Beniamino Pagliaro

Pathogenesis of target organ damage in hypertension: Role of mitochondrial oxidative stress

Hypertension causes target organ damage (TOD) that involves vasculature, heart, brain and kidneys. Complex biochemical, hormonal and hemodynamic mechanisms are involved in the pathogenesis of TOD. Common to all these processes is an increased bioavailability of reactive oxygen species (ROS). Both in vitro and in vivo studies explored the role of mitochondrial oxidative stress as a mechanism involved in the pathogenesis of TOD in hypertension, especially focusing on atherosclerosis, heart disease, renal failure, cerebrovascular disease. Both dysfunction of mitochondrial proteins, such as uncoupling protein-2 (UCP2), superoxide dismutase (SOD) 2, peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α), calcium channels, and the interaction between mitochondria and other sources of ROS, such as NADPH oxidase, play an important role in the development of endothelial dysfunction, cardiac hypertrophy, renal and cerebral damage in hypertension. Commonly used anti-hypertensive drugs have shown protective effects against mitochondrial-dependent oxidative stress. Notably, few mitochondrial proteins can be considered therapeutic targets on their own. In fact, antioxidant therapies specifically targeted at mitochondria represent promising strategies to reduce mitochondrial dysfunction and related hypertensive TOD. In the present article, we discuss the role of mitochondrial oxidative stress as a contributing factor to hypertensive TOD development. We also provide an overview of mitochondria-based treatment strategies that may reveal useful to prevent TOD and reduce its progression.

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.

Phytochemical Compounds and Protection from Cardiovascular Diseases: A State of the Art

Cardiovascular diseases represent a worldwide relevant socioeconomical problem. Cardiovascular disease prevention relies also on lifestyle changes, including dietary habits. The cardioprotective effects of several foods and dietary supplements in both animal models and in humans have been explored. It was found that beneficial effects are mainly dependent on antioxidant and anti-inflammatory properties, also involving modulation of mitochondrial function. Resveratrol is one of the most studied phytochemical compounds and it is provided with several benefits in cardiovascular diseases as well as in other pathological conditions (such as cancer). Other relevant compounds are Brassica oleracea, curcumin, and berberine, and they all exert beneficial effects in several diseases. In the attempt to provide a comprehensive reference tool for both researchers and clinicians, we summarized in the present paper the existing literature on both preclinical and clinical cardioprotective effects of each mentioned phytochemical. We structured the discussion of each compound by analyzing, first, its cellular molecular targets of action, subsequently focusing on results from applications in both ex vivo and in vivo models, finally discussing the relevance of the compound in the context of human diseases.

Atrial natriuretic peptide and regulation of vascular function in hypertension and heart failure: implications for novel therapeutic strategies.

Atrial natriuretic peptide (ANP) plays a pivotal role in modulation of vascular function and it is also involved in the pathophysiology of several cardiovascular diseases. We provide an updated overview of the current appraisal of ANP vascular effects in both animal models and humans. We describe the physiological implications of ANP vasomodulatory properties as well as the involvement of ANP, through its control of vascular function, in hypertension and heart failure. The principal molecular mechanisms underlying regulation of vascular tone, that is natriuretic peptide receptor type A/cyclic guanylate monophosphate, natriuretic peptide receptor type C, nitric oxide system, are discussed. We review the literature on therapeutic implications of ANP in hypertension and heart failure, examining the potential use of ANP analogues, neutral endopeptidase (NEP) inhibitors, ACE/NEP inhibitors, angiotensin receptor blocker (ARB)/NEP inhibitors, the new dual endothelin-converting enzyme (ECE)/NEP inhibitors and ANP-based gene therapy. The data discussed support the role of ANP in different pathological conditions through its vasomodulatory properties. They also indicate that ANP may represent an optimal therapeutic agent in cardiovascular diseases.

A survey on blood pressure levels and hypertension control in a sample of the italian general population

