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Backgruound: This study investigated the prognostic importance of the hemoglobin glycation index (HGI) for macrovascular and microvascular outcomes, mortality, and hypoglycemia occurrence in a type 2 diabetes cohort and compared it to glycated hemoglobin (HbA1c)., Methods: Baseline and mean first-year HGI and HbA1c, and the variability thereof, were assessed in 687 individuals with type 2 diabetes (median follow-up, 10.6 years). Multivariable Cox regression was conducted to evaluate the associations of HGI and HbA1c parameters with macrovascular (total and major cardiovascular events) and microvascular outcomes (microalbuminuria, advanced renal failure, retinopathy, and peripheral neuropathy), mortality (all-cause and cardiovascular), and moderate/severe hypoglycemia occurrence., Results: During follow-up, there were 215 total cardiovascular events (176 major) and 269 all-cause deaths (131 cardiovascular). Microalbuminuria developed in 126 patients, renal failure in 104, retinopathy in 161, and neuropathy in 177. There were 90 hypoglycemia episodes. Both HGI and HbA1c predicted all adverse outcomes, except microalbuminuria and hypoglycemia. Their adjusted risks were roughly equivalent for all outcomes. For example, the adjusted hazard ratios (HRs) with 95% confidence intervals (CIs), estimated for 1 standard deviation increments, of mean first-year HGI were 1.23 (1.05 to 1.44), 1.20 (1.03 to 1.38), 1.36 (1.11 to 1.67), 1.28 (1.09 to 1.67), and 1.29 (1.09 to 1.54), respectively, for cardiovascular events, all-cause mortality, renal failure, retinopathy, and neuropathy; whereas the respective HRs (95% CIs) of mean HbA1c were 1.31 (1.12 to 1.53), 1.28 (1.11 to 1.48), 1.36 (1.11 to 1.67), 1.33 (1.14 to 1.55), and 1.29 (1.09 to 1.53)., Conclusion: HGI was no better than HbA1c as a predictor of adverse outcomes in individuals with type 2 diabetes, and its clinical use cannot be currently advised.

Aims: To investigate the effects of body weight variability (BWV) on macro- and microvascular outcomes in a type 2 diabetes cohort., Methods: BWV parameters were assessed in 684 individuals. Multivariable Cox regressions examined associations between BWV parameters and cardiovascular outcomes (total cardiovascular events [CVEs], major CVEs [MACEs], cardiovascular deaths),all-cause mortality and microvascular outcomes. Interaction/subgroup analyses were performed according to being physically-active/sedentary and having/not lost ≥ 5 % of weight., Results: Median follow-up was 11 years over which 194 total CVEs (174 MACEs), and 223 all-cause deaths (110 cardiovascular), occurred. There were 215 renal, 152 retinopathy and 167 peripheral neuropathy development/worsening outcomes. In general, increased BWV was associated with higher risks of CVEs, MACEs, all-cause mortality, advanced renal failure and peripheral neuropathy outcomes, but not of microalbuminuria and retinopathy outcomes. On interaction/subgroup analyses, increased BWV was associated with higher risks of outcomes in sedentary individuals and in those who did not lose ≥ 5 % of body weight. In physically-active participants or in those who lost ≥ 5 % weight, the adjusted risks were null or protective., Conclusions: Increased BWV was associated with most adverse outcomes; however, in those who were physically-active or consistently losing weight, it was not hazardous and might be even beneficial., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Background: The prognostic value of on-treatment mean cumulative ambulatory blood pressures (BPs) in type 2 diabetes has never been investigated. We aimed to assess it in a prospective cohort of 647 individuals with type 2 diabetes., Methods: Clinic-office and ambulatory BPs were measured at baseline and serially during follow-up. Multivariable Cox analyses assessed the associations between baseline and mean cumulative BPs with the occurrence of cardiovascular events, major adverse cardiovascular events, all-cause and cardiovascular mortality, and microvascular outcomes (microalbuminuria, renal failure, retinopathy, and peripheral neuropathy). C statistics and the integrated discrimination improvement (IDI) index evaluated the improvement in risk discrimination by using cumulative ambulatory BPs instead of baseline BPs., Results: Over a median follow-up of 10.6 years, there were 202 cardiovascular events (163 major adverse cardiovascular events), 254 all-cause deaths (118 cardiovascular); 125 individuals had microalbuminuria development/progression, 104 developed advanced renal failure, 159 had retinopathy, and 174 individuals had peripheral neuropathy development/progression. The risks associated with mean cumulative ambulatory BPs were in general higher than those associated with baseline BPs, particularly for cardiovascular (HR, 1.42 versus 1.25 for increments of 1 SD in 24-hour systolic blood pressure) and mortality outcomes (1.56 versus 1.26). Compared with cumulative clinic BPs, mean cumulative ambulatory BPs improved risk discrimination for most outcomes, with IDIs from 11% to 14% for major adverse cardiovascular events and mortality up to 24% to 26% for microalbuminuria and neuropathy., Conclusions: Compared with clinic-office BPs, mean cumulative ambulatory BPs during follow-up improve risk discrimination for most complications and mortality in individuals with type 2 diabetes. Serial ambulatory BP monitoring shall be more widely used in clinical management., Competing Interests: Disclosures None.

