Impact of a short-term Mediterranean diet intervention on plasma metabolites: a pilot study.

BACKGROUND: Dietary habits significantly influence the risks of type 2 diabetes and cardiovascular disease. Through metabolomics, we've previously measured plasma metabolites to gauge dietary quality, introducing a healthy dietary metabolic signature (HDMS) linked to a decreased risk of future type 2 diabetes and coronary artery disease. OBJECTIVES: To assess the impact of a 6-day dietary intervention on plasma metabolites and the HDMS. METHODS: Fifty-nine Swedish participants (71% women, mean age 69 years) underwent a 6-day Mediterranean diet (MD) intervention in Italy's Cilento region. All meals, crafted from local recipes and ingredients, were provided. Metabolite profiling pre- and post-intervention was conducted with a UHPLC-QTOF. Alterations in metabolite levels and the HDMS were examined using paired T-test. RESULTS: The MD intervention notably enhanced the HDMS across participants (mean increase: 1.3 standard deviations (SD), 95% CI 1.1-1.4, p = 6E-25). Out of 109 metabolites, 66 exhibited significant alterations (fdr adjusted p < 0.05). Among the 10 most significant changes, increases were observed in several diet related metabolites such as pipecolate, hippurate, caffeine, homostachydrine, acylcarnitine C11:0, acetylornithine, beta-carotene and 7-methylguanine. The most significant decreases manifested in piperine and 3-methylhistidine. CONCLUSIONS: The HDMS, which is linked to a healthy diet and inversely associated with cardiometabolic disease, was significantly improved by the 6-day Mediterranean diet intervention. Notably, metabolite markers previously shown to be indicative of the intake of vegetables, fruits, grains, and legumes increased, while markers previously associated with red meat consumption decreased. These findings highlight the potential of short-term dietary interventions to induce significant changes in plasma metabolite profiles.

Mathematical model of COVID-19 transmission dynamics incorporating booster vaccine program and environmental contamination.

COVID-19 is one of the greatest human global health challenges that causes economic meltdown of many nations. In this study, we develop an SIR-type model which captures both human-to-human and environment-to-human-to-environment transmissions that allows the recruitment of corona viruses in the environment in the midst of booster vaccine program. Theoretically, we prove some basic properties of the full model as well as investigate the existence of SARS-CoV-2-free and endemic equilibria. The SARS-CoV-2-free equilibrium for the special case, where the constant inflow of corona virus into the environment by any other means, Ω is suspended ( Ω = 0 ) is globally asymptotically stable when the effective reproduction number R 0 c < 1 and unstable if otherwise. Whereas in the presence of free-living Corona viruses in the environment ( Ω > 0 ), the endemic equilibrium using the centre manifold theory is shown to be stable globally whenever R 0 c > 1 . The model is extended into optimal control system and analyzed analytically using Pontryagin's Maximum Principle. Results from the optimal control simulations show that strategy E for implementing the public health advocacy, booster vaccine program, treatment of isolated people and disinfecting or fumigating of surfaces and dead bodies before burial is the most effective control intervention for mitigating the spread of Corona virus. Importantly, based on the available data used, the study also revealed that if at least 70% of the constituents followed the aforementioned public health policies, then herd immunity could be achieved for COVID-19 pandemic in the community.

Early standardized clinical judgement for syncope diagnosis in the emergency department.

BACKGROUND: The diagnosis of cardiac syncope remains a challenge in the emergency department (ED). OBJECTIVE: Assessing the diagnostic accuracy of the early standardized clinical judgement (ESCJ) including a standardized syncope-specific case report form (CRF) in comparison with a recommended multivariable diagnostic score. METHODS: In a prospective international observational multicentre study, diagnostic accuracy for cardiac syncope of ESCJ by the ED physician amongst patients ≥ 40 years presenting with syncope to the ED was directly compared with that of the Evaluation of Guidelines in Syncope Study (EGSYS) diagnostic score. Cardiac syncope was centrally adjudicated independently of the ESCJ or conducted workup by two ED specialists based on all information available up to 1-year follow-up. Secondary aims included direct comparison with high-sensitivity cardiac troponin I (hs-cTnI) and B-type natriuretic peptide (BNP) concentrations and a Lasso regression to identify variables contributing most to ESCJ. RESULTS: Cardiac syncope was adjudicated in 252/1494 patients (15.2%). The diagnostic accuracy of ESCJ for cardiac syncope as quantified by the area under the curve (AUC) was 0.87 (95% CI: 0.84-0.89), and higher compared with the EGSYS diagnostic score (0.73 (95% CI: 0.70-0.76)), hs-cTnI (0.77 (95% CI: 0.73-0.80)) and BNP (0.77 (95% CI: 0.74-0.80)), all P < 0.001. Both biomarkers (alone or in combination) on top of the ESCJ significantly improved diagnostic accuracy. CONCLUSION: ESCJ including a standardized syncope-specific CRF has very high diagnostic accuracy and outperforms the EGSYS score, hs-cTnI and BNP.

