysis confirmed as independent prognostic factors GCS <9 (OR 7.15; CI 95%: 1.04-48.8) and leukocytosis (OR 3.31; CI 95%: 1.02-10.71).ConclusionsOur study identified several potential predictive risk factors for DNS. Treatment algorithms based on an appropriate risk-stratification of patients in the Emergency Department might reduce DNS incidence; however, more studies are needed. Adequate follow-up after hospital discharge, aimed at correct recognition of DNS, is also important.