Paolo Meani

Effects of Cancer Therapy Targeting Vascular Endothelial Growth Factor Receptor on Central Blood Pressure and Cardiovascular System.

BACKGROUND In the last 2 decades, new drugs that oppose the effects of vascular endothelial growth factor receptor (VEGFR), and thus angiogenesis, have considerably improved treatment of solid tumors. These anti-VEGFR drugs, however, are burdened by several side effects, particularly relevant on heart and vessels. The aim of this study was to analyze the changes in cardiovascular structure and function associated with use of anti-VEGFR drugs. METHODS Twenty-nine patients (27 affected by renal and 2 by thyroid cancer), received treatment with anti-VEGFR drugs. Brachial blood pressure (BP), central BP, carotid-femoral pulse wave velocity (cfPWV), augmentation index (Aix), and several echocardiographic markers of systolic and diastolic left ventricular functions including global longitudinal strain were measured before starting treatment (T0), after 2 (T1), and 6 weeks (T2) of treatment. RESULTS Anti-VEGFR treatment was accompanied by a significant increase of both peripheral (systolic BP +13±15.5mm Hg, diastolic BP +7.1±9.3mm Hg, P < 0.001) and central BP (systolic BP +14±14.2mm Hg, diastolic BP +7.3±10.4mm Hg, P < 0.001) and a significant raise of cfPWV (+1.3±1.8 m/sec, P = 0.003). There was also a significant alteration of markers of diastolic and subclinical left ventricular systolic function, including global longitudinal strain (-19.9±3.8% at T0, -17.8±2.6% at T2, P < 0.05). All the changes were already evident at T1, worsened at T2 in patients who maintained oncological treatment, but disappeared at T2 in patients in whom treatment was stopped. CONCLUSIONS All the changes regarding BP and cfPWV appear early after treatment initiation and seem to be reversible if treatment is stopped, instead diastolic and systolic left ventricular function are persistently altered by anti-VEGFR drugs.

Structural and Functional Abnormalities of Carotid Artery and Their Relation with EVA Phenomenon

Early vascular aging is a process characterized by a reduction in arterial elastin with an increase in collagen that has been related to cardiovascular risk factor and can determine an increased arterial stiffness and central blood pressure. It can be measured by several non invasive methods and in different arterial segment. The present paper will focus on functional (local stiffness parameter) and structural (intima media thickness) carotid arteries alterations typically evaluated by ultrasound methods. Methodological, research and clinical issue has been reviewed.

Does the 9p region affect arterial stiffness? Results from a cohort of hypertensive individuals

Abstract Objective. Evidence exists that arterial stiffness, i.e. an independent predictor of cardiovascular and all-causes mortality, has a genetic component. The 9p21 region is associated with a greater susceptibility to coronary disease. Whether this can be ascribed to the fact that genes located on chromosome 9p may also regulate arterial stiffness is largely unknown, however. We evaluate the influence of single nucleotide polymorphisms (SNPs) from 9p on carotid–femoral pulse wave velocity (C-F PWV), measured via the Complior method, in a cohort of 821 hypertensive subjects. Design. The selected tagSNPs were screened with a custom-designed 384-plex VeraCode GoldenGate Genotyping assay on Illumina BeadXpress Reader platform. Association analysis was done using PLINK considering C-F PWV as a quantitative trait (linear regression assuming an additive model) adjusting for sex, age, systolic blood pressure and body mass index (BMI). We used false discovery rate (FDR) to account for multiple testing. Results. Although none of the 384 SNPs was significant after adjusting for multiple testing, probably due to the small sample size of the study population, a trend of association with C-F PWV was observed for rs300622 and rs2381640. Conclusions. These data suggest that SNPs located on chromosome 9p may affect arterial stiffness. Further studies are needed to confirm our finding on a larger sample and define the physiopathological link of the present results.