Genetic polymorphisms associated to SDHI fungicides resistance in selected Aspergillus flavus strains and relation with aflatoxin production.

Aspergillus flavus is a common and ubiquitous fungal species able to colonize several agricultural commodities, in both pre- and post-harvest conditions. This species represents a very harmful plant pathogen for its ability to synthesize aflatoxin B1, responsible for human primary hepatocellular carcinoma and classified as a group I (human carcinogenic) by the International Agency for Research on Cancer. Several approaches have been proposed to control A. flavus development and related aflatoxin production in field and storage conditions. The Succinate Dehydrogenase Inhibitor (SDHI) fungicide boscalid has been shown to control A. flavus growth and aflatoxin contamination both in vitro and in field experiments. However, this compound is classified as medium-high risk fungicide for triggering fungal resistance and, indeed, resistant strains can occur on crops treated with boscalid. In this paper, we selected laboratory A. flavus strains resistant to boscalid grown on agar medium containing 50 mg/L of boscalid. In order to investigate the molecular mechanism responsible for the resistant phenotype, specific primer pairs were designed to amplify the whole SdhB, SdhC and SdhD genes. By amino acid sequence analysis, two point mutations, Tyrosine replacing Histidine at codon 249 of SdhB (H249Y) and Arginine replacing Glycine at codon 91 of SdhC (G91R), were identified. The effect of SDHI boscalid and isopyrazam on mycelial growth and conidial germination was evaluated. Both resistant genotypes showed high resistance (MIC and EC50 > 1000 mg/L) to boscalid. A positive cross-resistance was found between boscalid and isopyrazam. Specific sub-lethal doses of both fungicides (0.5 mg/L of boscalid and 0.01 mg/L of isopyrazam) interfered with the mechanisms associated to pigmentation of colonies. In particular, fungal colonies appeared depigmented lacking the typical A. flavus green colour shown on un-amended fungicide medium. A strict correlation between lack of pigmentation and increasing aflatoxin production was also observed.

Anticholinergic medications in patients admitted with cognitive impairment or falls (AMiCI). The impact of hospital admission on anticholinergic cognitive medication burden. Results of a multicentre observational study.

WHAT IS KNOWN AND OBJECTIVE: Drugs with anticholinergic properties increase the risk of falls, delirium, chronic cognitive impairment, and mortality and counteract procholinergic medications used in the treatment of dementia. Medication review and optimisation to reduce anticholinergic burden in patients at risk is recommended by specialist bodies. Little is known how effective this review is in patients who present acutely and how often drugs with anticholinergic properties are used temporarily during an admission. The aim of the study was to describe the changes in the anticholinergic cognitive burden (ACB) in patients admitted to hospital with a diagnosis of delirium, chronic cognitive impairment or falls and to look at the temporary use of anticholinergic medications during hospital stay. METHODS: This is a multi-centre observational study that was conducted in seven different hospitals in the UK, Finland, The Netherlands and Italy. RESULTS AND DISCUSSION: 21.1% of patients had their ACB score reduced by a mean of 1.7%, 19.7% had their ACB increased by a mean of 1.6%, 22.8% of DAP naïve patients were discharged on anticholinergic medications. There was no change in the ACB scores in 59.2% of patients. 54.1% of patients on procholinergics were taking anticholinergics. Out of the 98 medications on the ACB scale, only 56 were seen. Medications with a low individual burden were accounting for 64.9% of the total burden. Anticholinergic drugs were used temporarily during the admission in 21.9% of all patients. A higher number of DAPs used temporarily during admission was associated with a higher risk of ACB score increase on discharge (OR = 1.82, 95% CI for OR: 1.36-2.45, P < .001). WHAT IS NEW AND CONCLUSION: There was no reduction in anticholinergic cognitive burden during the acute admissions. This was the same for all diagnostic subgroups. The anticholinergic load was predominantly caused by medications with a low individual burden. More than 1 in 5 patients not taking anticholinergics on admission were discharged on them and similar numbers saw temporary use of these medications during their admission. More than half of patients on cholinesterase-inhibitors were taking anticholinergics at the same time on admission, potentially directly counteracting their effects.