Backgruound: This study investigated the effects of weight loss during follow-up on cardiovascular outcomes in a type 2 diabetes cohort and tested interactions with clinical and laboratory variables, particularly physical activity, that could impact the associations., Methods: Relative weight changes were assessed in 651 individuals with type 2 diabetes and categorized as ≥5% loss, <5% loss, or gain. Associations between weight loss categories and incident cardiovascular outcomes (total cardiovascular events [CVEs], major adverse cardiovascular events [MACEs], and cardiovascular mortality) were assessed using multivariable Cox regression with interaction analyses., Results: During the initial 2 years, 125 individuals (19.2%) lost ≥5% of their weight, 180 (27.6%) lost <5%, and 346 (53.1%) gained weight. Over a median additional follow-up of 9.3 years, 188 patients had CVEs (150 MACEs) and 106 patients died from cardiovascular causes. Patients with ≥5% weight loss had a significantly lower risk of total CVEs (hazard ratio [HR], 0.52; 95% confidence interval, 0.33 to 0.89; P=0.011) than those who gained weight, but non-significant lower risks of MACEs or cardiovascular deaths. Patients with <5% weight loss had risks similar to those with weight gain. There were interactions between weight loss and physical activity. In active individuals, ≥5% weight loss was associated with significantly lower risks for total CVEs (HR, 0.20; P=0.004) and MACEs (HR, 0.21; P=0.010), whereas in sedentary individuals, no cardiovascular protective effect of weight loss was evidenced., Conclusion: Weight loss ≥5% may be beneficial for cardiovascular disease prevention, particularly when achieved with regular physical activity, even in high-risk individuals with long-standing type 2 diabetes.

Background: The prognostic importance of changes in aortic stiffness for the occurrence of adverse cardiovascular outcomes and mortality has never been investigated in patients with type 2 diabetes. We aimed to evaluate it in a cohort of 417 patients., Methods: Changes in aortic stiffness were assessed by 2 carotid-femoral pulse wave velocity (CF-PWV) measurements performed over a 4-year period. Multivariable Cox analysis examined the associations between changes in CF-PWV, evaluated as a continuous variable with splines and as categorical ones (quartiles and stable/reduction/increase subgroups), and the occurrence of total cardiovascular events (CVEs), major adverse CVEs (MACEs), and all-cause and cardiovascular mortality., Results: Over a median follow-up of 8.2 years after the 2nd CF-PWV measurement, there were 101 total CVEs (85 MACEs) and 135 all-cause deaths (64 cardiovascular). As a continuous variable, the lowest risk nadir was at -2.5%/year of CF-PWV change, with significantly higher risks of mortality associated with CF-PWV increases, but no excess risks at extremes of CF-PWV reduction. Otherwise, in categorical analyses, patients in the 1st quartile (greatest CF-PWV reductions) had excess risks of all-cause and cardiovascular mortality (hazard ratios [HRs]: 2.0-2.7), whereas patients in 3rd quartile had higher risks of all outcomes (HRs: 2.0-3.2), in relation to the lowest risk 2nd quartile subgroup. Patients in the 4th quartile had higher risks of all-cause mortality. Categorization as stable/reduction/increase subgroups was confirmatory, with higher risks at greater reductions (HRs: 1.7-3.3) and at greater increases in CF-PWV (HRs: 1.9-3.4), in relation to those with stable CF-PWV., Conclusions: Changes in aortic stiffness, mainly increases and possibly also extreme reductions, are predictors of adverse cardiovascular outcomes and mortality in individuals with type 2 diabetes., (© 2022. The Author(s).)

