Marco Testa

Pathogenesis of Chronic Cardiorenal Syndrome: Is There a Role for Oxidative Stress?

Cardiorenal syndrome is a frequently encountered clinical condition when the dysfunction of either the heart or kidneys amplifies the failure progression of the other organ. Complex biochemical, hormonal and hemodynamic mechanisms underlie the development of cardiorenal syndrome. Both in vitro and experimental studies have identified several dysregulated pathways in heart failure and in chronic kidney disease that lead to increased oxidative stress. A decrease in mitochondrial oxidative metabolism has been reported in cardiomyocytes during heart failure. This is balanced by a compensatory increase in glucose uptake and glycolysis with consequent decrease in myocardial ATP content. In the kidneys, both NADPH oxidase and mitochondrial metabolism are important sources of TGF-β1-induced cellular ROS. NOX-dependent oxidative activation of transcription factors such as NF-kB and c-jun leads to increased expression of renal target genes (phospholipaseA2, MCP-1 and CSF-1, COX-2), thus contributing to renal interstitial fibrosis and inflammation. In the present article, we postulate that, besides contributing to both cardiac and renal dysfunction, increased oxidative stress may also play a crucial role in cardiorenal syndrome development and progression. In particular, an imbalance between the renin-angiotensin-aldosterone system, the sympathetic nervous system, and inflammation may favour cardiorenal syndrome through an excessive oxidative stress production. This article also discusses novel therapeutic strategies for their potential use in the treatment of patients affected by cardiorenal syndrome.

Increased temporal dispersion of myocardial repolarization in myotonic dystrophy Type 1: Beyond the cardiac conduction system

BACKGROUND AND OBJECTIVES The most frequently mechanism underlying sudden cardiac death in myotonic dystrophy type 1 (DM1) is bradyarrhythmias due to cardiac conduction abnormalities. However the risk of ventricular tachyarrhythmias remains a concern in clinical management as well as in its determinant. We therefore assessed autonomic nervous system activity aiming to disclose differences in the QT variability index (QTVI)-a marker of temporal myocardial repolarization lability-between DM1 patients and healthy controls. We also investigated the possible differences within DM1 patients by subdividing them according either to the presence of first degree atrioventricular block (1st AVB) or to the cytosine-thymine-guanine (CTG) repeat expansion size. METHODS Sixty-two DM1 patients and 20 healthy subjects underwent neurological and cardiological examinations, the latter including ECG, echocardiography and 24-hour Holter monitoring. All underwent a 5-minute ECG recording to assess heart rate variability power spectral components, and the QTVI values. RESULTS Power spectral data, namely total power, low frequency power and high frequency power, were lower, whereas QTVI values were higher in DM1 patients than in controls (p<.0001). Higher QTVI values were found in DM1 subgroups with 1st AVB (p=.009) and more than 500 CTG repeat (p=.014) with respect to DM1 patients without 1st AVB and CTG<500. Spectral data did not significantly differ. At multivariable analysis, QTVI and age were independently associated with PR interval and CTG repeat. CONCLUSIONS The increased values of QTVI argue in favour of an important heart involvement extending beyond the conduction system. Whether QTVI could be useful in predicting clinical course of DM1 clearly requires larger prospective studies.

Polypharmacy in heart failure patients.

In heart failure (HF), the progressive use of multiple drugs and a complex therapeutic regimen is common and is recommended by international guidelines. With HF being a common disease in the elderly, patients often have numerous comorbidities that require additional specific treatment, thus producing a heavy pill burden. Polypharmacy, defined as the chronic use of five or more medications, is an underestimated problem in the management of HF patients. However, polypharmacy has an important impact on HF treatment, as it often leads to inappropriate drug prescription, poor adherence to pharmacological therapies, drug-drug interactions, and adverse effects. The growing complexity of HF patients, whose mean age increases progressively and who present multiple comorbidities, suggests the need for newer models of primary care to improve the management of HF patients. Self-care, telemonitoring, and natriuretic peptide-guided therapy represent promising new HF care models to face the complexity of the disease and its therapeutic regimen.

The clinical relevance of dysfunctional HDL in patients with coronary artery disease: A 3-year follow-up study

