Introduction: The present real-world analysis aims to compare the drug utilization, hospitalizati... more Introduction: The present real-world analysis aims to compare the drug utilization, hospitalizations and direct healthcare costs related to the use of single-pill combination (SPC) or freeequivalent combination (FEC) of perindopril and bisoprolol (PER/BIS) in a large Italian population. Methods: This observational retrospective analysis was based on administrative databases covering approximately 7 million subjects across Italy. All adult subjects receiving PER/BIS as SPC or FEC between January 2017-June 2020 were included. Subjects were followed for 1 year after the first prescription of PER/BIS as FEC (± 1 month) or SPC. Before comparing the SPC and FEC cohorts, propensity score matching (PSM) was applied to balance the baseline characteristics. Drug utilization was investigated as adherence (defined by the proportion of days covered, PDC) and persistence (evaluated by Kaplan-Meier curves). Hospitalizations and mean annual direct healthcare costs (due to drug prescriptions, hospitalizations and use of outpatient services) were analyzed during follow-up. Results: The original cohort included 11,440 and 6521 patients taking the SPC and FEC PER/ BIS combination, respectively. After PSM, two balanced SPC and FEC cohorts of 4688 patients were obtained (mean age 70 years, approximately 50% male, 24% in secondary prevention). The proportion of adherent patients (PDC C 80%) was higher for those on SPC (45.5%) than those on FEC (38.6%), p \ 0.001. The PER/BIS combination was discontinued by 35.8% of patients in the SPC cohort and 41.7% in the FEC cohort (p \ 0.001). The SPC cohort had fewer cardiovascular (CV) hospitalizations (5.3%) than the free-combination cohort (7.4%), p \ 0.001. Mean annual total healthcare costs were lower in the SPC (1999€) than in the FEC (2359€) cohort (p \ 0.001). Conclusion: In a real-world setting, patients treated with PER/BIS SPC showed higher adherence, lower risk of drug discontinuation, reduced risk of CV hospitalization, and lower healthcare costs than those on FEC of the same drugs.
Objective: Long noncoding RNAs (lncRNAs) are involved in diabetogenesis in experimental models... more Objective: Long noncoding RNAs (lncRNAs) are involved in diabetogenesis in experimental models yet their role in humans is unclear. We investigated whether circulating lncRNAs associate with incident type 2 diabetes in older adults. Research Design and Methods: A preselected panel of lncRNAs was measured in serum of individuals without diabetes (n=296) from the VIenna Transdanube Aging (VITA) study, a prospective community-based cohort study. Participants were followed-up over 7.5 years. A second cohort of individuals with and without type 2 diabetes (n=90) was employed to validate our findings. Results: Four lncRNAs (ANRIL, MIAT, RNCR3, and PLUTO) were associated with incident type 2 diabetes and linked to HbA1c trajectories throughout the 7.5-year follow-up. Similar results (for MIAT and PLUTO also in combined analysis) were obtained in the validation cohort. Conclusion: We found a set of circulating lncRNAs which independently portends incident type 2 diabetes in older adults ...
Introduction The mechanisms underlying endothelial dysfunction (ED) in obesity are poorly underst... more Introduction The mechanisms underlying endothelial dysfunction (ED) in obesity are poorly understood. Neurofibromin 2 (NF2) is a scaffold-like protein involved in cell growth and survival. However, its role in the vascular endothelium is unknown. Purpose To investigate NF2 function in obesity-related ED. Methods Human aortic endothelial cells (HAECs) were exposed to palmitic acid (PA, 200 uM) or vehicle for 48 hours. Gene silencing of NF2 was performed by small interfering RNA (siRNA). Gene and protein expression were assessed by real time PCR and Western blot, respectively. The interaction of NF2 with endothelial proteins was investigated by co-immunoprecipitation. A constitutive active mutant form of NF2 (Ala518) was employed to study the effects of NF2 gain-of-function. To specifically investigate NF2 role in the vascular endothelium, we generated mice with endothelium-specific deletion of NF2 (NF2 ECKO) by crossing NF2flox/flox mice with tamoxifen-inducible endothelial-specific ...
Several studies have evaluated the role of QRS duration or QRS narrowing as predictor of response... more Several studies have evaluated the role of QRS duration or QRS narrowing as predictor of response to cardiac resynchronization therapy (CRT) in order to reduce nonresponders. However, their results have been conflicting. The aim of our study was to determine the association between the relative change in QRS narrowing index (QI) and clinical outcome and prognosis in patients who underwent CRT implantation. We included 115 patients in whom a CRT device was implanted in accordance with current guidelines. Baseline clinical variables, echocardiographic parameters, and pharmacological therapies were included. QRS duration before and after CRT implantation and QI [(pre implant QRS duration-QRS duration during CRT)/pre implant QRS duration  100] were measured. After 6 months, a significant improvement in all echocardiographic parameters was observed. In 103 (90%) patients, LVESV decreased by 10% or more. QI was significantly related to reverse remodelling (r ¼ þ0.19; 95% CI: 0.006-0.35, P ¼ 0.049). The cutoff value of QI that predicted best LV reverse remodelling after 6 months of CRT was 12.25% (sensitivity ¼ 65.5%, specificity ¼ 75%, area under the curve ¼ 0.737, P ¼ 0.001). An improvement in their HF clinical composite score at 12 months was found in 23 patients (21%). Considering the improvement in NYHA class, of the 73 patients with QI > 12.25%, 34 (46.5%) had a reduced NYHA class at 12 months post implantation. A statistically significant difference was found between patients with a QI < 12.25%, and those with a QI > 12.25%, in terms of NYHA class worsening (P 0.04). Also a statistically significant difference was found between the mean of the QI of patients who died from cardiovascular causes and patients who died of other causes. We have also investigated the possible sex differences related to QI; women with QI > 12.25% had a statistically significant greater improvement in LVEF at follow-up than men with QI > 12.25% (P 0.03). Patients with a larger decrease in QRSd after CRT initiation showed greater echocardiographic reverse remodelling and better outcome from death or cardiovascular hospitalization. Even if larger studies are needed, QI seems to be an easy-tomeasure variable that could be used or evaluated to predict CRT response.
