Michele M. Ciulla

Different effects of antihypertensive therapies based on losartan or atenolol on ultrasound and biochemical markers of myocardial fibrosis: results of a randomized trial.

Background—In hypertensive left ventricular hypertrophy (LVH), myocardial texture is altered by a disproportionate increase in fibrosis, but there is insufficient clinical evidence whether antihypertensive therapy or individual agents can induce regression of myocardial fibrosis. Methods and Results—We compared the effects of an angiotensin II receptor antagonist with a &bgr;-blocker on myocardial collagen volume (assessed by echoreflectivity and serum collagen markers) in 219 hypertensive patients with echocardiographically documented LVH. Patients were allocated randomly to receive losartan 50 to 100 mg/d (n=111) or atenolol 50 to 100 mg/d (n=99) with or without hydrochlorothiazide 12.5 to 25 mg/d for 36 weeks. Echoreflectivity analysis was conducted on ultrasound tracings of the midapex septum with specifically designed and validated software. A color histogram of reflecting echoes was obtained, and its spread (broadband [BB], previously shown to correlate directly with collagen volume fraction on endomyocardial biopsies) was used as the primary outcome measure. Mean color scale and serum markers of collagen synthesis (PIP, PIIIP) or degradation (CITP) were secondary outcome variables. Echoreflectivity analysis proved feasible in 106 patients (losartan 52, atenolol 54). Losartan reduced BB over 36 weeks (from 114.5 to 104.3 color levels, P<0.02), whereas atenolol treatment was associated with an increase in BB (from 109.0 to 113.6 color levels, P=NS), the difference between treatments being −12.8 color levels (95% CI −23.6 to −2.0, P=0.02). Secondary end points (mean color scale and collagen markers) also changed in the direction of decreased collagen in patients receiving losartan, but differences between groups were not statistically significant. Conclusions—In hypertensive patients with LVH, losartan decreases myocardial collagen content, whereas atenolol does not. The difference between the 2 treatments is statistically significant.

The Prognostic Value of Heart Rate Variability in the Elderly, Changing the Perspective: From Sympathovagal Balance to Chaos Theory

Heart rate variability (HRV) is the temporal beat‐to‐beat variation in successive RR intervals on an electrocardiographic (ECG) recording and it reflects the regulation of the heart rate (HR) by the autonomic nervous system (ANS). HRV analysis is a noninvasive tool for the assessment of autonomic function that gained momentum in the late 1980s when its clinical relevance as a predictor of mortality was established by a milestone study by Kleiger et al. in patients with postacute myocardial infarction. In the last few decades, the increasing availability of commercial ECG devices offering HRV analysis has made HRV a favorite marker for risk stratification in the setting of cardiovascular disease. The rapid aging of the world population and the growing popularity of HRV have also fueled interest for the prognostic value of HRV in the elderly, outside a specific cardiological context. However, the discussion of HRV measures in the elderly is still very much centered on the rather reductionistic model of sympathovagal balance, with the orthosympathetic and parasympathetic limbs of the ANS exercising opposing effects on the heart via autonomic tone. The expanding application of nonlinear dynamics to medicine has brought to the forefront the notion of system complexity, embedded in the mathematical concepts of chaos theory and fractals, and provides an opportunity to suggest a broader interpretation for the prognostic significance of HRV, especially in the elderly. Although the use of novel indices of HRV may be hampered by practical issues, a more holistic approach to HRV may still be safeguarded if traditional time‐ and frequency‐domain measures are viewed in terms of autonomic modulation. This review focuses on HRV in geriatric populations. It considers studies on the prognostic value of HRV in elderly subjects, discussing the potential confounding effect of erratic rhythm, and concentrates on the conceptual distinction between autonomic tone and autonomic modulation. It also briefly addresses the question of the practicality of ECG recordings and identifies a promising area for future research in the effects of common noncardioactive drugs on HRV. (PACE 2012;00:1–17)

Effects of angiotensin and angiotensin blockade on coronary circulation and coronary reserve