Annexin A5 in treated hypertensive patients and its association with target organ damage

Objective: Annexin A5 (AnxA5) has been previously linked to the presence of carotid and cardiac target organ damage (TOD) in the context of heart failure and rheumatologic patients. However, information is scant in the context of hypertension. Aim of our study was to evaluate AnxA5 in treated hypertension patients compared with normotensive controls and to determine whether it is associated with vascular and heart TOD evaluated as arterial stiffness, carotid plaque and left ventricular hypertrophy. Methods: We enrolled 123 consecutive treated hypertension and 124 normotensive controls. TOD was evaluated as pulse wave velocity (PWV, complior), left ventricular hypertrophy (echocardiography) and intima–media thickness and carotid plaque presence (ecographic methods). AnxA5 levels was dosed and compared in patients with and without hypertension and with and without TOD. Results: With similar age hypertension patients showed higher SBP, DBP and AnxA5 levels (13.9 ± 11.1 vs 10.1 ± 8.4 ng/ml, P < 0.001) compared with controls. Regarding TOD hypertension showed higher PWV (8.5 ± 1.8 vs 7.6 ± 1.5 m/s, P < 0.001) and LVMI (121.7 ± 29.3 vs 113.5 ± 21.1 g/m2, P < 0.05), whereas carotid intima–media thickness was superimposable. AnxA5 correlates with PWV (r = 0.13, P < 0.05) and DBP (r = 0.15, P < 0.01), whereas it has never been found as a significant independent predictor of TOD in linear regression analysis. Conclusion: Our data have shown that AnxA5 levels are increased in treated hypertension patients. In this condition, it is probably released in the plasma as a defensive mechanism through its anti-inflammatory and anticoagulants effects. We found a significant association with arterial stiffness, but AnxA5 was not found to be a significant predictor of TOD.

Impact of blood glucose variability on carotid artery intima media thickness and distensibility in type 1 diabetes mellitus

Abstract Aims. Diabetes mellitus is characterized by structural and functional alterations of the large- and medium-size arteries. Whether blood glucose variability, i.e. the glycemic oscillations occurring during the 24-h period, represents a risk factor for vascular alterations additional to and independent on HbA1c in type 1 diabetes mellitus is still undefined. The present study was carried out with the aim at investigating the impact of different measures of blood glucose variability on arterial structure and function. We studied 17 non-complicated type 1 diabetic patients (11 males, six females) with an age of 40.8 ± 7.6 years (mean ± SD). In each patient, 24-h glucose profile was obtained by continuous glucose monitoring system and glucose variability was expressed as mean ± SD of 24-h blood glucose levels, mean amplitude of glycemic excursions and postprandial hyperglycemic spikes. Arterial structure and function was measured as carotid IMT and stiffness. Major findings. The different approaches to assessing blood glucose variability well correlated between and with HbA1c. Carotid IMT and stiffness showed significant correlations with age, blood pressure, heart rate and daily insulin intake but a non- significant correlation with blood glucose variability. Principal conclusion. Thus, in type 1 diabetes mellitus, measures of glycemic variability are useful in predicting both actual and long-lasting glycemic control. In absence of diabetes-related complications and of any intima-media thickness alterations, the major predictors of arterial distensibility are represented by traditional risk factors beside glycemic 24-h control.

Acute coronary syndrome: a rare case of multiple endocrine neoplasia syndromes with pheochromocytoma and medullary thyroid carcinoma

Pheochromocytoma is a tumor arising from neuroectodermal chromaffin tissues in the adrenal gland or extra-adrenal paraganglia (paragangliomas). The prevalence of the tumor is 0.1%-0.6% in the hypertensive population, of which 10%-20% are malignant. Pheochromocytoma produces, stores, and secretes catecholamines, as well as leads to hypertensive crisis, arrhythmia, angina, and acute myocardial infarction without coronary artery diseases. We report a case of acute coronary syndrome (ACS) with a final diagnosis of multiple endocrine neoplasia with pheochromocytoma and medullary thyroid carcinoma (MTC).