Saccharomyces cerevisiae fungemia, a possible consequence of the treatment of Clostridium difficile colitis with a probioticum.

The yeast Saccharomyces boulardii is a biotherapeutic agent used for the prevention and treatment of several gastrointestinal diseases, such as diarrhoea caused by Clostridium difficile, in addition to the antibiotic therapy. In this study we report a case of Saccharomyces cerevisiae fungemia in a patient with Clostridium difficile-associated diarrhoea (CDAD) treated orally with S. boulardii in association with vancomycin. The identification of the S. cerevisiae was confirmed by molecular technique. Fungemia is a rare, but a serious complication to treatment with probiotics. We believe it is important to remind the clinicians of this risk when prescribing probiotics, especially to immunocompromised patients.

Management of atrial fibrillation in the Emergency Department: current approach and future expectations.

Atrial fibrillation (AF) is the most common cardiac dysrhythmia and occurs in 3.3%-10% of emergency admissions. It is frequently quoted for people over the age of 75, but the cases of AF in young subjects without structural heart disease are also increasing, therefore, leading to the evaluation of "lonely atrial fibrillation" as a new challenge for the clinician. The first diagnosis and treatment often occur in the emergency room and the emergency physician has therefore to evaluate the initial step towards the therapeutic decisions. Although international standard guidelines are available, AF treatment in the Emergency Department (ED) is still heterogeneous in terms of the management strategy chosen. There are two main strategies for the management of AF: rate and rhythm control. Moreover, antithrombotic treatment is pivotal in AF to prevent cardioembolic stroke and it is considered a primary objective after an accurate assessment of antithrombotic treatment risks and benefits. The introduction of innovative echocardiographic approach, directly in ED, seems to improve the management and risk stratification of patients with AF. This review aims to provide an overview about the current approach and the future expectations in the management of AF in ED. This manuscript represents a synopsis of the lectures on AF management in the ED of the Third Italian GREAT Network Congress, that was hold in Rome, 15-19 October 2012. We decided to use only the most relevant references for each contribution as suggested by each participant at this review.

Assessment of baseline characteristics and risk factors among Emergency Department patients presenting with recent onset atrial fibrillation: a retrospective cohort study.

BACKGROUND: The Cardioversion of Atrial Fibrillation in Emergency (CAFE) study was an observational, retrospective, multicenter study focusing on patients with recent onset atrial fibrillation (AF) seen in six different Emergency Departments (ED) of Rome, Italy. AIM: The aim of this study was to present the baseline characteristics and risk factors of the patients enrolled to the CAFE study. MATERIALS AND METHODS: We retrospectively reviewed 3085 eligible patients diagnosed with recent onset AF in any of the EDs between January 2008 and December 2009. Inclusion criteria required documented ICD-9 primary discharge/admission diagnosis of AF in the ED and stable hemodynamic conditions at presentation (systolic blood pressure > 90 mmHg). Exclusion criteria were permanent AF or an ongoing acute coronary syndrome. RESULTS: Median age was 71 years (interquartile ranges, 62-78 years) and 50.8% were men. Palpitations was the most common symptom at ED presentation and was present in 73.5% of the study subjects. Hypertension was the most prevalent comorbidity, affecting 59.3% of the patients evaluated, and the presence of previous episode(s) of AF was also common (52.3%). Regarding home treatment, the drugs most prescribed were antiplatelets (31.2%) and diuretics (25.2%). A CHADS2 score of 0 was found in 814 patients (26.4%), while a CHADS2 score of 1 was reported in 1114 patients (36.1%). Finally, a CHADS2 score ≥ 2 was reported in 1157 patients (37.5%). CONCLUSIONS: The present study represents an important snapshot of demographics, comorbidities, risk factors and anticoagulation management about patients with recent onset AF. Disparities were noted in anticoagulation management, suggesting that this is still a main problem among patients with AF.