The well known atheroprotective effects of high density lipoprotein cholesterol (HDL) are based on reverse cholesterol transport as well as anti-inflammatory properties [1,2]. Primary prevention studies have confirmed that HDL levels are strongly associated with reduced cardiovascular events [3]. However, recent evidence supports the notion that HDL functionality may be impaired under certain conditions [4,5]. Ansell and colleagues reported that HDL isolated from subjects with coronary artery disease (CAD) had less antiinflammatory activity than HDL derived from healthy controls, thus providing the first evidence that HDL may be dysfunctional in this setting [6]. Interestingly, in CAD patients HDL has shown to be even proinflammatory, thus increasing monocyte chemiotaxis, reactive oxygen species production, endothelial dysfunction and cellular apoptosis [6,7]. Hence, HDL may not be protective in secondary prevention of coronary artery disease. This issue needs to be rapidly clarified since therapies that raise HDL levels are being investigated for the treatment of CAD patients [8,9]. In the present study we sought to determine whether higher HDL levels maintain their protective effects also in patients with CAD. From March 2006 to April 2009 we consecutively enrolled 184 patients with a first manifestation of CAD (mean age 62±10 years, male/female ratio 3:1). All patients taking lipid-lowering agents or other cardiovascular medications at admission were excluded from the study. Moreover, patients with relevant comorbidities (renal failure, COPD, infective or inflammatory diseases, autoimmune disorders, cancer) were also not considered. All subjects underwent coronary angiography and routine blood chemistry including high sensitivity C-reactive protein (hs-CRP) and lipid profile comprehensive of ApoB-100 and ApoA1 determination. The study was approved by our Institute Committee and all patients signed an informed consent. The study population was divided into groups with higher (N50 for women, N40 formen) and lower HDL levels (≤50 for women, ≤40 for men, Table 1), according to ATPIII criteria [10]. Groups did not significantly differ for demographic and antropometric characteristics as well as for the prevalence of cardiovascular risk factors and left ventricular ejection fraction (EF). Serum creatinine, fasting plasma glucose, uric acid and Pro-BNP were similar in the two groups. HDL and ApoA1 were significantly different but the groups did not differ with regard to LDL and ApoB-100 levels (Table 1). Patients with high HDL had significantly lower triglycerides and hs-CRP values (Table 1). Notably, statin treatment and dose were similar between the two groups (Table 2). Cardiovascular end-points were assessed by clinic visits and programmed phone contacts up to 3 years after the first admission. Determinations of lipid fractions were performed both at baseline and follow-up. No significant changes in HDL levels were observed during follow-up either in patients with high or low HDL (Fig. 1A,B). Major adverse cardiovascular events (MACE) consisted of: (1) mortality for all causes; (2) myocardial infarction (MI); (3) revascularization by percutaneous coronary intervention or by-pass surgery; (4) cerebrovascular events including transient ischemic attack and stroke. Data analysis was performed with SPSS 13.0 software package (SPSS Inc., Chicago). Numerical data are reported as

An atypical clinical presentation of renovascular hypertension

1. IntroductionRenovascular hypertension is one of the most common forms ofsecondary hypertension, and its prevalence is estimated between 1and 5% in the general hypertensive population [1]. Amongst theseconditions, renal artery stenosis (RAS), defined as N50% stenosis of therenalarterylumen,representsoneoftheleadingcausesofrenovascularhypertension.Itisfrequentlyrelatedtothepresenceofrenalatheroscle-rosis (predominantly in elderly individuals), fibro-muscular dysplasia(FMD) and arteritis (more often in young women). Compared to otherclinical conditions, FMD shows different aetiology, as well as differentclinical presentation, prognosis and therapeutic options [2].We describe here an atypical clinical presentation of RAS due toFMD occurred in a young otherwise healthy woman, then analysingthe diagnostic and therapeutic work-out.2. Clinical case reportA 46-year-old woman had an acute hospital admission for 3-dayworsening dyspnoea on mild efforts (New York Health Association[NYHA] classes II–III) and dry cough by 3 weeks. In her medical historysmokinghabit,familyhistoryforcoronaryarterydiseaseandoccasionalepisodes of severe and pulsing headache, resolved with non-steroidalanti-inflammatory drug assumption (indomethacin), were reported.AttheadmissiontoEmergencyDepartment,thephysicalexaminationshowed a normal female phenotype with gallop rhythm, no detectableheart or vascular (including abdominal) bruits, and pulsating peripheralarteries. Slight swelling jugular and ankle oedema with decreasedbreath sounds at the bilateral lung bases were also described. Clinicblood pressure (BP) levels were 185/100 mm Hg, and heart rate was92bpm.The12-leadelectrocardiogramshowedasinusrhythm,biatrialenlargement signs and left ventricular hypertrophy, according toCornellvoltagecriteria(Fig.1).ThechestX-rayshowedbilateralpleuraleffusions and partial atelectasis of the lower lobes. Echocardiographicexamination confirmed the presence of concentric left ventricle hyper-trophy (left ventricular mass indexed for height^2.7 80.98 g/m^2.7,relative wall thickness 0.54), biatrial enlargement, mild reduction ofleft ventricular ejection fraction reduction (45%), and restrictive fillingat transvalvular Doppler assessment (E/A ratio 2.07). Moderate mitraland mild tricuspid regurgitations with slight increase of pulmonaryarterypressure,mildpericardialeffusionandanenlargementofinferiorvena cava, that was partially collapsible during inspiration, were alsodescribed.Haematological tests reported a slight hypokalaemia (2.9 mmol/l)with creatinine value of 1.5 mg/dl and estimated (Cockroft–Gaultformula) glomerular filtration rate (GFR) of 40 ml/min, slight anaemia(12.1 g/dl of haemoglobin) and increased levels of pro-BNP levels(11,886 pg/ml). The urine collection analysis revealed a slight protein-uria (266 mg/24 h). Also, thyroid hormonal profile and autoimmunityscreening with anti-double strand DNA, Anti Nuclear (ANA), andExtractable Nuclear Antigens (ENA) antibodies dosages did not showabnormal values.The patient was initially treated with intravenous infusion ofcentrally-acting alpha2-adrenergic agonist (clonidine) and potassiumsupplement with progressive BP reductions. In addition, antihyperten-sive treatment with angiotensin-converting enzyme inhibitors (ACEIs),beta-blockers (BBs), calcium channel blockers (CCBs), loop diureticsand spironolactone was started and titrated, with further BP reductionswithout achieving effective BP control [3].After admission to the Cardiology Division, sudden worsening ofrenal function (creatinine value of 2.2 mg/dl and estimated GFR of25 ml/min) was observed, paralleled by increased serum potassiumlevels (5.7 mmol/l) and worsened control of clinic BP levels, despiteoptimal antihypertensive therapy. In view of the clinical suspicion ofrenovascular hypertension, antihypertensive therapy was modified, by