Aims: To investigate interactions between more/less strict treatment targets (HbA 1c , systolic blood pressure, LDL-cholesterol) and clinical characteristics (age, diabetes duration and presence of complications) for occurrence of cardiovascular/microvascular complications and mortality in type 2diabetes., Methods: 690 individuals were followed-up for 10 years (median). Interactions between treatment targets, estimated as mean values during the first 2-years, and clinical characteristics were tested in multivariable Cox regressions adjusted for other risk factors. Hazard ratios (HRs) were estimated in stratified analyses for cardiovascular/microvascular outcomes and mortality., Results: During follow-up, 214 patients had a cardiovascular event (175 MACEs); and 265 died (132 cardiovascular deaths); there were 206 renal, 161 retinopathy and 181 peripheral neuropathy events. There were interactions between treatment parameters and clinical characteristics, in most of them the HRs were higher in older individuals, in those with longer diabetes durations and with complications, particularly for the cardiovascular outcomes and mortality. For microvascular outcomes the opposite was observed. For cardiovascular mortality, the HRs of higher HbA 1c were 1.31 (1.08-1.58) and 1.09 (0.88-1.34), respectively with longer/shorter diabetes duration (p-for-interaction 0.11); and 1.43 (1.14-1.79) and 1.02 (0.85-1.23) in older/younger individuals (p-for-interaction 0.019)., Conclusions: Our findings do not support less strict treatment targets for older individuals, with longer diabetes duration or with complications, particularly for cardiovascular and mortality prevention., (Copyright © 2021. Published by Elsevier Inc.)

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Background: Liver stiffness measurement (LSM, which reflects fibrosis) and controlled attenuation parameter (CAP, which reflects steatosis), two parameters derived from hepatic transient elastography (TE), have scarcely been evaluated as predictors of cardiovascular complications and mortality in individuals with type 2 diabetes and nonalcoholic fatty liver disease (NAFLD)., Methods: Four hundred type 2 diabetic patients with NAFLD had TE examination (by Fibroscan ® ) performed at baseline. Multivariate Cox analyses evaluated the associations between TE parameters and the occurrence of cardiovascular events (CVEs) and mortality. TE parameters were assessed as continuous variables and dichotomized at low/high values reflecting advanced liver fibrosis (LSM > 9.6 kPa) and severe steatosis (CAP > 296 or > 330 dB/m). Improvements in risk discrimination were assessed by C-statistic and by the relative Integrated Discrimination Improvement (IDI) index., Results: During a median follow-up of 5.5 years, 85 patients died (40 from cardiovascular causes), and 69 had a CVE. As continuous variables, an increasing LSM was a risk marker for total CVEs (hazard ratio [HR]: 1.05; 95% CI: 1.01-1.08) and all-cause mortality (HR: 1.04; 95% CI: 1.01-1.07); whereas an increasing CAP was a protective factor for both outcomes (HR: 0.93; 95% CI: 0.89-0.98; and HR: 0.92; 95% CI: 0.88-0.97; respectively). As dichotomized variables, a high LSM remained a risk marker of adverse outcomes (with HRs ranging from 2.5 to 3.0) and a high CAP was protective (with HRs from 0.3 to 0.5). The subgroup of individuals with low-LSM/high-CAP had the lowest risks while the opposite subgroup with high-LSM/low-CAP had the highest risks. Both LSM and CAP improved risk discrimination, with increases in C-statistics up to 0.037 and IDIs up to 52%., Conclusions: Measured by hepatic TE, advanced liver fibrosis is a risk marker and severe steatosis is a protective factor for cardiovascular complications and mortality in individuals with type 2 diabetes and NAFLD., (© 2021. The Author(s).)