Angiotensin is a potent coronary vasoconstrictor, but little is known of the effects of long-term activation of the renin-angiotensin system on coronary reserve in humans. The effects of exercise on coronary hemodynamics were determined in eight patients with mild essential uncomplicated hypertension, before and after treatment with furosemide (50 mg, to ensure activation of the renin-angiotensin system). Coronary sinus blood flow was measured by thermodilution technique, intra-arterial blood pressure was measured from the ascending aorta, and plasma renin activity was determined by radioimmunoassay. Oxygen supply and demand were derived (using coronary sinus blood flow multiplied by the arteriovenous oxygen difference to equal oxygen supply and heart rate multiplied by the mean systolic blood pressure to equal oxygen demand) both at rest and during isometric exercise (handgrip to 50 percent of maximal effort for three minutes). The study was a single-blind crossover (furosemide versus placebo) design. Furosemide produced a significant reduction in coronary sinus blood flow, associated with an increase in coronary vascular resistance. Changes in mean arterial pressure and heart rate were insignificant. Slight reductions in plasma volume and mean right atrial pressure were observed. During isometric exercise, the increase in oxygen supply for a given increment in oxygen demand was attenuated by furosemide. The contribution of the renin-angiotensin system to this effect was determined by the short-term administration of 25 mg of the angiotensin converting enzyme inhibitor captopril. Forty-five minutes after oral captopril, coronary reserve was restored to pretreatment values. In conclusion, furosemide modulates coronary reserve, and it is likely that this is because furosemide mediates activation of renin-angiotensin system, thus reducing the vasodilatory capacity of the coronary arteries.

Expression of endothelial protein C receptor and thrombomodulin in the intestinal tissue of patients with inflammatory bowel disease

Objective:Inflammatory bowel diseases are characterized by disorders of immunity, thrombosis of large vessels, and microthrombosis of mucosal vessels. The expression of endothelial protein C receptor (EPCR) and thrombomodulin—two receptors of the protein C pathway involved in thrombin scavenging and inflammation—was studied in intestinal resection specimens or mucosal biopsies from patients with inflammatory bowel disease and from controls. The soluble forms of the receptors in plasma were measured. Data Source:This study involved patients from two large university hospitals. After surgery or biopsy, tissue samples were either frozen or fixed in formalin and embedded in paraffin. Sections for immunohistochemistry examination were cut and tested with the specific antibodies to EPCR and thrombomodulin. RNA was extracted from frozen tissue for amplification via reverse-transcriptase polymerase chain reaction. Normal intestinal and diverticulitis tissue was used as a control. Resection samples from 36 patients with ulcerative colitis, 38 with Crohn’s disease, 38 with colonic cancer, and 32 with diverticulitis were studied by immunohistochemistry, and frozen sections from the same patients were studied by immunofluorescence. Twelve biopsy specimens of adjacent intestinal areas from six patients with inflammatory bowel disease were included in the study for reverse-transcriptase polymerase chain reaction. Soluble receptors were measured in the plasma of 52 inflammatory bowel disease patients and 52 controls. Data Summary:EPCR and thrombomodulin were expressed on the mucosal endothelium of controls, and the intensity of the signal decreased in inflammatory bowel disease patients. EPCR was expressed by dendritic-like cells in controls, which also stained positive for CD21. The EPCR+/CD21+ dendritic-like cells were not as commonly observed in sections from ulcerative colitis patients as they were in sections from control patients (12.0 ± 3.6 cells per high-power field vs. 23.8 ± 10.4 cells per high-power field, p = .03), and this decrease was less evident in sections from Crohn’s disease patients. Levels of messenger RNA for EPCR paralleled protein expression. Soluble thrombomodulin and EPCR levels were both higher in patients than in controls: 41.5 vs. 26.0 ng/mL (p <.0001) and 141 vs. 130 ng/mL (p <.05), respectively. Conclusions:EPCR expression on dendritic-like cells that bear the key complement receptor CD21 suggests a role for EPCR in innate immunity. The reduced expression of thrombomodulin and EPCR in the mucosal vessels in inflammatory bowel disease impairs protein C activation, favoring microthrombosis.

Blood pressure-independent cardiac hypertrophy in acromegalic patients.

