Pietro Nazzaro

Distinct and Combined Vascular Effects of ACE Blockade and HMG-CoA Reductase Inhibition in Hypertensive Subjects

Hypercholesterolemia and hypertension are frequently associated with elevated sympathetic activity. Both are independent cardiovascular risk factors and both affect endothelium-mediated vasodilation. To identify the effects of cholesterol-lowering and antihypertensive treatments on vascular reactivity and vasodilative capacity, we studied 30 hypercholesterolemic hypertensive subjects. They received placebo for 4 weeks, either enalapril or simvastatin for 14 weeks, and, finally, both medications for an additional 14 weeks. Postischemic forearm blood flow (MFBF) and minimal vascular resistance (mFVR) were used as indices of vasodilative capacity and structural vascular damage, respectively. Total (resting-stress-recovery phases) cardiovascular (blood pressure [BP] and heart rate [HR]) and regional hemodynamic (FBF and FVR) reactivity to stressful stimuli were calculated as area-under-the-curve (auc) (valuextime). Compared with baseline levels, simvastatin reduced total (TOT-C) and LDL cholesterol (LDL-C) (1.27 mmol/L, P<0.001 and 1.33 mmol/L, P<0.001, respectively). Enalapril also reduced TOT-C and LDL-C (0.6 mmol/L, P<0.001 and 0.58 mmol/L, P<0.05, respectively). MFBF was increased substantially by both treatments (P<0.001). Enalapril had a greater effect (-1.7 arbitrary units (AU), P<0.001) than simvastatin (-0.6 AU, P<0.05) on mFVR. During stress, FBF increased more with enalapril (4.4 FBFxminutes, P<0.001) than with simvastatin (1.8 FBFxminutes, P<0.01). Conversely, FVR stress response was reduced more with enalapril (9.1 FVRxminutes, P<0.001) than with simvastatin (2.9 FVRxminutes, P<0.01). During combination treatment, a significant (0.001>P<0.05) additive effect on hypercholesterolemia, structural vascular damage, BP, and FVR was shown. The findings suggest that angiotensin-converting enzyme (ACE) inhibition induces a larger reduction than HMG-CoA reductase blockade in vascular reactivity and structural damage in hypercholesterolemic hypertensive subjects.

Effect of clustering of metabolic syndrome factors on capillary and cerebrovascular impairment

BACKGROUND Hypertension and metabolic disorders, attended by impaired microcirculation, represent major risk factors for cerebrovascular impairment, as well as being individual components of the metabolic syndrome (MetS). Aim of the study was to establish whether mild hypertensives, aged ≤65years, may be affected by progressive microvascular damage impairing cerebrovascular perfusion, related to a progressive clustering of MetS components. METHODS Twenty-two normotensives with no MetS component (NTN-0), 29 hypertensives with no (HTN-0), 30 with one (HTN-1), 29 with two (HTN-2), 27 with three (HTN-3), 25 with all four (HTN-4) MetS components, were recruited. The study required office and twenty-four hour ambulatory blood pressure monitoring and video capillaroscopy. Functional (fCD), anatomical (aCD) and recruited (RECR) phalangeal skin capillarity were assessed. Cerebral vasodilatory reserve was measured by the breath-holding index (BHI), using transcranial Doppler, in HTN-1 and HTN-2 with MetS. RESULTS The fCD and aCD were reduced in hypertensives and progressively reduced in those with MetS, while RECR was also impaired. BHI was lower in HTN-2 than in HTN-1 (p<0.001). BHI was correlated with fCD in HTN-1 (.396, p: .046), HNT-2 (.497, p: .011), and with aCD in HTN-2 (.494, p: .012), by partial Pearson test. DISCUSSION The findings show that hypertensives exhibit an increasing microvascular rarefaction with MetS progression and that an impaired cerebral perfusion occurs when the MetS is established. The data underline the importance of preventing MetS in mild hypertensives, as it causes microvascular damage and impairs cerebral arterial perfusion.

NEOPLASTIC DISEASE AND DELETION 22q11.2: A MULTICENTRIC STUDY AND REPORT OF TWO CASES

Deletion 22q11.2 is a chromosomal abnormality detected in young patients with clinical manifestations of the DiGeorge/velocardiofacial syndrome. Conotruncal heart defects are also associated with del22q11.2. An association of these cardiac malformations with neoplasias has been observed. Our series includes two cases of malignancies, a hepatoblastoma and a renal-cell carcinoma, arising in children with complex cardiac malformations. The aim of the study was to determine if the deletion at 22q11.2 was present and could be responsible for both pathological processes. Del22q11.2 was identified in both cases. Comparative genomic hybridization revealed terminal gains on chromosomes 1q and Xq and terminal loss on 1p in the hepatoblastoma, and gains in 1p, 12q, 16p, 20q, 22q, and whole chromosome 19 and loss of Xq in the renal-cell carcinoma. Our results confirm a common genetic basis for cardiac malformations, and del22q11.2 presents a risk factor for the development of pediatric tumours.