High Blood Pressure & Cardiovascular Prevention, 2022
Arterial hypertension (AH) is a global burden and the leading risk factor for mortality worldwide... more Arterial hypertension (AH) is a global burden and the leading risk factor for mortality worldwide. Haemodynamic abnormalities, longstanding neurohormonal and inflammatory activation, which are commonly observed in patients with AH, promote cardiac structural remodeling ultimately leading to heart failure (HF) if blood pressure values remain uncontrolled. While several epidemiological studies have confirmed the strong link between AH and HF, the pathophysiological processes underlying this transition remain largely unclear. The combined cardiopulmonary-echocardiography stress test (CPET-ESE) represents a precious non-invasive aid to detect alterations in patients at the earliest stages of HF. The opportunity to study the response of the cardiovascular system to exercise, and to differentiate central from peripheral cardiovascular maladaptations, makes the CPET-ESE an ideal technique to gain insights into the mechanisms involved in the transition from AH to HF, by recognizing alterations that might be silent at rest but influence the response to exercise. Identifications of these subclinical alterations might allow for a better risk stratification in hypertensive patients, facilitating the recognition of those at higher risk of evolution towards established HF. This may also lead to the development of novel preventive strategies and help tailor medical treatment. The purpose of this review is to summarise the potential advantages of using CPET-ESE in the characterisation of hypertensive patients in the cardiovascular continuum.
Background Hyperuricemia is commonly observed in patients with chronic kidney disease (CKD). Howe... more Background Hyperuricemia is commonly observed in patients with chronic kidney disease (CKD). However, a better understanding of the relationship among uric acid (UA) values, glomerular filtration rate (GFR) and albuminuria may shed light on the mechanisms underlying the excess of cardiovascular mortality associated with both chronic kidney disease and hyperuricemia and lead to better risk stratification. Our main goal was to study the relationships between serum uric acid and kidney disease measures (namely estimated GFR [eGFR] and albuminuria) in a large cohort of individuals at cardiovascular risk from the URic acid Right for heArt Health (URRAH) Project database. Methods Clinical data of 26,971 individuals were analyzed. Factors associated with the presence of hyperuricemia defined on the basis of previously determined URRAH cutoffs for cardiovascular and all-cause mortality were evaluated through multivariate analysis. Chronic kidney disease was defined as eGFR < 60 ml/min pe...
Purpose: To evaluate the potential confounding effect of concomitant pneumonia (PNM) on lung ultr... more Purpose: To evaluate the potential confounding effect of concomitant pneumonia (PNM) on lung ultrasound (LUS) B-lines in acute heart failure (AHF).Methods: We enrolled 86 AHF patients with (31 pts, AHF/PNM) and without (55 pts, AHF) concomitant PNM. LUS B-lines were evaluated using a combined antero-lateral (AL) and posterior (POST) approach at admission (T0), after 24 h from T0 (T1), after 48 h from T0 (T2) and before discharge (T3). B-lines score was calculated at each time point on AL and POST chest, dividing the number of B-lines by the number of explorable scanning sites. The decongestion rate (DR) was calculated as the difference between the absolute B-lines number at discharge and admission, divided by the number of days of hospitalization. Patients were followed-up and hospital readmission for AHF was considered as adverse outcome.Results: At admission, AHF/PNM patients showed no difference in AL B-lines score compared with AHF patients [AHF/PNM: 2.00 (IQR: 1.44–2.94) vs. AH...
Systemic arterial hypertension (AH) is a multifaceted disease characterized by accelerated vascul... more Systemic arterial hypertension (AH) is a multifaceted disease characterized by accelerated vascular aging and high cardiometabolic morbidity and mortality. Despite extensive work in the field, the pathogenesis of AH is still incompletely understood, and its treatment remains challenging. Recent evidence has shown a deep involvement of epigenetic signals in the regulation of transcriptional programs underpinning maladaptive vascular remodeling, sympathetic activation and cardiometabolic alterations, all factors predisposing to AH. After occurring, these epigenetic changes have a long-lasting effect on gene dysregulation and do not seem to be reversible upon intensive treatment or the control of cardiovascular risk factors. Among the factors involved in arterial hypertension, microvascular dysfunction plays a central role. This review will focus on the emerging role of epigenetic changes in hypertensive-related microvascular disease, including the different cell types and tissues (end...