Procalcitonin variations after Emergency Department admission are highly predictive of hospital mortality in patients with acute infectious diseases.

BACKGROUND AND AIM: To evaluate the diagnostic and prognostic usefulness of procalcitonin (PCT) in patients admitted to the Emergency Department (ED) with signs of infections and to assess the prognostic value of repeated measurements in predicting hospital mortality. MATERIALS AND METHODS: A prospective, observational study was conducted in our 400-bed General Teaching Hospital. 261 patients arriving in ED with signs/symptoms of infection were enrolled. PCT was performed upon arrival in the ED (T0), and 5 days after antibiotic therapy (T5). Blood cultures were performed in all patients upon arrival in the ED. RESULTS: Mean T0 PCT value was 7.1±17.9 ng/ml, and at T5 3±9.1 ng/ml (p < 0.0001). Mean PCT in septic non-survivors was increased at T5 compared to T0 but not significantly. The PCT increase at T5 was an independent factor of mortality (OR = 1.29, p < 0.02) in septic patients. Compared to baseline mean delta % PCT decrease at T5 was 28%. Patients with a decrease delta % PCT > 28% showed a lower number of deaths, with a statistical significant difference if compared to those patients with a < 28% decrease (p < 0.004). ROC curve of delta % PCT for prediction of death has an AUC = 0.82 (p < 0.03). CONCLUSIONS: PCT is a useful marker for diagnosis of systemic and local infections, and for prognostic stratification in patients with acute infectious diseases at their arrival in ED. PCT variations after antibiotic therapy are highly predictive for in-hospital mortality. PCT normalization during antibiotic therapy suggests a good response to infection possibly leading to less infection-related deaths.

Chronic systemic inflammatory syndrome in patients with AECOPD presenting to emergency department.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is the fourth cause of dead in the world. Because of high incidence of comorbidities in COPD patients, it has been proposed a new hypothesis that inscribe this disease in a complex contest named chronic systemic inflammatory syndrome (CSIS). Either COPD and the most common comorbidities responsible for its clinical and natural history, like hypertension, diabetes, coronary artery disease, heart failure, recognize a pro-inflammatory state, marked, for example, by elevated C reactive protein (CRP). METHODS: 113 consecutive patients presenting to emergency department (ED) with acute exacerbated COPD were enrolled. They underwent to full medical history and physical examination. CRP was measured at ED arrival, discharge and at 1-6-12 month follow up. CSIS was diagnosed according to specified criteria. RESULTS: CSIS was diagnosed in 84% patients. CRP was maximally increased at admission during the exacerbation, but didn't correlate with the severity of it. At discharge, CRP values were lowest; during follow up, CRP demonstrated a chaotic behavior growing up till 6 month without any correlation with new exacerbation events. At 1 year it decreased, never reaching normal values in the majority of our patients thus confirming the presence of a persistent inflammation in COPD. CONCLUSIONS: CSIS was diagnosed in 84% of our population demonstrating that COPD patients need to be approached in a multidisciplinary way.

Role of biomarkers in patients with dyspnea.

BACKGROUND: The use of biomarkers has been demonstrated useful in many acute diseases both for diagnosis, prognosis and risk stratification. OBJECTIVES: The purpose of this review is to analyze several biomarkers of potential use in patients referring to Emergency Department with acute dyspnea. STATE OF THE ART: The role of natriuretic peptides has a proven utility in the diagnosis, risk stratification, patient management and prediction of outcome in acute and chronic heart failure (HF). New immunoassays are available for the detection of mid-region prohormones in patients with acute dyspnea such as Mid-region pro-adrenomedullin (MR-proADM) and Mid-region pro-atrial natriuretic peptide (MR-proANP). Also procalcitonin, copeptin and D-dimer, which are markers of inflammation, bacterial infections and sepsis, seem to be useful in the differential diagnosis of dyspnea. Conventional and high-sensitivity troponins are fundamental, not only in the diagnosis of acute coronary syndromes, but also as indicators of mortality in patients with acute decompensated heart failure. PERSPECTIVES: Further studies with randomized controlled clinical trials will be needed to prove the theoretical clinical advantages offered by a shortness of breath biomarkers in terms of diagnostic, prognostic, cost effective work-up and management of patients with acute dyspnea. CONCLUSIONS: A multimarker pannel approach performed by rapid and accurate assays could be useful for emergency physicians to promptly identify different causes of dyspnea thus managing to improve diagnosis, treatment and risk stratification.

