Intravascular ultrasound-guided shockwave treatment of stents overlapping underexpansion of calcified left anterior descending artery.

Heavily calcified lesions may limit optimal stent deployment resulting in stent underexpansion, thus increasing the risk of restenosis and thrombosis. We describe the case of overlapping stents underexpansion treated with a shockwave intravasuclar lithoplasty system (Shockwave Medical Inc., Santa Clara, CA, USA). A 65-year-old man with angina, underwent coronary angiography and intravascular ultrasound showing restenosis, in a site of overlapping stents, due to calcified tissue. Shockwave lithoplasty balloon was able to break calcified tissue in a site of overlapping stents, allowing subsequent vessel dilation and repeat stent implantation with optimal final stent expansion. Heavily calcified lesions may limit optimal stent deployment resulting in stent underexpansion. Treating stent underexpansion or restenosis due to calcified tissue is a great challenge. Shockwave lithoplasty is effective in breaking calcified tissue also in a site of overlapping stents. The improved plaque compliance allows to repeat stent implantation with optimal final stent expansion.

Uric Acid Impairs Insulin Signaling by Promoting Enpp1 Binding to Insulin Receptor in Human Umbilical Vein Endothelial Cells.

High levels of uric acid (UA) are associated with type-2 diabetes and cardiovascular disease. Recent pieces of evidence attributed to UA a causative role in the appearance of diabetes and vascular damage. However, the molecular mechanisms by which UA induces these alterations have not been completely elucidated so far. Among the mechanisms underlying insulin resistance, it was reported the role of a transmembrane glycoprotein, named either ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) or plasma cell antigen 1, which is able to inhibit the function of insulin receptor (IR) and it is overexpressed in insulin-resistant subjects. In keeping with this, we stimulated human umbilical vein endothelial cells (HUVECs) with insulin and UA to investigate the effects of UA on insulin signaling pathway, testing the hypothesis that UA can interfere with insulin signaling by the activation of ENPP1. Cultures of HUVECs were stimulated with insulin, UA and the urate transporter SLC22A12 (URAT1) inhibitor probenecid. Akt and endothelial nitric oxide synthase (eNOS) phosphorylation levels were investigated by immunoblotting. ENPP1 binding to IR and its tyrosine phosphorylation levels were tested by immunoprecipitation and immunoblotting. UA inhibited insulin-induced Akt/eNOS axis. Moreover, UA induced ENPP1 binding to IR that resulted in an impairment of insulin signaling cascade. Probenecid reverted UA effects, suggesting that UA intracellular uptake is required for its action. In endothelial cells, UA directly interferes with insulin signaling pathway at receptor level, through ENPP1 recruitment. This evidence suggests a new molecular model of UA-induced insulin resistance and vascular damage.

Renal function is impaired in normotensive chronic HCV patients: role of insulin resistance.

Renal dysfunction is an independent predictor for cardiovascular morbidity and mortality. We investigated whether chronic hepatitis C virus (HCV) infection and the related insulin resistance/hyperinsulinemia influence renal function in comparison with a group of healthy subjects and with another group with metabolic syndrome. We enrolled 130 newly diagnosed HCV outpatients matched for age and gender with 130 patients with metabolic syndrome and 130 healthy subjects. Renal function was evaluated by calculation of glomerular filtration rate (e-GFR, mL/min/1.73 m(2)) using the CKD-EPI equation. The following laboratory parameters were measured: fasting plasma glucose and insulin, total, LDL- and HDL-cholesterol, triglyceride, creatinine, and HOMA to evaluate insulin sensitivity. HCV patients with respect to both healthy subjects and metabolic syndrome patients have a decreased e-GFR: 86.6 ± 16.1 vs 120.2 ± 23.1 mL/min/1.73 m(2) (P < 0.0001) and 94.9 ± 22.6 mL/min/1.73 m(2) (P = 0.003), respectively. Regarding biochemical variables, HCV patients, in comparison with healthy subjects, have a higher triglyceride level, creatinine, fasting insulin and HOMA (3.4 ± 1.4 vs 2.6 ± 1.3; P < 0.0001). At linear regression analysis, the correlation between e-GFR and HOMA is similar in the metabolic syndrome (r = -0.555, P < 0.0001) and HCV (r = -0.527, P < 0.0001) groups. At multiple regression analysis, HOMA is the major determinant of e-GFR in both groups, accounting for, respectively, 30.8 and 27.8 % of its variation in the metabolic syndrome and HCV. In conclusion, we demonstrate that HCV patients have a significant reduction of e-GFR and that insulin resistance is the major predictor of renal dysfunction.