Updates in Hypertension and Cardiovascular Protection, 2018
Endothelial dysfunction can be considered the first, asymptomatic step of the atherosclerotic pro... more Endothelial dysfunction can be considered the first, asymptomatic step of the atherosclerotic process. It is characterised by an imbalance between substances with vasodilating, antimitogenic and anti-thrombogenic properties (first of all nitric oxide, NO) and substances with vasoconstricting, prothrombotic and proliferative characteristics (also known with the generic term endothelium-derived contracting factors, EDCFs).
High Blood Pressure & Cardiovascular Prevention, 2021
Healthcare systems encumbered by cardiovascular diseases demand adequate cardiovascular preventio... more Healthcare systems encumbered by cardiovascular diseases demand adequate cardiovascular prevention. Indeed, even with the most novel therapies, the residual cardiovascular risk still fuels morbidity and mortality. Addressing inflammation as a putative mediator of this risk has brought along promising in vitro results, though large clinical trials have only in part confirmed them. To fully exploit the therapeutic potential between the inflammatory hypothesis, a change of viewpoint is required. Focus on microcirculation, whose dysfunction is the primary driver of cardiometabolic disease, is mandatory. Several factors play a pivotal role in the capacity of microvascular inflammation to promote a health-to-disease transition: the adipose tissue (in particular, perivascular and epicardial), the mitochondria function, the hyperglycemic damage and their epigenetic signature. Indeed, the low-grade inflammatory response, which is now an acknowledged hallmark of cardiometabolic disease, is promoted by these mediators and leaves a permanent epigenetic scar on the microvasculature. Even if a more profound knowledge about the mechanisms of metabolic memory has been brought to light by recent evidence, we still have to fully understand its mechanisms and clinical potential. Addressing the detrimental role of inflammation by targeting the microvascular phenotype and leveraging epigenetics is the road down which we must go to achieve satisfactory cardiovascular prevention, ultimately leading to disease-free ageing.
A symposium held at the 29th European Meeting on Hypertension and Cardiovascular Protection in Mi... more A symposium held at the 29th European Meeting on Hypertension and Cardiovascular Protection in Milan, Italy, discussed the potential impact and long-term benefits of early active management of cardiovascular disease (CVD) risk in patients with hypertension, and potential barriers to this strategy. Hypertension often aggregates with other cardiovascular risk factors, exponentially increasing morbidity and mortality. While effective therapies to treat hypertension exist, a substantial number of patients still experience major cardiovascular events. Two major issues account for these Enhanced Digital Features To view enhanced digital features for this article go to:
Introduction: High sensitivity troponin T (hsTnT) is a strong predictor of adverse outcome during... more Introduction: High sensitivity troponin T (hsTnT) is a strong predictor of adverse outcome during SARS-CoV-2 infection. However, its determinants remain partially unknown. We aimed to assess the relationship between severity of inflammatory response/coagulation abnormalities and hsTnT in Coronavirus Disease 2019 (COVID-19). We then explored the relevance of these pathways in defining mortality and complications risk and the potential effects of the treatments to attenuate such risk.Methods: In this single-center, prospective, observational study we enrolled 266 consecutive patients hospitalized for SARS-CoV-2 pneumonia. Primary endpoint was in-hospital COVID-19 mortality. Results: hsTnT, even after adjustment for confounders, was associated with mortality. D-dimer and CRP presented stronger associations with hsTnT than PaO2. Changes of hsTnT, D-dimer and CRP were related but only D-dimer was associated with mortality. Moreover, low molecular weight heparin showed attenuation of the ...
Background: Serum uric acid predicts the onset and progression of kidney disease, and the occurre... more Background: Serum uric acid predicts the onset and progression of kidney disease, and the occurrence of cardiovascular and all-cause mortality. Nevertheless, it is unclear which is the appropriate definition of hyperuricemia in presence of chronic kidney disease (CKD). Our goal was to study the independent impact of uric acid and CKD on mortality.Methods: We retrospectively investigated 21,963 patients from the URRAH study database. Hyperuricemia was defined on the basis of outcome specific cut-offs separately identified by ROC curves according to eGFR strata. The primary endpoints were cardiovascular and all-cause mortality.Results: After a mean follow-up of 9.8 year, there were 1,582 (7.20%) cardiovascular events and 3,130 (14.25%) deaths for all causes. The incidence of cardiovascular and all-cause mortality increased in parallel with reduction of eGFR strata and with progressively higher uric acid quartiles. During 215,618 person-years of follow-up, the incidence rate for cardio...