Objective: The prognostic importance of the nocturnal blood pressure (BP) fall and early-morning surge were scarcely investigated in patients with resistant hypertension (RHT). We investigated them in a prospective cohort of 1726 RHT individuals., Methods: The nocturnal fall and morning surge were calculated from the baseline ambulatory BP monitoring (ABPM) and also as mean cumulative values using all ABPMs performed during follow-up. Dipping patterns (normal, extreme, reduced, and reverse) were defined by classic cut-off values of the night-to-day ratio, while MS (difference between early-morning and night-time BP) was categorized into quartiles and at the extremes of its distribution (5th, 10th, 90th, and 95th percentiles). The primary outcomes were total cardiovascular events (CVEs), major adverse cardiovascular events (MACEs), all-cause and cardiovascular mortalities. Multivariate Cox analyses examined the associations between nocturnal BP fall and morning surge and outcomes., Results: Over a median follow-up of 8.3 years, 417 CVEs occurred (358 MACEs), and 391 individuals died (233 cardiovascular deaths). Reduced and reverse dipping patterns were significant predictors of CVEs and MACEs, with hazard ratios between 1.6 and 2.5, whereas extreme dipping was a protective factor in younger individuals (hazard ratios 0.3--0.4) but a hazardous factor in elderly (hazard ratios 3.7--5.0) and in individuals with previous cardiovascular diseases (hazard ratios 2.6--4.4). No morning surge parameter was predictive of any outcome in fully adjusted analyses., Conclusion: Abnormal dipping patterns but not the early-morning BP surge, were important prognostic markers for future cardiovascular morbidity in RHT patients. The prognosis of extreme dippers depended on age and the presence of cardiovascular diseases., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

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Objective: To evaluate the prognostic importance of short-term blood pressure variability (BPV) for the occurrence of macrovascular and microvascular complications in individuals with type 2 diabetes., Methods: Six hundred and forty patients had 24-h ambulatory BP monitoring performed at baseline and were followed-up over a median of 11.2 years. Daytime, night-time and 24-h SBP and DBPV parameters (standard deviations and variation coefficients) were calculated. Multivariate Cox analysis, adjusted for risk factors and mean BPs, examined the associations between BPV and the occurrence of microvascular (retinopathy, microalbuminuria, renal function deterioration, peripheral neuropathy) and macrovascular complications [total cardiovascular events (CVEs), major adverse CVEs [MACEs]), and cardiovascular and all-cause mortalities. Improvements in risk discrimination were assessed by the C-statistic and Integrated Discrimination Improvement (IDI) index., Results: During follow-up, 186 patients had a CVE (150 MACEs), and 237 patients died (107 from cardiovascular diseases); 155 newly developed or worsened diabetic retinopathy, 200 achieved the renal composite outcome (124 newly developed microalbuminuria and 102 deteriorated renal function), and 170 newly developed or worsened peripheral neuropathy. Daytime DBPV was the best predictor for all cardiovascular outcomes and mortality, with hazard ratios (for increments of 1SD) ranging from 1.27 (95% CI 1.09-1.48) for all-cause mortality to 1.55 (1.29-1.85) for MACEs, and it improved cardiovascular risk discrimination (with increases in C-statistic of up to 0.026, and IDIs of up to 22.8%). No BPV parameter predicted any microvascular outcome., Conclusion: Short-term BPV, particularly daytime DBPV, predicts future development of macrovascular complications and mortality and improves cardiovascular risk discrimination in patients with diabetes., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Background The long-term prognosis of refractory hypertension (RfHT), defined as failure to control blood pressure (BP) levels despite an antihypertensive treatment with ≥5 medications including a diuretic and mineraloreceptor antagonist, has never been evaluated. Methods and Results In a prospective cohort study with 1576 patients with resistant hypertension, patients were classified as refractory or nonrefractory based on uncontrolled clinic (or office) and ambulatory BPs during the first 2 years of follow-up. Multivariate Cox analyses examined the associations between the diagnosis of RfHT and the occurrence of total cardiovascular events (CVEs), major adverse CVEs, and cardiovascular and all-cause mortality, after adjustments for other risk factors. In total, 135 patients (8.6%) had RfHT by uncontrolled ambulatory BPs and 167 (10.6%) by uncontrolled clinic BPs. Over a median Follow-Up of 8.9 years, 338 total CVEs occurred (288 major adverse CVEs, including 124 myocardial infarctions, and 96 strokes), and 331 patients died, 196 from cardiovascular causes. The diagnosis of RfHT, using either classification by clinic or ambulatory BPs, was associated with significantly higher risks of major adverse CVEs, cardiovascular mortality, and stroke incidence, with hazard ratios varying from 1.54 to 2.14 in relation to patients with resistant nonrefractory hypertension; however, the classification based on ambulatory BPs was better in identifying higher risk patients than the classification based on clinic BP levels. Conclusions Patients with RfHT, particularly when defined by uncontrolled ambulatory BP levels, had higher risks of major adverse CVEs and mortality in relation to patients with resistant but nonrefractory hypertension, supporting the concept of refractory hypertension as a true extreme phenotype of antihypertensive treatment failure.