Comparative genomic hybridisation in malignant deciduoid mesothelioma

Background: Malignant deciduoid mesothelioma is a rare variant of epithelioid mesothelioma. This tumour generally has poor prognosis, and can be asbestos related. Aim: To identify peculiar genetic changes responsible for critical phases in pathogenesis of malignant deciduoid mesothelioma and their prognostic relevance. Methods: Comparative genomic hybridisation was carried out in six cases of malignant pleural deciduoid mesothelioma, four sporadic and two familial. All cases were found to be asbestos related. Four patients died during follow-up and the mean survival was 29.5 (SD 14.2, range 12–43) months. Results: Genetic abnormalities were found in all the tumour tissues, the most frequent being chromosomal gains at 1p, 12q, 17, 8q, 19 and 20 and losses at 13q, 6q and 9p. Survival was found to be longer in those patients who presented a smaller number of losses (⩽2) in the tumorous chromosomes. Conclusions: Although numerous genetic changes are presented by deciduoid mesotheliomas, certain chromosomal regions are preferentially affected. The clinical outcome for this mesothelioma subtype is predicted by the number of losses.

Endothelin-1-receptor-mediated responses in resistance vessels of young and adult spontaneously hypertensive rats.

Objective To assess whether primary changes in endothelin-1 (ET-1) receptor responsiveness or secondary vessel functional modifications could characterize the effects evoked by ET-1 in the mesenteric vascular bed (MVB) of prehypertensive 5-week-old and 12-week-old spontaneously hypertensive rats (SHRs). Design and methods We used male 5-week-old and 12-week-old SHRs and sex- and age-matched Wistar-Kyoto (WKY) rats as controls. ET-1 receptor responsiveness was evaluated by ET-1 (0.04–2 μmol/l) concentration-response curves and repeated with indomethacin and BQ-123 (0.1–0.5 μmol/l), the latter a selective ETA receptor antagonist. ETB receptor responsiveness was tested by sarafotoxin S6c (1–100 nmol/l) and IRL-1620 (0.1–10 nmol/l) concentration-response curves, obtained in the noradrenaline-precontracted MVB. Results At 5 weeks of age, ET-1 induced a similar concentration-dependent contraction in SHRs and WKY rats, with an overlapping BQ-123 pA2 value (negative common logarithm of the antagonist that produces an agonist dose ratio of 2) in the two strains. Indomethacin was ineffective in both groups. Sarafotoxin S6c and IRL-1620 both evoked an ETB-mediated, significant relaxation, only in WKY rats. In 12-week-old SHRs, ET-1 evoked a markedly increased maximal effect compared with the response in WKY rats (P < 0.01); this was prevented by treatment with indomethacin. The BQ-123 pA2 value was higher in SHRs than in WKY rats (P < 0.01). Both sarafotoxin S6c and IRL-1620 evoked a significant concentration-dependent relaxation in WKY rats, which was not detected in SHR preparations. Conclusions Our results could suggest that the different responses evoked by ET-1 in the MVB of SHRs during the onset of hypertension may be related partially to primary alterations in the ET-1 receptorial pattern and partially to the onset of high blood pressure, leading to an impairment in the haemodynamic balance.

Impaired cognitive executive dysfunction in adult treated hypertensives with a confirmed diagnosis of poorly controlled blood pressure.

Background. High blood pressure (BP) poses a major risk for cognitive decline. Aim of the study was to highlight the relationship between cognitive assessment scores and an effective therapeutic BP control. Methods. By medical visit and ambulatory BP monitoring (ABPM), we studied 302 treated hypertensives, subdivided according to office/daytime BP values into 120 with good (GC) and 98 poor (PC) BP control, 40 with “white coat hypertension” (WCH) and 44 a “masked-hypertension” phenomenon (MH). Patients underwent neuropsychological assessment to evaluate global cognitive scores at the Mini Mental State Examination (MMSE) and Frontal Assessment Battery (FAB) and attention/executive functions (Delayed Recall, Digit Span Forwards, Digit Span Backwards, Selective Attention, Verbal Fluency, Stroop Test and Clock Drawing). Carotid intima-media thickness (IMT) served as the index of vascular damage. Results. There were no differences among the groups in terms of gender, age, education, metabolic assessment, clinical history and hypertension treatment. GC presented lower office and ambulatory BP values and IMT. PC performed worse than GC on global executive and attention functions, especially executive functions. In PC, office systolic BP (SBP) was significantly associated to the MMSE and FAB scores and, in particular, to Verbal Fluency, Stroop Errors and Clock Drawing tests. Office diastolic BP (DBP) was associated to Selective attention, nocturnal SBP to Digit Span backwards and Verbal Fluency. Worse cognitive assessment scores were obtained in WCH than GC. Conclusions. The findings showed that in adult treated hypertensives, a poor BP control, as both doctors office and daytime scores, is associated to impaired global cognitive and especially executive/attention functions.