Sympathovagal balance and 1-h postload plasma glucose in normoglucose tolerant hypertensive patients.

AIMS: Normoglucose tolerant (NGT) subjects with a 1-h postload plasma glucose (PLPG) value ≥155 mg/dL have an increased risk of type-2 diabetes and subclinical organ damage. Heart rate variability (HRV) reflects cardiac autonomic balance, frequently impaired in course of diabetes. At this time, no data support the association between 1-h PLPG and HRV; thus, we investigated the possible association between 1-h PLPG and HRV. METHODS: We enrolled 92 never-treated hypertensive subjects (56 women, 36 men), aged 55 ± 9.8 years. During OGTT, the patients underwent electrocardiographic recordings to evaluate HRV in the time domain (SDNN). Insulin sensitivity was assessed by Matsuda index. RESULTS: Among participants, 56 were NGT, 20 had impaired glucose tolerance (IGT), and 16 had type-2 diabetes. According to the 1-h PLPG cutoff point of 155 mg/dL, we divided NGT subjects into: NGT < 155 (n = 38) and NGT ≥ 155 (n = 18). Glucose tolerance status was associated with a significant (P < 0.0001) increase in PLPG and insulin and the reduction in Matsuda index. In all groups, the SDNN values significantly (P < 0.0001) decreased during the first hour of OGTT. A complete recovery in NGT groups was observed at the end of the second hour; in IGT and type-2 diabetes, SDNN remained significantly lower with respect to baseline values. At multiple regression analysis, Matsuda index resulted in the only determinant of SDNN modification, explaining the 12.3 % of its variability. CONCLUSIONS: Our data demonstrate that during OGTT, sympathovagal balance is acutely affected by both glucose and insulin modifications. Particularly, NGT ≥ 155 subjects behave in the same way of IGT and type-2 diabetes patients.

Uric acid is an independent predictor of cardiovascular events in post-menopausal women.

BACKGROUND: Uric acid (UA) is a risk factor for cardiovascular (CV) disease. In post-menopause UA levels are increased and strongly associated with subclinical organ damage. We investigated the prognostic significance of UA levels in predicting CV morbidity and mortality in post-menopausal women. METHODS: We considered 645 post-menopausal outpatients not taking hormone replacement therapy or any drugs interfering with UA levels. We evaluated major adverse cardiovascular events (MACE) as primary endpoint, with coronary, stroke or total events as secondary endpoint. Survival curves for tertiles of UA were obtained by using the Kaplan-Meier and Mantel methods. Effect of prognostic factors on survival was evaluated by multivariable Cox regression model, considering P<0.05 as statistically significant. RESULTS: During a mean (SD) follow-up at 72.5 (23.5) months, there were 90 new CV events (2.31%): 62 coronary and 28 cerebrovascular events. The rate of nonfatal CV events (3.15% versus 2.03% and 1.52%, P=0.009) as well as that of MACE (3.23% versus 2.11% and 1.59%, P=0.011) were significantly higher in the third tertile than in the other two groups. Interestingly, cerebrovascular (1.15% versus 0.62% and 0.30%, P=0.027) but not coronary events were significantly different among the three groups. In the Cox regression model, UA was independently and strongly associated with the incident risk of MACE (HR=1.248, P=0.001), cerebrovascular (HR=1.657, P<0.0001) and total events (HR=1.391, P<0.0001). CONCLUSIONS: In post-menopause, independently of other CV risk factors and menopause duration, UA levels are associated with increased risk of death and MACE, in particular cerebrovascular but not coronary events.

CHADS2 and CHA2DS2-VASc scores are independently associated with incident atrial fibrillation: the Catanzaro Atrial Fibrillation Project.