Background: The prognostic importance of an increased visit-to-visit blood pressure variability (BP-VVV) for the future development of micro- and macrovascular complications in type 2 diabetes has been scarcely investigated and is largely unsettled. We aimed to evaluate it in a prospective long-term follow-up study with 632 individuals with type 2 diabetes., Methods: BP-VVV parameters (systolic and diastolic standard deviations [SD] and variation coefficients) were measured during the first 24-months. Multivariate Cox analysis, adjusted for risk factors and mean BP levels, examined the associations between BP-VVV and the occurrence of microvascular (retinopathy, microalbuminuria, renal function deterioration, peripheral neuropathy) and macrovascular complications (total cardiovascular events [CVEs], major adverse CVEs [MACE] and cardiovascular and all-cause mortality). Improvement in risk discrimination was assessed by the C-statistic and integrated discrimination improvement (IDI) index., Results: Over a median follow-up of 11.3 years, 162 patients had a CVE (132 MACE), and 212 patients died (95 from cardiovascular diseases); 153 newly-developed or worsened diabetic retinopathy, 193 achieved the renal composite outcome (121 newly-developed microalbuminuria and 95 deteriorated renal function), and 171 newly-developed or worsened peripheral neuropathy. Systolic BP-VVV was an independent predictor of MACE (hazard ratio: 1.25, 95% CI 1.03-1.51 for a 1-SD increase in 24-month SD), but not of total CVEs, cardiovascular and all-cause mortality, and of any microvascular outcome. However, no BP-VVV parameter significantly improved cardiovascular risk discrimination (increase in C-statistic 0.001, relative IDI 0.9%)., Conclusions: Systolic BP-VVV was an independent predictor of MACE, but it did not improve cardiovascular risk stratification. The goal of anti-hypertensive treatment in patients with type 2 diabetes shall remain in controlling mean BP levels, not on decreasing their visit-to-visit variability.

The prognostic importance of the nocturnal systolic blood pressure (SBP) fall, adjusted for average 24-hour SBP levels, is unclear. The Ambulatory Blood Pressure Collaboration in Patients With Hypertension (ABC-H) examined this issue in a meta-analysis of 17 312 hypertensives from 3 continents. Risks were computed for the systolic night-to-day ratio and for different dipping patterns (extreme, reduced, and reverse dippers) relative to normal dippers. ABC-H investigators provided multivariate adjusted hazard ratios (HRs), with and without adjustment for 24-hour SBP, for total cardiovascular events (CVEs), coronary events, strokes, cardiovascular mortality, and total mortality. Average 24-hour SBP varied from 131 to 140 mm Hg and systolic night-to-day ratio from 0.88 to 0.93. There were 1769 total CVEs, 916 coronary events, 698 strokes, 450 cardiovascular deaths, and 903 total deaths. After adjustment for 24-hour SBP, the systolic night-to-day ratio predicted all outcomes: from a 1-SD increase, summary HRs were 1.12 to 1.23. Reverse dipping also predicted all end points: HRs were 1.57 to 1.89. Reduced dippers, relative to normal dippers, had a significant 27% higher risk for total CVEs. Risks for extreme dippers were significantly influenced by antihypertensive treatment (P<0.001): untreated patients had increased risk of total CVEs (HR, 1.92), whereas treated patients had borderline lower risk (HR, 0.72) than normal dippers. For CVEs, heterogeneity was low for systolic night-to-day ratio and reverse/reduced dipping and moderate for extreme dippers. Quality of included studies was moderate to high, and publication bias was undetectable. In conclusion, in this largest meta-analysis of hypertensive patients, the nocturnal BP fall provided substantial prognostic information, independent of 24-hour SBP levels., (© 2016 American Heart Association, Inc.)