Identification, mycotoxin risk and pathogenicity of Fusarium species associated with fig endosepsis in Apulia, Italy.

In a survey carried out on 87 rotted fig fruits samples collected in the Apulia region of Italy, the authors isolated 126 Fusarium strains identified as F. ramigenum (69 strains), F. solani (49), F. proliferatum (five) and three not identified. Investigation on the fertility of the strains belonging to F. proliferatum and F. ramigenum revealed that only strains of F. proliferatum were fertile. The identity of F. ramigenum strains was confirmed by sequencing a portion of the translation elongation factor-1alpha gene. When Fusarium species were analysed for their toxigenicity, 37/69 strains of F. ramigenum produced fusaric acid (FA) up to 525 mg kg(-1); 30 strains produced beauvericin (BEA) up to 190 mg kg(-1); 60 strains produced fumonisin B(1) (FB(1)) and fumonisin B(2) (FB(2)) up to 1575 mg kg(-1) of total FBs; and two strains produced fusaproliferin (FUP) up to 345 mg kg(-1); all five strains of F. proliferatum produced FA at low levels; two strains produced BEA up to 205 mg kg(-1); one strain produced FB(1) and FB(2), 1100 and 470 mg kg(-1), respectively; and one strain produced FUP, 820 mg kg(-1); F. solani (30 strains) produced FA, 13 strains up to 215 mg kg(-1). Few fungal extracts showed high toxicity toward brine shrimp larvae and in some cases in relation to BEA and FA content. A pathogenic assay on fig fruits showed that all three species were pathogenic, with higher virulence of F. ramigenum. These data report for the first time the production of BEA and FB(1)/FB(2) by F. ramigenum and show that it is a main agent of fig endosepsis in Apulia and can contribute to fumonisin contamination of fresh and dried figs.

Trichothecene and beauvericin mycotoxin production and genetic variability in Fusarium poae isolated from wheat kernels from northern Italy.

The importance and widespread incidence of Fusarium poae as a natural contaminant of wheat in different climatic areas warrants investigation into the genetic diversity and toxin profile of a northern Italy population. Eighty-one strains of F. poae isolated from durum wheat kernels, identified by species-specific polymerase chain reaction and translation elongation factor-1alpha gene sequence analysis, were genetically characterized by the amplified fragment length polymorphism (AFLP) technique and analysed by high-pressure liquid chromatography for their ability to produce the beauvericin (BEA) and trichothecene mycotoxins. A high level of variability was observed by using AFLP analyses, with the lowest level of genetic similarity among the strains being approximately 61%. Most of the strains, 95%, produced BEA at <2655 microg g(-1); 88% produced the trichothecene nivalenol at <865 microg g(-1) and 76% produced the trichothecene fusarenon-X at <167 microg g(-1). These data show that F. poae can produce high amounts of BEA together with trichothecenes, and can represent a high potential mycotoxin risk in Italy for wheat colonized by this species.

PCR identification of durum wheat BAC clones containing genes coding for carotenoid biosynthesis enzymes and their chromosome localization.

Carotenoids are essential components in all plants. Their accumulation in wheat seed determines the endosperm colour, which is an important quality trait in wheat. In this study, we report the isolation of BAC clones containing genes coding for three different enzymes of the carotenoid biosynthesis pathway: phytoene synthase (PSY), phytoene desaturase (PDS), and zeta-carotene desaturase (ZDS). Primers were designed on the basis of wheat ESTs similar to the sequences of these three genes in other species, and used to screen a BAC library from Triticum turgidum var. durum (2n = 28, genomes AABB). Eight, six, and nine 384-well plates containing at least one positive clone were found for PSY, PDS, and ZDS, respectively. BACs selected for each of these genes were then divided in two groups corresponding to the A and B genomes of tetraploid wheat, based on differences in the length of the PCR amplification products, conformation-sensitive gel electrophoresis (CSGE), or cleavage amplification polymorphisms. Positive clones were then assigned to chromosomes using a set of D genome substitution lines in T. turgidum var. durum 'Langdon'. PSY clones were localized on chromosomes 5A and 5B, PDS on chromosomes 4A and 4B, and ZDS on chromosomes 2A and 2B. The strategies used for the PCR screening of large BAC libraries and for the differentiation of BAC clones from different genomes in a polyploid species are discussed.