Stress-induced hemodynamic responses are associated with insulin resistance in mild hypertensives

BACKGROUND High blood pressure (BP) and pulse pressure (PP) are recognized as independent risk factors for cardiovascular diseases, whereas insulin resistance (IR) is often associated with hypertension. The purpose of the study was to verify whether PP, taken at the doctors office and during laboratory stimuli, might be predictive of IR. METHODS Homeostasis model assessment insulin resistance index (HOMA) was calculated in 75 grade 1 hypertensives (148 +/- 2/92 +/- 1 mm Hg). Then, patients underwent hemodynamic reactivity study, induced by color word stroop, cold pressor, and handgrip tests. Stress response was calculated as total area (value x time) - baseline area (baseline value x time). RESULTS Patients with similar age, history of hypertension, blood lipids and office blood pressure, but different HOMA (IR-low: 36.3 +/- 1.7 v IR-medium: 62.6 +/- 1.6, P <.001; IR-high: 123.1 +/- 12.8, P <.001 v IR-low and IR-medium), were divided in tertiles. They demonstrated a significant reactivity of systolic BP (IR-low: 225 +/- 58 v IR-medium: 448 +/- 43, P <.01; IR-high: 625 +/- 55, P <.001 v IR-low and P <.01 v IR-medium), PP (IR-low: -8 +/- 19 v IR-medium: 83 +/- 13, P <.001; IR-high: 201 +/- 19, P <.001 v IR-low and IR-medium), and stroke volume (SV) (IR-low: -138 +/- 43 v IR-medium: 1 +/- 27, P <.01; IR-high: 28 +/- 24, P <.001 v IR-low), but similar arterial stiffness (PP/SV) response. Partial correlation between IR and hemodynamic measurements showed a significant association only for systolic BP (0.54, P <.001), PP (0.686, P <.001), and SV (0.384, P <.001) reactivity, but not for office and baseline values. Stepwise multiple regression showed that only PP (beta: 0.634, P <.001) and, among hemodynamic determinants, SV (beta: 0.401, P <.001) response entered into the equation. CONCLUSIONS The findings demonstrate that increased stress-induced PP, maintained by SV response, is the most predictive hemodynamic variable of reduced insulin sensitivity in mild hypertensives.

Excess dietary sodium and inadequate potassium intake by hypertensive patients in Italy: Results of the Minisal-SIIA study program

Introduction: The aim of the study was to assess the age-specific, sex-specific, and region-specific average sodium and potassium intake and its association with anthropometric characteristics in a sample of the Italian adult hypertensive population. Methods: A total of 1232 hypertensive patients were recruited consecutively by 47 centers recognized by the Italian Society of Hypertension. The enrolled participants were on stable antihypertensive treatment. Anthropometric indices, blood pressure, 24-h urinary sodium, and potassium excretion were measured and used as proxy for the average daily sodium and potassium intake. Results: The average sodium intake was 172 mmol (or 10.1 g of salt/day) among men and 138 (or 8.1) among women, with no difference among geographical areas. Over 90% of men and 81% of women had a consumption higher than the recommended standard dietary intake of 5 g/day. The average potassium intake was 63 and 56 mmol, respectively in men and women, again without geographical differences, nearly 92% of men and 95% of women having an intake lower than the recommended intake (100 mmol/day or 3.9 g/day). There was a significant trend to a gradual decrease in sodium intake with age in both sexes (P <0.001). There was also a direct association between BMI and sodium intake in both sexes, this association being independent of age (P < 0.001). Conclusion: In this national sample of the Italian hypertensive population, dietary sodium intake was largely higher and potassium intake much lower than the recommended intakes, and this was true for all geographical areas. Overweight and obese hypertensive patients had particularly high sodium intakes.

High Wilms’ tumour gene (WT1) expression and low mitotic count are independent predictors of survival in diffuse peritoneal mesothelioma

Scattone A, Serio G, Marzullo A, Nazzaro P, Corsi F, Cocca M P, Mattoni M, Punzi A, Gentile M, Buonadonna A L & Pennella A 
(2012) Histopathology60, 472–481 
High Wilms’ tumour gene (WT1) expression and low mitotic count are independent predictors of survival in diffuse peritoneal mesothelioma

Characterization of a complex chromosome aberration in two cases of peritoneal mesothelioma arising primarily in the hernial sac

Malignant mesotheliomas of the hernial sac are uncommon and only a few cases have been diagnosed incidentally during herniorrhaphy procedures. The prognosis is poor and patient management is difficult because current treatment modalities do little to prolong survival. Molecular markers could be useful to identify potential therapeutic targets. Using microarray‐comparative genomic hybridization (aCGH), two cases of peritoneal mesothelioma that were found incidentally at the time of hernia repair, were investigated. A high number of genetic aberrations was detected in both cases. The gains were prevalent. The tumors showed identical lost regions at 2q13, 6q25.3, 6q26, 6q26→q27, 9q31.1→9q31.3, 10p15.3, 11q13.2, 13q14.2, 19q13.42→q43, and gains at 1p36.33, 3q29, 5p15.33, 7p22.3, 10p15.1→10p14, 11q13.2, 12q24.23, 12q24.33, 16p13.3, 17p13.3, 18p11.31, 19q13.43, 21q21.1→q21.2, 22q11.1→q11.22, Xp21.2, Xq28. Survival was longer in the patient with a lower total number of genetic defects. aCGH provides a high‐resolution map of copy number changes that may be critical to mesothelioma progression.