The prognostic importance of baseline and serial glycated hemoglobin (HbA1c) changes for cardiovascular outcomes is still debated. We aimed to evaluate it in 620 high-risk individuals with type 2 diabetes (mean age 60.4 years, 37 % males, 55 % Caucasians). Patients had HbA1c levels measured at study entry and serially during follow-up. Primary end points were total cardiovascular events (CVEs), major CVEs (non-fatal myocardial infarctions and strokes plus cardiovascular deaths) and all-cause mortality. Cardiovascular and non-cardiovascular mortalities were secondary end points. HbA1c was evaluated either as a continuous variable and categorized at clinically relevant cutoffs. Multivariate Cox regressions assessed the associations with end points. After a median follow-up of 6.6 years, 125 total CVEs occurred (90 major CVEs), and 111 patients died (64 from cardiovascular diseases). After statistical adjustments for other cardiovascular risk factors, baseline and mean first-year HbA1c predicted all end points, except non-cardiovascular deaths; and hazard ratios tended to be higher for mean first year than for baseline HbA1c. Each 1 % (10.9 mmol/mol) increase in mean first-year HbA1c increased 27 % the risk of major CVEs occurrence (95 % CI 11-45 %). Updating HbA1c for values obtained beyond the second year of follow-up did not improve its predictive performance. The cardiovascular protection was observed until HbA1c values lower than 6.5 % (48 mmol/mol). Moreover, the magnitude of HbA1c reduction during the first year of follow-up was predictive of better cardiovascular outcomes, independent of baseline HbA1c levels. In conclusion, better glycemic control, especially during the first year of follow-up, is determinant of better cardiovascular outcomes in high-risk patients with type 2 diabetes, without any detectable lower threshold level of HbA1c.

Frontal plane T-wave axis and QRS-T angle are novel electrocardiographic ventricular repolarization parameters that have been scarcely evaluated in type 2 diabetes. The aim was to investigate the factors associated with these parameters of abnormal ventricular repolarization in a cross-sectional analysis of 594 patients with type 2 diabetes. Clinical, laboratory, 2D-echocardiographic, ambulatory blood pressure (BP) monitoring, aortic pulse wave velocity (PWV) and carotid ultrasonographic data were obtained. Digital 12-lead ECG was recorded, and frontal plane T-wave axis and QRS-T angle were automatically measured. T-wave axis was considered abnormal if >75° or <15° and QRS-T angle if ≥73° in men and ≥67° in woman. Associations were assessed by bivariate tests and multivariate logistic regressions. One hundred and four (20.9 %) patients had abnormal T-wave axis, and 84 (14 %) had increased QRS-T angle. Patients with abnormal ventricular repolarization were older and had greater prevalence of micro- and macrovascular diabetic complications than patients with normal repolarization. They had higher office and ambulatory BPs, greater prevalence of the non-dipping pattern, and greater left ventricular mass, aortic PWV and carotid intima-media thickness. On multivariate analysis, abnormal ventricular repolarization parameters were independently associated with left ventricular hypertrophy, non-dipping pattern, higher ambulatory systolic BPs, glycated hemoglobin and common carotid intima-media thickness, and with the presence of coronary artery disease. In conclusion, abnormal frontal plane T-wave axis and QRS-T angle are independently associated with several markers of pre-clinical atherosclerotic disease; whether these associations represent additional cardiovascular risk in type 2 diabetes shall be confirmed in prospective studies.

Objective: The prognostic importance of carotid-femoral pulse wave velocity (PWV), the gold standard measure of aortic stiffness, has been scarcely investigated in type 2 diabetes and never after full adjustment for potential confounders. The aim was to evaluate the prognostic impact of carotid-femoral PWV for cardiovascular morbidity and all-cause mortality in a cohort of 565 high-risk type 2 diabetic patients., Research Design and Methods: Clinical, laboratory, ambulatory blood pressure (BP) monitoring, and carotid-femoral PWV data were obtained at baseline. The primary end points were a composite of fatal and nonfatal cardiovascular events and all-cause mortality. Multiple Cox survival analysis was used to assess the associations between carotid-femoral PWV, as a continuous variable and categorized at 10 m/s, and the end points., Results: After a median follow-up of 5.75 years, 88 total cardiovascular events and 72 all-cause deaths occurred. After adjustments for potential cardiovascular risk factors, including micro- and macrovascular complications, ambulatory BP, and metabolic control, carotid-femoral PWV was predictive of the composite end point but not of all-cause mortality both as a continuous variable (hazard ratio 1.13 [95% CI 1.03-1.23], P = 0.009 for increments of 1 m/s) and as categorized at 10 m/s (1.92 [1.16-3.18], P = 0.012). On sensitivity analysis, carotid-femoral PWV was a better predictor of cardiovascular events in younger patients (<65 years), in those with microvascular complications, and in those with poorer glycemic control (HbA1c ≥7.5% [58.5 mmol/mol])., Conclusions: Carotid-femoral PWV provides cardiovascular risk prediction independent of standard risk factors, glycemic control, and ambulatory BPs and improves cardiovascular risk stratification in high-risk type 2 diabetes.