Purpose A derangement of the coagulation process and thromboinflammatory events have emerged as p... more Purpose A derangement of the coagulation process and thromboinflammatory events have emerged as pathologic characteristics of severe COVID-19, characterized by severe respiratory failure. CC motive chemokine ligand 2 (CCL2), a chemokine originally described as a chemotactic agent for monocytes, is involved in inflammation, coagulation activation and neoangiogenesis. We investigated the association of CCL2 levels with coagulation derangement and respiratory impairment in patients with COVID-19. Methods We retrospectively evaluated 281 patients admitted to two hospitals in Italy with COVID-19. Among them, CCL2 values were compared in different groups (identified according to D-dimer levels and the lowest PaO2/FiO2 recorded during hospital stay, P/Fnadir) by Jonckheere-Terpstra tests; linear regression analysis was used to analyse the relationship between CCL2 and P/Fnadir. We performed Mann-Whitney test and Kaplan-Meier curves to investigate the role of CCL2 according to different clinical outcomes (survival and endotracheal intubation [ETI]). Results CCL2 levels were progressively higher in patients with increasing D-dimer levels and with worse gas exchange impairment; there was a statistically significant linear correlation between log CCL2 and log P/Fnadir. CCL2 levels were significantly higher in patients with unfavourable clinical outcomes; Kaplan-Meier curves for the composite outcome death and/or need for ETI showed a significantly worse prognosis for patients with higher (> median) CCL2 levels. Conclusions CCL2 correlates with both indices of activation of the coagulation cascade and respiratory impairment severity, which are likely closely related in COVID-19 pathology, thus suggesting that CCL2 could be involved in the thromboinflammatory events characterizing this disease.
Journal of the American Society of Nephrology, 2006
The relationship among inflammation (plasma high-sensitivity C-reactive protein [CRP]), endotheli... more The relationship among inflammation (plasma high-sensitivity C-reactive protein [CRP]), endothelial function (hemodynamic response to acetylcholine [ACh] in the forearm), and renal function (serum creatinine and GFR [Modification of Diet in Renal Disease formula]) was investigated in 264 never-treated individuals with uncomplicated essential hypertension and serum creatinine within the normal range. Multiple regression models of renal function (creatinine) were constructed in sequence including Framingham risk factors as well the hemodynamic response to ACh and plasma CRP. The inclusion of endothelial function into a model based on Framingham risk factors added highly significant (P < 0.001) power to this model (؉5%). Of note, in an alternative model that included CRP (instead of endothelial function), the creatinine variance explained by this factor was two times higher (؉10%) than that associated with endothelial function in the first model. In the full model that included both endothelial function and CRP, CRP maintained a much stronger independent link with the outcome measure than endothelial function. In individuals with untreated, uncomplicated essential hypertension, multivariate modeling indicated that inflammation is a crucial mechanism mediating the endothelial-renal function link. The proatherogenic potential of inflammation associated with subtle impairment in renal function may contribute to the cardiovascular risk of essential hypertension.
Background and aims. Enhanced release of triglycerides (TG) by the liver is implicated in the pat... more Background and aims. Enhanced release of triglycerides (TG) by the liver is implicated in the pathogenesis of the metabolic syndrome. The aim of the study was to evaluate whether a primary elevation in hepatic glucose utilization (HGU), as induced by an acute rise in circulating glucose values during physiological hyperinsulinemia, promotes TG synthesis in spite of the reduction in free fatty acids (FFA) levels. Methods. Glucose dose-response studies were conducted in anesthetized pigs using positron emission tomography (PET) to quantify HGU during fasting euglycemic conditions (EF), and under two-step hyperglycemic hyperinsulinemia (1st-HH +3.0, 2nd-HH +6.0 mmol/L over EF glucose values). Liver biopsies were obtained in three animals to evaluate the relationship between glucose exposure and hepatic fat content. Results. Plasma glucose levels were progressively increased in the two-step studies, and otherwise stable within every hour of PET scanning. HGU increased almost fivefold with raising glucose levels, from 0.033 ± 0.009 in EF to 0.149 ± 0.043 in 1st-HH, p = 0.02, and to 0.138 ± 0.050 μmol/min/g in 2nd-HH, p = 0.03. Circulating TG concentrations increased by 50 and 100% in the two hyperglycemic conditions (p = 0.03 2nd-HH vs. EF), in spite of a 70% suppression in plasma FFA levels. The hepatic TG content paralleled the glucose loads. Plasma γ-glutamyl transferase (γ-GT) was increased by 17% (p < 0.05). Conclusions. A short-term elevation in circulating glucose levels within the physiological postprandial range was sufficient to increase HGU, resulting in a significant synthesis and release of TG by the liver, which was accompanied by an acute rise in γ-GT and liver fat content.
Aortic stiffness is an important clinical parameter for predicting cardiovascular events. Carotid... more Aortic stiffness is an important clinical parameter for predicting cardiovascular events. Carotid–femoral pulse wave velocity (cf-PWV) has been proposed for performing this evaluation non-invasively; however, it requires dedicated equipment and experienced operators. We explored the possibility of measuring aortic stiffness using ultrasound scans of the abdominal aorta coupled with the Bramwell–Hill equation. Healthy subjects were investigated; measurements of cf-PWV were taken by arterial tonometry and aortic systo-diastolic pressure difference was estimated using a validated model. Pulsatility of an abdominal tract of aorta was assessed by automated processing of ultrasound scans. Through a Bland–Altmann analysis, we found large biases when estimating each parameter by applying the Bramwell–Hill equation to the measured values of the other two paramters (bias, ± 1.96 SD; PWV, about 2.1 ± 2.5 m/s; pulsatility, 12 ± 14%; pressure jump, 47 ± 55 mmHg). These results indicate that the ...