No data exist concerning a possible association between CHADS2 or CHA2DS2-VASc scores and atrial fibrillation (AF). In this prospective observational study, we tested the hypothesis whether thromboembolic risk scores predict AF. We investigated 3549 subjects, 1829 men and 1720 women, aged 60.7 ± 10.6 years, without baseline AF. Patients with thyroid disorders were excluded. CHADS2 and CHA2DS2-VASc scores were evaluated as categorical variables. To test the effect of some clinical confounders on incident AF, we constructed different models including clinical and laboratory parameters. During follow-up (53.3 ± 18.1 months), 546 subjects developed AF (4.5 events/100 patient-years). Progressors to AF are older, have a higher body mass index (BMI), blood pressure, LDL-cholesterol, and glucose. Hypertension, metabolic syndrome, diabetes and carotid wall thickening were more common among AF cases than among control subjects. In the final Cox-regression model, variables that remained significantly associated with incident AF were BMI (HR = 1.022, 95% CI = 1.008-1.037), LDL-cholesterol (HR = 1.032, 95% CI = 1.008-1.056), CHA2DS2-VASc score (HR = 1.914, 95% CI = 1.439-2.546), and CHADS2 score (HR = 2.077, 95% CI = 1.712-2.521). In conclusion, CHADS2 and CHA2DS2-VASc scores are independent predictors of AF.

Renal disease and left atrial remodeling predict atrial fibrillation in patients with cardiovascular risk factors.

OBJECTIVES: In this prospective population-based study, we tested the possible interaction between chronic kidney disease (CKD) and left atrium volume index (LAVI) in predicting incident atrial fibrillation (AF). METHODS: We enrolled 3549 Caucasian subjects, 1829 men and 1720 women, aged 60.7 ± 10.6 years, without baseline AF and thyroid disorders. Echocardiographic left ventricular mass and LAVI were measured. Renal function was calculated by estimated glomerular filtration rate (e-GFR). To test the effect of some clinical confounders on incident AF, we constructed different models including clinical and laboratory parameters. AF diagnosis was made by standard electrocardiogram or 24-h ECG-Holter, hospital discharge diagnoses, and by the all-clinical documentation. RESULTS: During the follow-up (53.3 ± 18.1 months), 546 subjects developed AF (4.5 events/100 patient-years). Progressors to AF were older, had a higher body mass index, blood pressure, LDL-cholesterol, glucose, cardiac mass, and LAVI, and had lower e-GFR. Hypertension, metabolic syndrome, diabetes, cardiac hypertrophy and CKD were more common among AF cases than controls. In the final Cox regression model, variables that remained significantly associated with AF were: cardiac hypertrophy (HR=1.495, 95% CI=1.215-1.841), renal disease (HR=1.528, 95% CI=1.261-1.851), age (HR=1.586, 95% CI=1.461-1.725) and LAVI (HR=2.920, 95% CI=2.426-3.515). The interaction analysis demonstrated a synergic effect between CKD and cardiac hypertrophy (HR=4.040, 95% CI=2.661-6.133), as well as between CKD and LAVI (HR=4.875, 95% CI=2.699-8.805). The coexistence of all three subclinical organ damages significantly increases the arrhythmic risk (HR=7.185, 95% CI=5.041-10.240). CONCLUSIONS: Our data demonstrate that LAVI and CKD significantly interact in a synergic manner in increasing AF risk.

3'-UTR OLR1/LOX-1 gene polymorphism and endothelial dysfunction: molecular and vascular data in never-treated hypertensive patients.