Objective: The prognostic value of microalbuminuria is unsettled in resistant hypertension. The objective was to evaluate the importance of baseline and serial changes in albuminuria as predictors of cardiovascular morbidity and mortality in patients with resistant hypertension., Methods: 531 resistant hypertensives had urinary albumin excretion rate (UAER) measured prospectively at baseline and at the 2nd year of follow-up. Primary endpoints were a composite of fatal and non-fatal cardiovascular events, all-cause and cardiovascular mortalities. Total strokes and coronary heart disease (CHD) events were secondary endpoints. Multiple Cox regression assessed the associations between UAER and endpoints., Results: After a median follow-up of 4.9 years, 72 patients died, 42 from cardiovascular causes; 96 cardiovascular events occurred, 42 strokes and 47 CHD events. After adjustment for several cardiovascular risk factors, baseline UAER, either analyzed as a continuous variable or dichotomized at different cut-off values, was an independent predictor of the composite endpoint, all-cause and cardiovascular mortality, strokes and CHD events. Each 10-fold increase in UAER implied a significant 1.6, 1.5, 2.0, 1.5 and 1.6-fold higher risk, respectively, for each of the above endpoints. Serial changes in microalbuminuria status during follow-up tended to parallel changes in cardiovascular risk, regression of microalbuminuria was associated with a 27% lower risk and development with a 65% higher risk of having a cardiovascular event., Conclusions: Baseline albuminuria strongly predicts cardiovascular morbidity and mortality in resistant hypertensive patients and serial changes in microalbuminuria may translate into changes in risk. Microalbuminuria reduction may be a goal of anti-hypertensive treatment., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Background: The prognostic value of office and ambulatory blood pressures (BPs) in patients with resistant hypertension is uncertain., Methods: This prospective study investigates the importance of office and ambulatory BPs as predictors of cardiovascular morbidity and mortality. At baseline, 556 resistant hypertensive patients underwent clinical-laboratory and 24-hour ambulatory BP monitoring examinations. Primary end points were a composite of fatal and nonfatal cardiovascular events and all-cause and cardiovascular mortalities. Multiple Cox regression was used to assess associations between BP and subsequent end points., Results: After median follow-up of 4.8 years, 109 patients (19.6%) reached the primary end point, and 70 all-cause deaths (12.6%) occurred (46 had cardiovascular causes). After adjustment for age, sex, body mass index, diabetes mellitus, smoking, physical inactivity, dyslipidemia, previous cardiovascular diseases, serum creatinine level, and number of antihypertensive drugs in use, no office BP showed any prognostic value. After further adjustment for office BP, higher mean ambulatory BPs were independent predictors of the composite end point. The hazard ratios associated with a 1-SD increment in daytime and nighttime systolic BP were 1.26 (95% confidence interval, 1.04-1.53) and 1.38 (1.13-1.68), respectively; the corresponding values for diastolic BP were 1.31 (1.05-1.63) and 1.36 (1.10-1.69). Ambulatory systolic and diastolic BP were equivalent predictors, and both were better than pulse pressure; nighttime BP was superior to daytime BP. For all-cause mortality, only the ambulatory BP monitoring diagnosis of true resistant hypertension was an independent predictor., Conclusion: Higher ambulatory BP predicts cardiovascular morbidity and mortality in resistant hypertensive patients, whereas office BP has no prognostic value.