OBJECTIVE Acromegaly is frequently associated with an increase in left ventricular mass, even in the absence of systemic hypertension. Pathological studies on acromegalic hearts have shown an extensive interstitial fibrosis, suggesting the existence of a specific acromegalic cardiomyopathy. The aim of this study was to assess left ventricular wall structure in acromegaly by ultrasonic tissue characterization. DESIGN AND METHODS We studied 10 untreated acromegalic patients and 10 age-matched healthy control subjects. The echo patterns of two-dimensional long-axis end-diastolic echocardiograms were assessed by colour-scale analysis of the interventricular septum, with estimates of the mean colour scale value, the broad band (Bb) and the derived collagen volume fraction (dCVF). We also measured electrocardiographic QT interval dispersion (QTd) as a marker of dyshomogeneous ventricular repolarization. RESULTS Seven patients had left ventricular hypertrophy according to the sex-independent criteria; of these, two had arterial hypertension. None of our patients had echocardiographic evidence of diastolic or systolic dysfunction. All patients showed significantly increased myocardial echoreflectivity (Bb = 106.4+/-12.1 versus 79.3+/-6.5; dCVF% = 2.78+/-0.53 versus 1.58+/-0.29; P < 0.0001) and QTd (66+/-13 ms versus 54+/-8 ms, P < 0.05). A significant correlation was found between dCVF and the duration of acromegaly (r = 0.80; P = 0.005). CONCLUSIONS Left ventricular remodelling observed in acromegaly is not related to the presence of arterial hypertension; we hypothesize that the increased echoreflectivity and QTd are long-term consequences of cardiac hypertrophy and prolonged exposure to high levels of growth hormone and insulin-like growth factor-I.

Assessment of carotid plaque composition in hypertensive patients by ultrasonic tissue characterization: a validation study

Objective Ultrasonic tissue characterization of epi-aortic vessels may be useful to define the composition of atherosclerotic plaques. Videodensitometry provides a histogram representing the frequency distribution of gray levels corresponding to different compositions of the carotid wall. However, lack of standardization limits the clinical application of this technique. In the present study, the echoreflectivity (ER) pattern of atherosclerotic plaques in vivo was compared with their histological pattern after surgical removal, and the reproducibility of measurement was tested. Design and methods We studied 19 hypertensive patients with a carotid artery stenosis ⩾ 70%, eligible for carotid thromboendarterectomy (TEA). Before TEA, all patients underwent standard high-resolution B-mode carotid ultrasound. ER parameters (mean gray level, broad band, skewness, and kurtosis) were obtained in a region of interest selected along the whole plaque, between the intima–blood and the media–adventitia interfaces. The plaques removed during TEA were examined by a histologist and classified into three groups on the basis of fibrous tissue (FT) content: lipidic (FT < 20%), fibrolipidic (20 ⩽ FT ⩽ 50%), and fibrous (FT > 50%). Discriminant function analysis was used to evaluate classification efficacy of different histological groups based on ER parameters. Results Histologically, five lesions were classified as lipidic, six as fibrolipidic and eight as fibrous. Analysis of variance showed significant between group differences in all ER parameters. The combined use of all ER parameters provided correct classification of plaques in 94.73% of cases (P < 0.0001), improving the classification made using single parameters. Intra-observer and inter-observer variabilities (Bland–Altman method) of mean gray level measurements were small. Conclusions Videodensitometry can discriminate between tissue composition of carotid lesions and complement the quantitative assessment of intima–media thickness by additionally providing a well-reproducible semiquantitative evaluation of vascular wall constituents.

Carotid wall composition in hypertensive patients after 4-year treatment with lacidipine or atenolol: an echoreflectivity study.