Introduction: The present real-world analysis aims to compare the drug utilization, hospitalizati... more Introduction: The present real-world analysis aims to compare the drug utilization, hospitalizations and direct healthcare costs related to the use of single-pill combination (SPC) or freeequivalent combination (FEC) of perindopril and bisoprolol (PER/BIS) in a large Italian population. Methods: This observational retrospective analysis was based on administrative databases covering approximately 7 million subjects across Italy. All adult subjects receiving PER/BIS as SPC or FEC between January 2017-June 2020 were included. Subjects were followed for 1 year after the first prescription of PER/BIS as FEC (± 1 month) or SPC. Before comparing the SPC and FEC cohorts, propensity score matching (PSM) was applied to balance the baseline characteristics. Drug utilization was investigated as adherence (defined by the proportion of days covered, PDC) and persistence (evaluated by Kaplan-Meier curves). Hospitalizations and mean annual direct healthcare costs (due to drug prescriptions, hospitalizations and use of outpatient services) were analyzed during follow-up. Results: The original cohort included 11,440 and 6521 patients taking the SPC and FEC PER/ BIS combination, respectively. After PSM, two balanced SPC and FEC cohorts of 4688 patients were obtained (mean age 70 years, approximately 50% male, 24% in secondary prevention). The proportion of adherent patients (PDC C 80%) was higher for those on SPC (45.5%) than those on FEC (38.6%), p \ 0.001. The PER/BIS combination was discontinued by 35.8% of patients in the SPC cohort and 41.7% in the FEC cohort (p \ 0.001). The SPC cohort had fewer cardiovascular (CV) hospitalizations (5.3%) than the free-combination cohort (7.4%), p \ 0.001. Mean annual total healthcare costs were lower in the SPC (1999€) than in the FEC (2359€) cohort (p \ 0.001). Conclusion: In a real-world setting, patients treated with PER/BIS SPC showed higher adherence, lower risk of drug discontinuation, reduced risk of CV hospitalization, and lower healthcare costs than those on FEC of the same drugs.
Objective: Long noncoding RNAs (lncRNAs) are involved in diabetogenesis in experimental models... more Objective: Long noncoding RNAs (lncRNAs) are involved in diabetogenesis in experimental models yet their role in humans is unclear. We investigated whether circulating lncRNAs associate with incident type 2 diabetes in older adults. Research Design and Methods: A preselected panel of lncRNAs was measured in serum of individuals without diabetes (n=296) from the VIenna Transdanube Aging (VITA) study, a prospective community-based cohort study. Participants were followed-up over 7.5 years. A second cohort of individuals with and without type 2 diabetes (n=90) was employed to validate our findings. Results: Four lncRNAs (ANRIL, MIAT, RNCR3, and PLUTO) were associated with incident type 2 diabetes and linked to HbA1c trajectories throughout the 7.5-year follow-up. Similar results (for MIAT and PLUTO also in combined analysis) were obtained in the validation cohort. Conclusion: We found a set of circulating lncRNAs which independently portends incident type 2 diabetes in older adults ...
Introduction The mechanisms underlying endothelial dysfunction (ED) in obesity are poorly underst... more Introduction The mechanisms underlying endothelial dysfunction (ED) in obesity are poorly understood. Neurofibromin 2 (NF2) is a scaffold-like protein involved in cell growth and survival. However, its role in the vascular endothelium is unknown. Purpose To investigate NF2 function in obesity-related ED. Methods Human aortic endothelial cells (HAECs) were exposed to palmitic acid (PA, 200 uM) or vehicle for 48 hours. Gene silencing of NF2 was performed by small interfering RNA (siRNA). Gene and protein expression were assessed by real time PCR and Western blot, respectively. The interaction of NF2 with endothelial proteins was investigated by co-immunoprecipitation. A constitutive active mutant form of NF2 (Ala518) was employed to study the effects of NF2 gain-of-function. To specifically investigate NF2 role in the vascular endothelium, we generated mice with endothelium-specific deletion of NF2 (NF2 ECKO) by crossing NF2flox/flox mice with tamoxifen-inducible endothelial-specific ...
Several studies have evaluated the role of QRS duration or QRS narrowing as predictor of response... more Several studies have evaluated the role of QRS duration or QRS narrowing as predictor of response to cardiac resynchronization therapy (CRT) in order to reduce nonresponders. However, their results have been conflicting. The aim of our study was to determine the association between the relative change in QRS narrowing index (QI) and clinical outcome and prognosis in patients who underwent CRT implantation. We included 115 patients in whom a CRT device was implanted in accordance with current guidelines. Baseline clinical variables, echocardiographic parameters, and pharmacological therapies were included. QRS duration before and after CRT implantation and QI [(pre implant QRS duration-QRS duration during CRT)/pre implant QRS duration  100] were measured. After 6 months, a significant improvement in all echocardiographic parameters was observed. In 103 (90%) patients, LVESV decreased by 10% or more. QI was significantly related to reverse remodelling (r ¼ þ0.19; 95% CI: 0.006-0.35, P ¼ 0.049). The cutoff value of QI that predicted best LV reverse remodelling after 6 months of CRT was 12.25% (sensitivity ¼ 65.5%, specificity ¼ 75%, area under the curve ¼ 0.737, P ¼ 0.001). An improvement in their HF clinical composite score at 12 months was found in 23 patients (21%). Considering the improvement in NYHA class, of the 73 patients with QI > 12.25%, 34 (46.5%) had a reduced NYHA class at 12 months post implantation. A statistically significant difference was found between patients with a QI < 12.25%, and those with a QI > 12.25%, in terms of NYHA class worsening (P 0.04). Also a statistically significant difference was found between the mean of the QI of patients who died from cardiovascular causes and patients who died of other causes. We have also investigated the possible sex differences related to QI; women with QI > 12.25% had a statistically significant greater improvement in LVEF at follow-up than men with QI > 12.25% (P 0.03). Patients with a larger decrease in QRSd after CRT initiation showed greater echocardiographic reverse remodelling and better outcome from death or cardiovascular hospitalization. Even if larger studies are needed, QI seems to be an easy-tomeasure variable that could be used or evaluated to predict CRT response.