Determinants of carotid-femoral pulse wave velocity progression in hypertensive patients over a 3.7 years follow-up

Abstract Objective: The role of risk factors on the progression of arterial stiffness has not yet been extensively evaluated. The aim of the current longitudinal study was to evaluate the determinants of the PWV progression over a 4 years follow-up period in hypertensive subjects. Materials and Methods: We enrolled 333 consecutive hypertensive outpatients 18–80 aged, followed by the Hypertension Unit of St. Gerardo Hospital (Monza, Italy). At baseline anamnestic, clinical, BP, laboratory data and cfPWV were assessed. We performed a PWV follow-up examination with a median time amounting to 3.75 ± 0.53 years. Results: At baseline the mean age was 54.5 ± 12.6 years, SBP and DBP were 141.3 ± 18.6 and 86.4 ± 10.4 mmHg and PWV was 8.56 ± 1.92 m/s. Despite an improvement in BP control (from 37 to 60%), at follow-up the population showed a PWV increase (ΔPWV 0.87 ± 3.05 m/s). PWV and ΔPWV gradually increased in age decades. In patients with uncontrolled BP values at follow-up ΔPWV showed a greater increase as compared to patients with controlled BP (1.46 ± 3.67 vs 0.62 ± 2.61 m/s, p < .05). The independent predictors of ΔPWV were age, baseline PWV, baseline SBP/MBP and ΔSBP/MBP. Conclusions: the accelerated arterial aging in treated hypertensive subjects is in large measure explained by age and BP values. PWV changes over time would probably give important information that need further future research studies.

1B.01: 24 HOUR MODULATION OF PERIPHERAL AND CENTRAL BLOOD PRESSURE, HEART RATE AND ARTERIAL STIFFNESS IN HEART TRANSPLANT HYPERTENSIVE INDIVIDUALS.

Objective: After transplantation heart is denervated, resulting in increased resting heart rate (HR) and altered physiologic response to exercise. In heart transplant (HTX) recipients, absence of blood pressure (BP) dipping phenomenon has been reported, but information on central blood pressure, pulse wave velocity (PWV) and Augmentation Index (Aix) is scanty. Aim of our study was to investigate 24 h modulation not only of brachial BP but also of central-aortic BP (CABPM), HR, PWV and Aix in hypertensive HTX patients. Design and method: We enrolled 24 hypertensive patients, 12 HTX recipients (Ht-HTX), at a mean time after HTX of 10,4 years, and 12 matched controls (Ht-C). All the patients were clinically stable and had normal LV systolic function. Ambulatory brachial BP, CABPM, PWV and Aix were recorded over 24 hours by Mobilograph device. Results: Baseline brachial and central BP were similar in Ht-HTX vs Ht-C, as were 24 h brachial (128/78 mmHg ± 11/8Vs124/79mmHg ± 14/2) and central BP (119/81 mmHg ± 12/8 vs114/79 mmHg ± 13/7), HR (74.5 ± 11 vs 69 ± 10 bpm), PWV (8.15 ± 1.8 vs 8.2 ± 1.3 m/s) and Aix (23.6 ± 7.5 vs 22.8 ± 5.8%). PWV showed a dipping phenomenon in Ht-C (daily 8.3 ± 1.2, night 7.9 ± 1.4 m/s), p < 0.001) but not in Ht-HTX (daily 8.15 ± 1.8, night 8.15 ± 1.8). This was the case also for HR. Central systolic BP remained unchanged from day to night in Ht-HTX (118 ± 12 vs 119 ± 16 mmHg) but not in Ht-C (117 ± 15 vs 95 ± 33 mmHg), with night central systolic BP being higher in Ht-HTX vs Ht-C (p < 0.05). An index of 24 h variability (standard deviation) of BP and HR was lower in Ht-HTX than in Ht-C, reaching statistical significance only for 24h-HR (4.3 ± 1.7 vs 6.7 ± 2.3, p: 0.01). Conclusions: Our study shows for the first time that in Ht-HTX there is no nocturnal dipping not only of brachial BP and HR but also of CABPM, and PWV up to 10 years after HTX, probably due to persistent cardiac denervation and/or interference by immunosuppressant drugs. Altered autonomic cardiovascular modulation could play a role in the development of restrictive physiology and possibly also of graft vasculopathy.