Objective In the European Lacidipine Study on Atherosclerosis (ELSA), against a similar antihypertensive effect, a significantly greater effect of lacidipine was found on carotid intima–media thickness (IMT) progression, indicating a specific anti-atherosclerotic effect of lacidipine. However, not only the extent but also the composition of an atherosclerotic plaque is a determinant of subsequent events. Design and methods Among the 2334 patients enrolled in ELSA, 420 with 4-year treatment were chosen, videodensitometric analysis of their ultrasound carotid scan was performed and the maximum wall lesion (Tmax) was classified as lipidic, fibrolipidic and fibrotic by means of software previously validated against histology. Of the 420 patients, 244 had scans suitable for videodensitometry. Results Excellent reproducibility of videodensitometry analysis was found using the Bland–Altman and other methods. At baseline, ELSA hypertensive patients had predominantly fibrolipidic walls (70%), with an echoreflectivity indicating a mean collagen content of 25%. After 4 years of antihypertensive treatment, little change in the frequency distribution of carotid lesions (fibrolipidic 73%) was found, with no significant differences between patients randomized to lacidipine or atenolol. Conclusions Our study provides previously unavailable information that carotid wall composition changes to an extremely small extent during 4-year effective blood pressure lowering. With lacidipine, stable composition is associated with a lower IMT progression than with atenolol.

Synchronous adenocarcinoma and carcinoid tumor of the terminal ileum in a Crohn's disease patient

BackgroundSeveral malignancies have been described in association with inflammatory bowel diseases, the most common being adenocarcinoma. Carcinoid tumor and Crohn disease has also been previously reported, however the coexistence of both neoplasms is quite rare and the clinical diagnosis is very difficult. Here we report what we believe to be the fourth case of a mixed adenocarcinoid tumor coexisting with Crohns disease.Case reportThe patient presented with clinical and radiological features of intestinal obstruction. Laparotomy showed a stricturing lesion in the last 6 cm of the terminal ileum with proximal dilation. Only the histology of the resected surgical specimen proved the presence of a mixed adenocarcinoid tumor involving the terminal ileum.ConclusionCarcinoid tumor should be suspected in elderly patients with Crohns disease presenting with intestinal obstruction and laparotomy should be considered to exclude malignancy.

Poorly differentiated carcinoma arising from adenolymphoma of the parotid gland

BackgroundThere is only one previous case report of a poorly differentiated carcinoma arising from an adenolymphoma of the parotid gland (Warthins tumour). The absence of clinical symptoms, and the aspecificity of the radiological pattern make the diagnosis very difficult.Case presentationWe here report the case of a 73-year-old man with Warthins tumour who was brought to our attention because of a swelling in the parotid region.ConclusionsIn this case with an atypical clinical presentation, the intra-operative examination of a frozen section of the parotid mass allowed us to diagnose the malignant tumour correctly and consequently undertake its radical excision.

Endothelial Colony Forming Capacity is Related to C-Reactive Protein Levels in Healthy Subjects

The majority of clinical studies on endothelial progenitor cells (EPCs) focuses on the role of these cells in cardiovascular diseases and no systematic studies exist regarding their variations in healthy subjects. In order to define the burden of angiogenesis in physiological conditions we assessed the frequency of peripheral blood endothelial colonies (PB-ECs) and their relation with other factors possibly involved in their function such as high-sensitivity C-reactive protein (hs-CRP), endothelial cell-specific mitogen factor (VEGF) and tissue inhibitor of metalloproteinases-1 (TIMP-1) in a highly selected healthy population. A PB sample was obtained from 37/47 healthy subjects (age 40.2+/-15.0yrs; M/F 15/22) without known cardiovascular risk factors. The serum level of hs-CRP, VEGF, TIMP-1, the frequency of PB-ECs by clonogenic assay, and the number of early EPCs and late EPCs by flow cytometry analysis were evaluated. PB-ECs were formed by 40.5% of studied subjects with a mean of 0.40+/-0.82 colonies/10(6) cells. The differences in the frequency of colony formation between genders were not statistically significant. The subjects with PB-ECs were characterized by higher values of hs-CRP, when compared with those not forming colonies, 0.276+/-0.230 vs 0.095+/-0.077 mg/l (p=0.003) respectively, and of VEGF, 328.3+/-162.9 vs 202.68+/-118.53 pg/ml (p=0.02). No significant differences were found in TIMP-1 values. The EPC clonogenic potential seems to be related to hs-CRP and VEGF levels even in healthy population supporting the concept that these mediators are involved in physiological ECs function.