High Blood Pressure & Cardiovascular Prevention, 2022
Arterial hypertension (AH) is a global burden and the leading risk factor for mortality worldwide... more Arterial hypertension (AH) is a global burden and the leading risk factor for mortality worldwide. Haemodynamic abnormalities, longstanding neurohormonal and inflammatory activation, which are commonly observed in patients with AH, promote cardiac structural remodeling ultimately leading to heart failure (HF) if blood pressure values remain uncontrolled. While several epidemiological studies have confirmed the strong link between AH and HF, the pathophysiological processes underlying this transition remain largely unclear. The combined cardiopulmonary-echocardiography stress test (CPET-ESE) represents a precious non-invasive aid to detect alterations in patients at the earliest stages of HF. The opportunity to study the response of the cardiovascular system to exercise, and to differentiate central from peripheral cardiovascular maladaptations, makes the CPET-ESE an ideal technique to gain insights into the mechanisms involved in the transition from AH to HF, by recognizing alterations that might be silent at rest but influence the response to exercise. Identifications of these subclinical alterations might allow for a better risk stratification in hypertensive patients, facilitating the recognition of those at higher risk of evolution towards established HF. This may also lead to the development of novel preventive strategies and help tailor medical treatment. The purpose of this review is to summarise the potential advantages of using CPET-ESE in the characterisation of hypertensive patients in the cardiovascular continuum.
Background Hyperuricemia is commonly observed in patients with chronic kidney disease (CKD). Howe... more Background Hyperuricemia is commonly observed in patients with chronic kidney disease (CKD). However, a better understanding of the relationship among uric acid (UA) values, glomerular filtration rate (GFR) and albuminuria may shed light on the mechanisms underlying the excess of cardiovascular mortality associated with both chronic kidney disease and hyperuricemia and lead to better risk stratification. Our main goal was to study the relationships between serum uric acid and kidney disease measures (namely estimated GFR [eGFR] and albuminuria) in a large cohort of individuals at cardiovascular risk from the URic acid Right for heArt Health (URRAH) Project database. Methods Clinical data of 26,971 individuals were analyzed. Factors associated with the presence of hyperuricemia defined on the basis of previously determined URRAH cutoffs for cardiovascular and all-cause mortality were evaluated through multivariate analysis. Chronic kidney disease was defined as eGFR < 60 ml/min pe...
Purpose: To evaluate the potential confounding effect of concomitant pneumonia (PNM) on lung ultr... more Purpose: To evaluate the potential confounding effect of concomitant pneumonia (PNM) on lung ultrasound (LUS) B-lines in acute heart failure (AHF).Methods: We enrolled 86 AHF patients with (31 pts, AHF/PNM) and without (55 pts, AHF) concomitant PNM. LUS B-lines were evaluated using a combined antero-lateral (AL) and posterior (POST) approach at admission (T0), after 24 h from T0 (T1), after 48 h from T0 (T2) and before discharge (T3). B-lines score was calculated at each time point on AL and POST chest, dividing the number of B-lines by the number of explorable scanning sites. The decongestion rate (DR) was calculated as the difference between the absolute B-lines number at discharge and admission, divided by the number of days of hospitalization. Patients were followed-up and hospital readmission for AHF was considered as adverse outcome.Results: At admission, AHF/PNM patients showed no difference in AL B-lines score compared with AHF patients [AHF/PNM: 2.00 (IQR: 1.44–2.94) vs. AH...
Systemic arterial hypertension (AH) is a multifaceted disease characterized by accelerated vascul... more Systemic arterial hypertension (AH) is a multifaceted disease characterized by accelerated vascular aging and high cardiometabolic morbidity and mortality. Despite extensive work in the field, the pathogenesis of AH is still incompletely understood, and its treatment remains challenging. Recent evidence has shown a deep involvement of epigenetic signals in the regulation of transcriptional programs underpinning maladaptive vascular remodeling, sympathetic activation and cardiometabolic alterations, all factors predisposing to AH. After occurring, these epigenetic changes have a long-lasting effect on gene dysregulation and do not seem to be reversible upon intensive treatment or the control of cardiovascular risk factors. Among the factors involved in arterial hypertension, microvascular dysfunction plays a central role. This review will focus on the emerging role of epigenetic changes in hypertensive-related microvascular disease, including the different cell types and tissues (end...