Endothelial dysfunction represents an independent predictor for clinical events. Genetic background may promote deleterious alterations of endothelial physiology. The aim of the study was to investigate the relationship between the rs1050283 polymorphism in the 3'-UTR of OLR1/LOX-1 gene and endothelial dysfunction in 178 never-treated hypertensive patients and 36 healthy subjects. The rs1050283 C/T single nucleotide polymorphism was detected, by TaqMan allelic discrimination assay. The influence of polymorphism on gene transcription rate was tested in 12 heterozygous hypertensive patients, by using an allelic imbalance assay. Forearm blood flow (FBF) was measured during intra-arterial infusion of acetylcholine (ACh), and sodium nitroprusside at increasing doses. Analysis of endothelium-dependent and endothelium-independent vasodilatation was tested according to rs1050283 polymorphism. In hypertensive patients, ACh-stimulated FBF is significantly reduced in T allele carriers (P < 0.0001), even when the allelic imbalance assay indicates an overexpression of C allele. In healthy subjects, there is no significant difference for ACh-dependent vasodilatation among genotypic groups (P = 0.660). In essential hypertensive patients, the T allele of OLR1/LOX-1 gene is strongly associated with an impaired endothelium-dependent vasodilatation, a powerful predictor of cardiovascular events.

Endothelial dysfunction predicts regression of hypertensive cardiac mass.

BACKGROUND: Subclinical organ damage is a condition with an increased risk for fatal and nonfatal cardiovascular events. Particularly, endothelial dysfunction and left ventricular mass (LVM) are recognized as independent predictors of cardiovascular events in hypertensive patients. Besides, LVM in hypertensives is inversely related to forearm blood flow (FBF) responses to the endothelium-dependent vasodilating agent. We evaluated the role of endothelium-dependent vasodilation in the progression/regression of LVM in a group of hypertensive subjects. METHODS: We enrolled 170 hypertensive outpatients (88 men, 92 women; age 47 ± 11 years). LVM was calculated with the Devereux formula and indexed by surface area (LVMI). Endothelium-dependent vasodilation was investigated by intra-arterial infusions of acetylcholine (ACh). RESULTS: During the follow-up blood pressure (BP) decreased from 150/91 ± 17/11 to 135/80 ± 14/9 mm Hg (P=0.0001), and LVMI from 120 ± 28 to 118 ± 28 g/m(2) (P=0.194). The mean annual rate of variation of LVMI was -0.38 ± 3.9 g/m(2), which was not statistically different in men and women. It was correlated with baseline ACh-stimulated FBF (r=-0.272, P=0.0001) and BMI (r=0.164, P=0.016). At multivariate analysis, FBF was the only baseline covariate that remained significantly associated with LVMI variation, also after correction for antihypertensive treatment and BP reduction. The interaction between baseline LVM and ACh-stimulated FBF was investigated in a multiple linear regression model showing that a fixed reduction in ACh-stimulated FBF (100%) induces different variation of annual rate of LVMI at different levels of baseline LVM. CONCLUSIONS: Our data demonstrate, for the first time, the role of endothelial function in the progression/regression of LVMI, independently of traditional cardiovascular risk factors and antihypertensive therapy.

One-hour post-load plasma glucose and IGF-1 in hypertensive patients.

BACKGROUND: In normoglucose-tolerant subjects (NGT), 1-h post-load plasma glucose value ≥155 mg/dL, during an oral glucose tolerance test (OGTT), is associated with an increased risk of type-2 diabetes (T2D) and subclinical organ damage. Insulin-like growth factor-1 (IGF-1) is involved in the pathogenesis of insulin resistance (IR) and T2D. Moreover, hypertensives have different degrees of IR and different levels of IGF-1. Actually, there are no data supporting the association between post-load glucose and IGF-1; thus, the aim of the study was to investigate this relationship. MATERIALS AND METHODS: We enrolled 1126 never-treated hypertensive subjects who underwent an OGTT and clinical characterization. Insulin sensitivity was assessed by the Matsuda index. IGF-1 was measured by a sensitive immunoradiometric assay. RESULTS: Among participants, 764 had NGT, 263 had impaired glucose tolerance (IGT) and 99 had T2D. According to the 1-h post-load plasma glucose cut-off point of 155 mg/dL, we divided NGT subjects into NGT < 155 mg/dL and NGT ≥ 155 mg/dL. NGT ≥ 155 in comparison with NGT < 155 had significantly reduced insulin sensitivity and IGF-1 levels. At multiple regression analysis, IGF-1 was the major determinant of 1-h post-load glucose in NGT ≥ 155 subjects, IGT and diabetics, accounting for 20·9%, 17·7% and 15·5% of its variation in the respective models. CONCLUSIONS: In hypertensive NGT ≥ 155 subjects, IGF-1 results strongly associated with 1-h post-load glucose, similarly to that observed in IGT and diabetics. This finding has clinical relevance because both low IGF-1 levels and 1-h post-load glucose in NGT subjects are associated with subclinical organ damage, an independent predictor of cardiovascular events.