Desmin-free cardiomyocytes and myocardial dysfunction in end stage heart failure.

Our aim was to evaluate the desmin content in the myocardial tissue of patients with end-stage heart failure of ischaemic origin and to assess its role on cardiac function. We studied 18 explanted hearts from patients transplanted for end-stage heart failure due to ischaemic cardiomyopathy (ICM). Control myocardial tissue was obtained from the cardiac biopsies of six women with breast cancer taken prior to commencing chemotherapy with anthracyclines, four male donors for heart transplantation and two autoptic hearts from patients who died due to non-cardiac events. Myocardial tissue, obtained from the left ventricle (remote zone from infarcted area), was analyzed by light and confocal immunochemistry (desmin) microscopy. The desmin content of myocardial tissue was obtained by real-time PCR. Cardiac function was evaluated by echocardiographic and right heart catheterization data, obtained before heart transplantation. Confocal microscopy evaluation showed a significant decrease in the number of desmin-positive myocytes (P<0.01) in ICM hearts compared to controls. At real-time PCR evaluation, there was a reduction (P<0.01) in desmin content in the ICM patients compared to controls. A negative correlation was found between desmin-free cardiomyocytes and ejection fraction (EF) (r=-0.834; P<0.02) on echocardiogram. A negative relationship (r=-0.688) was also found between desmin-negative myocytes and capillary wedge pressure. In conclusion, the myocardial tissue of patients with end-stage heart failure of ischaemic origin, shows a decreased number in desmin-positive myocytes at immunochemistry evaluation compared to normal individuals. This deficiency in cytoskeletal intermediate filament content is associated with reduced cardiac function.

Comparison of benazepril-amlodipine and captopril-thiazide combinations in the management of mild-to-moderate hypertension.

OBJECTIVE: To compare the efficacy and tolerability of benazepril 10 mg + amlodipine 5 mg combination (BZ+AM) versus captopril 50 mg + hydrochlorothiazide 25 mg (CP+HT) combination. MATERIAL: 405 outpatients with mild-to-moderate arterial hypertension not adequately controlled by a monotherapy with ACE inhibitors or calcium channel blockers or diuretics entered this multicenter, double-blind, randomized, parallel-group study. METHOD: After a 2-week placebo run-in, 397 patients with sitting diastolic (D) blood pressure (BP) > 95 mmHg and/or sitting systolic (S) BP > 160 mmHg were randomized to receive either BZ+AM (201 patients) or CP+HT (196 patients) once daily for 12 weeks. Main outcome measure was sitting DBP and SBP values at the end of active treatment. The response rate was defined as the proportion of patients with either a final sitting DBP < 90 mmHg or decreased by at least 10 mmHg or a sitting SBP < 150 mmHg or decreased by at least 20 mmHg from baseline. RESULTS: The DBP and SBP values obtained with BZ+AM were, respectively, 2.7 and 3.7 mmHg lower than those obtained with CP+HT (both p < 0.001 vs. CP+HT). The response rate in the BZ+AM group (94.8%) was better than that observed in the CP+HT group (86.0%, p = 0.004). The incidence of adverse events was similar with the 2 treatment regimens (17.9% for both). CONCLUSIONS: These data suggest a higher antihypertensive efficacy of the fixed combination BZ 10 mg+AM 5 mg as compared with CP 50 mg+HT 25 mg.

Changes in myocardial cytoskeletal intermediate filaments and myocyte contractile dysfunction in dilated cardiomyopathy: an in vivo study in humans.