Updates in Hypertension and Cardiovascular Protection, 2018
Endothelial dysfunction can be considered the first, asymptomatic step of the atherosclerotic pro... more Endothelial dysfunction can be considered the first, asymptomatic step of the atherosclerotic process. It is characterised by an imbalance between substances with vasodilating, antimitogenic and anti-thrombogenic properties (first of all nitric oxide, NO) and substances with vasoconstricting, prothrombotic and proliferative characteristics (also known with the generic term endothelium-derived contracting factors, EDCFs).
High Blood Pressure & Cardiovascular Prevention, 2021
Healthcare systems encumbered by cardiovascular diseases demand adequate cardiovascular preventio... more Healthcare systems encumbered by cardiovascular diseases demand adequate cardiovascular prevention. Indeed, even with the most novel therapies, the residual cardiovascular risk still fuels morbidity and mortality. Addressing inflammation as a putative mediator of this risk has brought along promising in vitro results, though large clinical trials have only in part confirmed them. To fully exploit the therapeutic potential between the inflammatory hypothesis, a change of viewpoint is required. Focus on microcirculation, whose dysfunction is the primary driver of cardiometabolic disease, is mandatory. Several factors play a pivotal role in the capacity of microvascular inflammation to promote a health-to-disease transition: the adipose tissue (in particular, perivascular and epicardial), the mitochondria function, the hyperglycemic damage and their epigenetic signature. Indeed, the low-grade inflammatory response, which is now an acknowledged hallmark of cardiometabolic disease, is promoted by these mediators and leaves a permanent epigenetic scar on the microvasculature. Even if a more profound knowledge about the mechanisms of metabolic memory has been brought to light by recent evidence, we still have to fully understand its mechanisms and clinical potential. Addressing the detrimental role of inflammation by targeting the microvascular phenotype and leveraging epigenetics is the road down which we must go to achieve satisfactory cardiovascular prevention, ultimately leading to disease-free ageing.
A symposium held at the 29th European Meeting on Hypertension and Cardiovascular Protection in Mi... more A symposium held at the 29th European Meeting on Hypertension and Cardiovascular Protection in Milan, Italy, discussed the potential impact and long-term benefits of early active management of cardiovascular disease (CVD) risk in patients with hypertension, and potential barriers to this strategy. Hypertension often aggregates with other cardiovascular risk factors, exponentially increasing morbidity and mortality. While effective therapies to treat hypertension exist, a substantial number of patients still experience major cardiovascular events. Two major issues account for these Enhanced Digital Features To view enhanced digital features for this article go to:
Introduction: High sensitivity troponin T (hsTnT) is a strong predictor of adverse outcome during... more Introduction: High sensitivity troponin T (hsTnT) is a strong predictor of adverse outcome during SARS-CoV-2 infection. However, its determinants remain partially unknown. We aimed to assess the relationship between severity of inflammatory response/coagulation abnormalities and hsTnT in Coronavirus Disease 2019 (COVID-19). We then explored the relevance of these pathways in defining mortality and complications risk and the potential effects of the treatments to attenuate such risk.Methods: In this single-center, prospective, observational study we enrolled 266 consecutive patients hospitalized for SARS-CoV-2 pneumonia. Primary endpoint was in-hospital COVID-19 mortality. Results: hsTnT, even after adjustment for confounders, was associated with mortality. D-dimer and CRP presented stronger associations with hsTnT than PaO2. Changes of hsTnT, D-dimer and CRP were related but only D-dimer was associated with mortality. Moreover, low molecular weight heparin showed attenuation of the ...
Background: Serum uric acid predicts the onset and progression of kidney disease, and the occurre... more Background: Serum uric acid predicts the onset and progression of kidney disease, and the occurrence of cardiovascular and all-cause mortality. Nevertheless, it is unclear which is the appropriate definition of hyperuricemia in presence of chronic kidney disease (CKD). Our goal was to study the independent impact of uric acid and CKD on mortality.Methods: We retrospectively investigated 21,963 patients from the URRAH study database. Hyperuricemia was defined on the basis of outcome specific cut-offs separately identified by ROC curves according to eGFR strata. The primary endpoints were cardiovascular and all-cause mortality.Results: After a mean follow-up of 9.8 year, there were 1,582 (7.20%) cardiovascular events and 3,130 (14.25%) deaths for all causes. The incidence of cardiovascular and all-cause mortality increased in parallel with reduction of eGFR strata and with progressively higher uric acid quartiles. During 215,618 person-years of follow-up, the incidence rate for cardio...