Renal artery stenosis as the cause of resistant arterial hypertension: an unusual technique for revascularization.

To the Editor: A 45-year-old Caucasian man in hypertensive crisis was referred to our hospital with general malaise, cephalalgia, and chest pain (blood pressure [BP], 210/ 100 mm Hg). The patient’s medical history included never-treated hypertension, dyslipidemia, and smoking. At admission, the patient was oriented and alert. Results from physical examination were normal and the patient was in hemodynamic balance. The abdomen auscultation revealed a periumbilical bruit. Findings from resting electrocardiography showed signs of left ventricular hypertrophy and negative T-wave changes in V4–V6. Laboratory findings showed a modest increase in troponin Ths (56 ng/L) and no other significant alterations. Findings from 2-dimensional echocardiography showed concentric hypertrophy of the left ventricle, with no decrease of left ventricular contraction and with a conserved ejection fraction (0.50). Color Doppler analysis showed normal function of all heart valves. To correctly study the renin-angiotensin-aldosterone axis and noradrenergic system and to exclude secondary hypertension, the patient was initially treated with a-blockers only. All bioassay results were in the high-normal range according to the presence of high BP. Therapy was later modified and implemented with calcium antagonists, angiotensin-converting enzyme (ACE) inhibitors, furosemide, and aand b-blockers without reaching adequate BP control (160/90 mm Hg). Subsequent findings from computed tomography angiography of the abdomen showed a significant hemodynamic stenosis at the origin of the left kidney artery of 10 mm, normal contralateral renal artery, and no evidence of adrenal or renal parenchyma tumefactions (Figure 1). After case assessment by the radiologists and collegial discussion, it was decided to treat the renal artery stenosis (RAS). Findings from angiography of the renal arteries confirmed the stenosis very tightened to the origin of the left renal artery. The attempt of crossing the stenosis via intraluminal procedure using a 0.014-inch guidewire and a microcatheter failed. Following multiple subintimal passages, the renal artery dissection at the end of the stenotic occlusion was reported, and the procedure was stopped. The patient was discharged, and, after 2 months, a new right transfemoral arteriography and an aortoiliac angiography were performed. The evidence was a revascularizated left kidney from the left spermatic artery, which was hypertrophic and with inverted flow. After several failed attempts of crossing the obstruction, it was decided to perform the procedure with retrograde access: the occlusion was crossed using a 0.035-inch guidewire that was rescued in the aorta and via anterograde procedure and, after predilation, the premounted stent on a 6918 mm balloon was positioned (Figure 2). Following the procedure, the patient underwent treatment with 5 antihypertensive agents, ie, ACE inhibitors, diuretics, calcium antagonists, and aand b-blockers, and aspirin 100 mg/d was added to obtain good BP control (130/80 mm Hg). Hypertension induced by RAS is a form of secondary hypertension caused by renin overproduction, and atherosclerotic disease is the most common cause. It is known that RAS affects 1% to 5% of hypertensive patients. Furthermore, many studies have shown an elevated prevalence of RAS in patients with coronary artery disease diagnosed by cardiac catheterization. Angiography is the gold standard for the diagnosis of RAS, and the most common technique uses a reverse-curve catheter that advances cephalic from below the renal artery until it engages the renal artery ostium. The specificity of this case was the unusual angiographic approach, ie, a retrograde access from the spermatic artery, due to the unavailability of the standard access. According to our knowledge, this approach is rarely used; therefore, information about the results is limited. In our patient, the results produced a complete resolution of RAS, as well as optimal BP control, with no procedural complications. doi: 10.1111/jch.12331 FIGURE 1. Computed tomographic angiography revealing a significant hemodynamic stenosis at the origin of the left kidney artery.