AIM: To investigate in vivo the intermediate cytoskeletal filaments desmin and vimentin in myocardial tissues from patients with dilated cardiomyopathy, and to determine whether alterations in these proteins are associated with impaired contractility. METHODS: Endomyocardial biopsies were performed in 12 patients with dilated cardiomyopathy and in 12 controls (six women with breast cancer before anthracycline chemotherapy and six male donors for heart transplantation). Biopsy specimens were analysed by light microscopy and immunochemistry (desmin, vimentin). Myocyte contractile protein function was evaluated by the actin-myosin in vitro motility assay. Left ventricular ejection fraction was assessed by echocardiography and radionuclide ventriculography. RESULTS: Patients with dilated cardiomyopathy had a greater cardiomyocyte diameter than controls (p < 0.01). The increase in cell size was associated with a reduction in contractile function, as assessed by actin-myosin motility (r = -0.643; p < 0.01). Quantitative immunochemistry showed increased desmin and vimentin contents (p < 0.01), and the desmin distribution was disturbed in cardiomyopathy. There was a linear relation between desmin distribution and actin-myosin sliding in vitro (r = 0.853; p < 0.01) and an inverse correlation between desmin content and ejection fraction (r = -0.773; p < 0.02). Negative correlations were also found between myocardial vimentin content and the actin-myosin sliding rate (r = -0.74; p < 0.02) and left ventricular ejection fraction (r = -0.68; p < 0.01). CONCLUSIONS: Compared with normal individuals, the myocardial tissue of patients with dilated cardiomyopathy shows alterations of cytoskeletal intermediate filament distribution and content associated with reduced myocyte contraction.

Ischemic cardiomyopathy and the cellular renin-angiotensin system.

BACKGROUND: Ischemic cardiomyopathy produced by non-occlusive coronary artery constriction is characterized by left ventricular failure and right ventricular dysfunction, but whether the local renin-angiotensin system (RAS) is implicated in myocyte dysfunction and cell death remains unclear. METHODS: Changes in single-cell mechanics, the localization of the various constituents of RAS in the myocardium, and the effects of angiotensin II (Ang II) stimulation on myocyte performance and cell death were measured. RESULTS: Chronic ischemia is coupled with alterations in the mechanical properties and calcium (Ca2+) transients of the remaining viable myocytes. The abnormalities in myocyte mechanics consist of depression in peak shortening and velocity of shortening. Moreover, peak systolic Ca2+ is significantly decreased in the cells. In vitro stimulation with Ang II ameliorates myocyte function and systolic Ca2+. Additionally, adult myocytes express genes for renin, angiotensinogen, angiotensin-converting enzyme (ACE), and Ang II receptors. Renin, ACE, and Ang II receptors mRNAs increase under the setting of impaired coronary perfusion. Similarly, the percentage of myocytes containing renin, Ang I, and Ang II increases as well. In vitro studies of neonatal and adult ventricular myocytes indicate that Ang II triggers programmed myocyte cell death and this phenomenon is mediated by activation of the AT1 receptor sub-type. Importantly, the AT1-receptor blocker, losartan, completely inhibits apoptosis. CONCLUSIONS: These multiple observations are consistent with the notion that Ang II may exert 3 separate functions on the heart: (1) stimulation of myocyte hypertrophy, (2) amelioration of myocyte contractile performance, and (3) activation of the suicide program of myocytes.

Effects of short-term reduction in serum cholesterol with simvastatin in patients with stable angina pectoris and mild to moderate hypercholesterolemia.

To evaluate the effects of short-term cholesterol-lowering treatment on myocardial effort ischemia, 22 patients with stable effort ischemia and mild to moderate hypercholesterolemia (low density lipoprotein [LDL] cholesterol 160 to 220 mg/dl) were randomly allocated at baseline (TO) in 2 groups. Group A included 12 patients treated with simvastatin 10 mg bid; group B included 10 patients treated with placebo. All patients underwent a treadmill electrocardiography (ECG) test; total cholesterol, HDL and LDL cholesterol, triglycerides, plasma, and blood viscosity were measured. All tests were repeated after 4 and 12 weeks. For 18 of the same patients (11 taking simvastatin, 7 receiving placebo), forearm strain-gouge plethysmography was performed at baseline and after 4 weeks, both at rest and during reactive hyperemia. At 4 and 12 weeks, group A showed a significant reduction in total cholesterol (p <0.05) and LDL (p <0.05), with unchanged HDL, triglycerides, blood, and plasma viscosity. Effort was unmodified, ST-segment depression at peak effort and ischemic threshold were significantly improved after 4 and 12 weeks (all p <0.05) with unchanged heart rate x systolic blood pressure product. A significant increase in the excess flow response to reactive hyperemia was detected in group A (p <0.03); group B showed no changes in hematochemical and ergometric parameters. These data suggest that cholesterol-lowering treatment is associated with an improvement in myocardial effort ischemia; this might be explained by a more pronounced increase of coronary blood flow and capacity of vasodilation in response to effort.