BACKGROUND Hypertension represents a major cardiovascular risk factor with relevant consequences on morbidity and mortality in the general population. An optimal control of blood pressure (BP) is far from being achieved. AIM The objective of this study was to explore awareness of BP levels, prevalence of risk factors and status of hypertension control in a sample of the Italian general population. METHODS Subjects aged 18 years or older were enrolled on a voluntary basis during the 7th and 8th World Hypertension Days at our hospital centre, S. Andrea Hospital in Rome, and at other hospitals throughout the Italian Lazio region. Along with BP measurement, a short questionnaire was completed at the time of the interview. RESULTS Of 1165 individuals enrolled into the analysis, 71.7% were aware of their BP levels (82.5% among hypertensive patients). Within the whole cohort, 31.9% of subjects were under antihypertensive treatment, while the overall rate of subjects found to be hypertensive patients at our visit was 52.9% (n = 616). Among hypertensive patients taking antihypertensive drugs, 47.1% had controlled BP values with the remaining 52.9% showing uncontrolled hypertension. Mean systolic blood pressure (SBP) was 138.2 ± 20.7 mmHg and mean diastolic blood pressure (DBP) was 80.4 ± 11.3 mmHg in subjects receiving antihypertensive treatment. Among older hypertensive patients (71-94 years of age), only 76.9% were under treatment. Hypertensive males were more frequently treated than females in all age groups (p = 0.001). Smoking habit negatively affected efficacy of antihypertensive therapy in the age groups of 48-53 and 54-62 years (p = 0.008 and p = 0.01, respectively). Diabetic patients had higher mean SBP values than non-diabetic subjects (137.3 ± 22.1 vs 129.3 ± 18.2 mmHg, p = 0.02). CONCLUSION The results of our survey strongly support the need for a continuing educational effort aimed at providing correct advertisement of healthy lifestyles and awareness of adequate BP control. Based on our observations, particular attention has to be paid to women, younger subjects, elderly subjects and diabetic patients in order to reach appropriate BP control and reduction of cardiovascular risk in these subject categories.

Blood Pressure Levels at the Time of Percutaneous Coronary Revascularization and Risk of Coronary In-Stent Restenosis

BACKGROUND High blood pressure (BP) levels expose patients treated with percutaneous coronary interventions (PCI) to very high risk of 10-year cardiovascular morbidity and mortality. OBJECTIVE To investigate the role of BP levels at the time of PCI on the risk of in-stent restenosis (ISR). METHODS We retrospectively included 796 patients previously treated with PCI, who underwent repeated angiography for recurrent angina or reversible myocardial ischemia. Patients were stratified into either case (n = 354) and control (n = 442) groups in the presence or absence of ISR (defined as in-stent diameter stenosis ≥50%). BP levels were measured at the time of first and second procedures. Normal BP levels were defined for <140/90 mm Hg. RESULTS Patients with normal BP showed significantly higher ISR-free survival (Log-rank: 5.937; P = 0.015). Both systolic (HR (95% CI): 0.731 (0.590-0.906)) and systolic/diastolic BP (HR (95% CI): 0.757 (0.611-0.939)) were significantly and independently associated with lower risk of ISR at Cox-regression analysis, adjusted for potential confounding factors, including stent type and concomitant medications. Patients with ISR showed lower rates of normal systolic/diastolic BP values (166 (47%) vs. 254 (57%); P = 0.003) compared to controls. They also received higher stent number (1.40±0.74 vs. 1.24±0.51; P < 0.001) with higher stent length (24.3±15.6 vs. 21.7±13.9 mm; P = 0.012), and lower rate of drug-eluting stents (DESs) (210 (48%) vs. 139 (40%); P = 0.025) compared to controls. CONCLUSIONS Normal BP at the time of PCI is associated with nearly 24% risk reduction of ISR as evaluated in a new angiography in patients with coronary artery disease.

T2238C ANP gene variant and risk of recurrent acute coronary syndromes in an Italian cohort of ischemic heart disease patients

Background The role of C2238/atrial natriuretic peptide (ANP) minor allele, at the T2238C ANP gene variant, as a predisposing risk factor for acute cardiovascular events, has been previously reported. We aimed at evaluating, by a retrospective approach, the long-term impact of C2238/ANP-minor allele carrier status toward the risk of recurrent acute coronary syndromes (re-ACS) in an Italian cohort of ischemic heart disease patients. Methods A total of 379 patients (males = 80.5%; mean age = 62.5 ± 9.2 years) presenting with ACS were retrospectively analyzed. Mean follow-up was 5.1 ± 3.5 years (range 1–26 years). Occurrence of new episodes of unstable angina, non-ST-segment elevation myocardial infarction and STE myocardial infarction over the years was recorded and compared between subjects not carrying and carrying C2238/ANP-minor allele. Results At univariate analysis, C2238/ANP-minor allele carrier status and treatment with beta-blocker, aspirin and statin were associated with risk of re-ACS. Multivariate analysis confirmed that hypercholesterolemia (P < 0.0001) and C2238/ANP-minor allele carrier status (P < 0.05) were both significantly and independently associated with increased risk of re-ACS. Both treatments with beta-blocker and with statin were significantly associated with reduced risk of re-ACS (P = 0.01 and P < 0.01, respectively). Age above 55 years was associated with recurrence of ACS in C2238/ANP-minor allele carriers (hazard ratio 1.427, 95% confidence interval 1.066–1.911, P = 0.017). Kaplan–Meier curves confirmed highest risk of new events occurrence in C2238/ANP-minor allele carriers (P = 0.035). Conclusions The present results demonstrate that C2238/ANP-minor allele carrier status is an independent risk factor for ACS recurrence in an Italian cohort of ischemic heart disease patients over the long term, and they support the role of C2238/ANP-minor allele as a negative prognostic factor in coronary artery disease patients.

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