Oxidative stress impairs endothelial function in nondipper hypertensive patients.

AIMS: Essential hypertension, as well as other established cardiovascular risk factors, is associated with endothelial dysfunction. Hypertensive patients with a nondipper circadian pattern have a greater risk of cerebrovascular and cardiovascular complications in comparison with those with a dipper circadian pattern. In this study, we evaluated the association between nondipper pattern and endothelial function in patients with essential hypertension. METHODS: We evaluated the forearm blood flow (FBF) response to intraarterial acetylcholine (ACh), an endothelium-dependent vasodilator, and sodium nitroprusside (SNP), an endothelium-independent vasodilator, infusions in 190 hypertensive patients stratified according to dipper and nondipper status. The FBF was measured by strain-gauge plethysmography. Effects of oxidative stress on FBF were evaluated by intraarterial infusion of vitamin C. Ambulatory BP monitorings were obtained by a validated oscillometric device (SpaceLabs 90207 Monitor Inc., Issaquah, WA, USA). RESULTS: Systolic and diastolic blood pressures were higher during daytime and lower during night-time in dipper subjects than in nondippers. The peak percent increase in ACh-stimulated FBF was higher in dippers than in nondippers (473% vs. 228%, P < 0.001). The FBF responses to SNP were similar in dipper and nondipper patients. The FBF response to ACh during coinfusion of vitamin C was higher in nondippers rather than in dipper hypertensives. CONCLUSIONS: Present data demonstrate that endothelium-dependent vasodilation is impaired in patients who have nondipper hypertension. The effects of vitamin C on impaired ACh-stimulated vasodilation support the hypothesis that oxidative stress contributes to endothelial dysfunction of nondipper hypertensive patients.

One-hour postload plasma glucose levels and diastolic function in hypertensive patients.

OBJECTIVE: To address whether glucose tolerance status, and in particular 1-h postload plasma glucose levels, may affect diastolic function in 161 never-treated hypertensive white subjects. Impaired left ventricular relaxation, an early sign of diastolic dysfunction, represents the first manifestation of myocardial involvement in diabetic cardiomyopathy. A plasma glucose value ≥155 mg/dL for the 1-h postload plasma glucose during an oral glucose tolerance test (OGTT) is able to identify subjects with normal glucose tolerance (NGT) at high risk for type 2 diabetes and with subclinical organ damage. RESEARCH DESIGN AND METHODS: Subjects underwent OGTT and standard echocardiography. Diastolic function was assessed by pulsed Doppler transmitral flow velocity and tissue Doppler imaging. Insulin sensitivity was assessed by Matsuda index. RESULTS: Among the participants, 120 had NGT, 26 had impaired glucose tolerance (IGT), and 15 had type 2 diabetes. According to the 1-h postload plasma glucose cutoff point of 155 mg/dL, we divided NGT subjects as follows: NGT <155 mg/dL (n = 90) and NGT ≥155 mg/dL (n = 30). Those with NGT ≥155 mg/dL had higher left atrium dimensions (P < 0.0001) and isovolumetric relaxation time (IVRT) (P = 0.037) than those with NGT <155 mg/dL. By contrast, early/late transmitral flow velocity and all tissue Doppler parameters were significantly lower in those with NGT ≥155 mg/dL than in those with NGT<155 mg/dL. At multiple regression analysis, 1-h glucose was the major determinant of left atrium area, IVRT, septal e', septal e'-to-a' ratio, lateral e', and lateral e'-to-a' ratio. CONCLUSIONS: The main finding of this study is that 1-h postload plasma glucose is associated with left ventricular diastolic dysfunction. Subjects with NGT ≥155 mg/dL had significantly worse diastolic function than those with NGT<155 mg/dL.