Novel Lipids Targets in the Era of Metabolic Syndrome

During the last decades, the prevalence of obesity, diabetes mellitus and metabolic syndrome (MetS) has dramatically risen in developed countries. A further increase in MetS and diabetes can be anticipated because of projections of a greater prevalence of obesity in the future. Albeit the cardiovascular (CV) risk in patients with MetS has been considered high, a large proportion of these patients present with normal low-density lipoprotein-cholesterol (LDL-C) levels. Conversely, these patients often display high levels of apolipoprotein B-100 (apoB), triglycerides (TG) and non-high-density lipoprotein-cholesterol (non-HDL-C). Among routine lipoprotein assessment, the use of non-HDL-C has shown several advantages over LDL-C, particularly in the presence of hypertriglyceridaemia. Non-HDL-C is a combined measurement of LDL-C, lipoprotein (a), small dense LDL-C (sd-LDL-C), chilomicron remnants, and intermediate-density lipoproteins. Several studies have shown that non-HDL-C is a strong predictor of subclinical atherosclerosis and CV events as well as a reasonable surrogate of apoB measurement. Moreover, current evidence is supporting that non-HDL-C accurately predicts major CV events even in patients with normal TG values. However, current recommendations suggest non-HDL-C only when TG exceeds 200 mg/dL, recommending the use of LDL-C as the primary target of therapy in all the other conditions. These definitions contrast with the finding of normal LDL-C in obesity, diabetes and MetS, all considered high-risk conditions. Therefore, a redefinition of LDL-C as a predictor of CV events is needed also in the view of an increased prevalence of insulin resistance, abdominal obesity and diabetes.

Chronic heart failure is characterized by altered mitochondrial function and structure in circulating leucocytes

Oxidative stress is currently viewed as a key factor in the genesis and progression of Heart Failure (HF). The aim of this study was to characterize the mitochondrial changes linked to oxidative stress generation in circulating peripheral blood mononuclear cells isolated from chronic HF patients (HF_PBMCs) in order to highlight the involvement of mitochondrial dysfunction in the pathophysiology of HF. To assess the production of reactive oxygen species (ROS), mitochondrial function and ultrastructure and the mitophagic flux in circulating PBMCs we enrolled 15 patients with HF and a control group of ten healthy subjects. The HF_PBMCs showed a mitochondrial population consisting of damaged and less functional organelles responsible of higher superoxide anion production both at baseline and under in vitro stress conditions, with evidence of cellular apoptosis. Although the mitophagic flux at baseline was enhanced in HF_PBMCs at level similar to those that could be achieved in control PBMCs only under inflammatory stress conditions, the activation of mitophagy was unable to preserve a proper mitochondrial dynamics upon stress stimuli in HF. In summary, circulating HF_PBMCs show structural and functional derangements of mitochondria with overproduction of reactive oxidant species. This mitochondrial failure sustains a leucocyte dysfunctional status in the blood that may contribute to development and persistence of stress conditions within the cardiovascular system in HF.

Pathophysiological Mechanisms and Prognostic Significance of Renal Functional Impairment in Cardiac Patients

Heart and kidney dysfunction are often associated, the primary disorder of one of these two organs being the cause of secondary involvement of the other. These interactions represent the pathophysiological basis of cardiorenal syndrome. Renal dysfunction is very common in heart failure patients, with a highly variable prevalence according to the subgroup of patients considered. The complex pathophysiologic interactions between heart and kidney are far from being completely understood. Several “cardiorenal connectors,” which represent the major players of the neurohumoral response in heart failure, have been identified. They act both through and independently from extracellular fluid volume control. Another mechanism, more recently taken into great consideration, is that of increased central venous pressure. Anemia, very frequent in both heart and renal failure, is most probably the third condition of this deadly syndrome, sometimes also called cardiorenal-anemia syndrome. In patients with heart failure, renal function has a powerful prognostic significance. This is true both in chronic heart failure over a long follow-up and in acutely decompensated heart failure for in-hospital mortality. In patients with advanced heart failure, baseline glomerular filtration rate has been reported to be even more powerful than left ventricular ejection fraction in predicting mortality. The prognostic meaning of worsening renal failure during hospitalization for acute decompensated heart failure is, on the contrary, less clear.