Purpose A derangement of the coagulation process and thromboinflammatory events have emerged as p... more Purpose A derangement of the coagulation process and thromboinflammatory events have emerged as pathologic characteristics of severe COVID-19, characterized by severe respiratory failure. CC motive chemokine ligand 2 (CCL2), a chemokine originally described as a chemotactic agent for monocytes, is involved in inflammation, coagulation activation and neoangiogenesis. We investigated the association of CCL2 levels with coagulation derangement and respiratory impairment in patients with COVID-19. Methods We retrospectively evaluated 281 patients admitted to two hospitals in Italy with COVID-19. Among them, CCL2 values were compared in different groups (identified according to D-dimer levels and the lowest PaO2/FiO2 recorded during hospital stay, P/Fnadir) by Jonckheere-Terpstra tests; linear regression analysis was used to analyse the relationship between CCL2 and P/Fnadir. We performed Mann-Whitney test and Kaplan-Meier curves to investigate the role of CCL2 according to different clinical outcomes (survival and endotracheal intubation [ETI]). Results CCL2 levels were progressively higher in patients with increasing D-dimer levels and with worse gas exchange impairment; there was a statistically significant linear correlation between log CCL2 and log P/Fnadir. CCL2 levels were significantly higher in patients with unfavourable clinical outcomes; Kaplan-Meier curves for the composite outcome death and/or need for ETI showed a significantly worse prognosis for patients with higher (> median) CCL2 levels. Conclusions CCL2 correlates with both indices of activation of the coagulation cascade and respiratory impairment severity, which are likely closely related in COVID-19 pathology, thus suggesting that CCL2 could be involved in the thromboinflammatory events characterizing this disease.
Journal of the American Society of Nephrology, 2006
The relationship among inflammation (plasma high-sensitivity C-reactive protein [CRP]), endotheli... more The relationship among inflammation (plasma high-sensitivity C-reactive protein [CRP]), endothelial function (hemodynamic response to acetylcholine [ACh] in the forearm), and renal function (serum creatinine and GFR [Modification of Diet in Renal Disease formula]) was investigated in 264 never-treated individuals with uncomplicated essential hypertension and serum creatinine within the normal range. Multiple regression models of renal function (creatinine) were constructed in sequence including Framingham risk factors as well the hemodynamic response to ACh and plasma CRP. The inclusion of endothelial function into a model based on Framingham risk factors added highly significant (P < 0.001) power to this model (؉5%). Of note, in an alternative model that included CRP (instead of endothelial function), the creatinine variance explained by this factor was two times higher (؉10%) than that associated with endothelial function in the first model. In the full model that included both endothelial function and CRP, CRP maintained a much stronger independent link with the outcome measure than endothelial function. In individuals with untreated, uncomplicated essential hypertension, multivariate modeling indicated that inflammation is a crucial mechanism mediating the endothelial-renal function link. The proatherogenic potential of inflammation associated with subtle impairment in renal function may contribute to the cardiovascular risk of essential hypertension.
Background and aims. Enhanced release of triglycerides (TG) by the liver is implicated in the pat... more Background and aims. Enhanced release of triglycerides (TG) by the liver is implicated in the pathogenesis of the metabolic syndrome. The aim of the study was to evaluate whether a primary elevation in hepatic glucose utilization (HGU), as induced by an acute rise in circulating glucose values during physiological hyperinsulinemia, promotes TG synthesis in spite of the reduction in free fatty acids (FFA) levels. Methods. Glucose dose-response studies were conducted in anesthetized pigs using positron emission tomography (PET) to quantify HGU during fasting euglycemic conditions (EF), and under two-step hyperglycemic hyperinsulinemia (1st-HH +3.0, 2nd-HH +6.0 mmol/L over EF glucose values). Liver biopsies were obtained in three animals to evaluate the relationship between glucose exposure and hepatic fat content. Results. Plasma glucose levels were progressively increased in the two-step studies, and otherwise stable within every hour of PET scanning. HGU increased almost fivefold with raising glucose levels, from 0.033 ± 0.009 in EF to 0.149 ± 0.043 in 1st-HH, p = 0.02, and to 0.138 ± 0.050 μmol/min/g in 2nd-HH, p = 0.03. Circulating TG concentrations increased by 50 and 100% in the two hyperglycemic conditions (p = 0.03 2nd-HH vs. EF), in spite of a 70% suppression in plasma FFA levels. The hepatic TG content paralleled the glucose loads. Plasma γ-glutamyl transferase (γ-GT) was increased by 17% (p < 0.05). Conclusions. A short-term elevation in circulating glucose levels within the physiological postprandial range was sufficient to increase HGU, resulting in a significant synthesis and release of TG by the liver, which was accompanied by an acute rise in γ-GT and liver fat content.
Aortic stiffness is an important clinical parameter for predicting cardiovascular events. Carotid... more Aortic stiffness is an important clinical parameter for predicting cardiovascular events. Carotid–femoral pulse wave velocity (cf-PWV) has been proposed for performing this evaluation non-invasively; however, it requires dedicated equipment and experienced operators. We explored the possibility of measuring aortic stiffness using ultrasound scans of the abdominal aorta coupled with the Bramwell–Hill equation. Healthy subjects were investigated; measurements of cf-PWV were taken by arterial tonometry and aortic systo-diastolic pressure difference was estimated using a validated model. Pulsatility of an abdominal tract of aorta was assessed by automated processing of ultrasound scans. Through a Bland–Altmann analysis, we found large biases when estimating each parameter by applying the Bramwell–Hill equation to the measured values of the other two paramters (bias, ± 1.96 SD; PWV, about 2.1 ± 2.5 m/s; pulsatility, 12 ± 14%; pressure jump, 47 ± 55 mmHg). These results indicate that the ...
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Papers by Stefano Masi