The pathophysiological mechanisms linking cardiovascular dysautonomy to mortality are unclear. The aim of this study was to investigate the pattern of 24-h ambulatory blood pressure (BP) monitoring (ABPM) in diabetic patients with cardiovascular autonomic neuropathy (CAN). We evaluated 391 type 2 diabetic patients in a cross-sectional study. Five clinical tests of CAN were performed: heart-rate variation during deep breathing, the Valsalva maneuver, and standing, and BP variation during handgrip and standing. Patients were considered to have initial CAN if one heart-rate test was abnormal or two were borderline, and to have definite or severe CAN if at least two tests were abnormal. Differences between patients with and without CAN were assessed by bivariate tests and ANCOVA. Of the 391 patients, 230 (59%) presented clinical CAN, of whom 53 had definite or severe involvement. Patients with CAN were older, had diabetes of longer duration, and had an equal prevalence of hypertension but used more antihypertensive drugs than those without CAN. On ABPM, patients with definite or severe CAN had higher systolic BP (SBP) and pulse pressures (PP) than those without CAN, particularly in the nighttime (SBP: 128 +/- 18 vs. 117 +/- 16 mmHg, p = 0.007; PP: 58 +/- 13 vs. 50 +/- 11 mmHg, p = 0.003) and early morning (SBP: 140 +/- 18 vs. 131 +/- 17 mmHg, p = 0.05) after adjustment for potential confounders, as well as a higher prevalence of the systolic nondipping pattern (75.5% vs. 50.9%, p = 0.021). In conclusion, type 2 diabetic patients with more severe CAN have higher SBP and PP, especially during the nighttime and early morning, as well as a higher prevalence of nondipping status. This unfavorable 24-h ABPM pattern may contribute to the increased cardiovascular risk of diabetic patients with dysautonomy.

Objective: To evaluate the prognostic importance of resistant hypertension (RHT) for the development of complications in a cohort of individuals with type 2 diabetes.Research Design and Methods: A total of 646 patients had the diagnosis of apparent treatment-resistant hypertension (aRHT) based on mean office blood pressure (BP) levels during the 1st year of follow-up. They were reclassified as white-coat/controlled or true/uncontrolled RHT according to 24-h ambulatory BP monitoring (ABPM), using the traditional BP cutoffs and the new 2017 American College of Cardiology (ACC)/American Heart Association (AHA) criteria. Multivariate Cox analyses examined the associations between RHT diagnoses and the occurrence of microvascular and cardiovascular complications and all-cause and cardiovascular mortality.Results: During a median follow-up of 10 years, 177 patients had a cardiovascular event (145 major ones); 222 patients died (101 from cardiovascular diseases); 200 had a renal event; 156 had a retinopathy event; and 174 patients had a neuropathy event. In relation to non-RHT individuals, aRHT (present in 44.6% and 50% by the traditional and new criteria, respectively) predicted all cardiovascular and mortality outcomes, with hazard ratios (HRs) between 1.64 and 2.16, but none of the microvascular outcomes. True RHT increased the HRs (from 1.81 to 2.25) and additionally predicted renal outcomes. White-coat/controlled RHT implied an increased risk (HRs 1.33-1.86) that was intermediate between non-RHT and true RHT individuals. Classifications using the traditional and the new ACC/AHA criteria were equivalent.Conclusions: In patients with type 2 diabetes, the presence of aRHT implied an increased risk of cardiovascular and mortality outcomes, and classification based on ABPM predicted renal outcomes and improved cardiovascular/mortality risk stratification. [ABSTRACT FROM AUTHOR]

The prognostic importance of aortic stiffness in patients with resistant hypertension has never been investigated. We aimed to evaluate it for the occurrence of adverse cardiovascular outcomes and mortality in a prospective cohort of resistant hypertensive patients. Aortic stiffness was assessed by carotid-femoral pulse wave velocity (cf-PWV) at baseline in 891 resistant hypertensive patients who were followed-up for a median of 7.8 years. Multivariate Cox analysis examined the associations between cf-PWV and the occurrence of total cardiovascular events (CVE), major adverse CVEs, and cardiovascular and all-cause mortalities. The improvement in risk stratification was assessed by C statistics and the integrated discrimination improvement index. During follow-up, 138 patients had a CVE (123 major adverse CVE) and 142 patients died (91 from cardiovascular causes). The cf-PWV, analyzed either as a continuous or as a categorical variable, predicted all cardiovascular and mortality outcomes. Patients with increased aortic stiffness (cf-PWV ≥10 m/s after correction for the white-coat effect, or uncorrected directly measured ≥11 m/s) had a significant 2.2- to 2.6-fold increased risk of CVEs and mortality, after adjustments for other risk factors, including 24-hour ambulatory blood pressures and dipping patterns. Aortic stiffness significantly improved cardiovascular risk stratification, with integrated discrimination improvement indices ranging from 13% (for total CVEs) to 18% (for major adverse CVE). In conclusion, increased aortic stiffness predicts adverse cardiovascular outcomes and mortality and improves cardiovascular risk stratification in resistant hypertensive patients. cf-PWV measurement should be included into the routine clinical management of resistant hypertension. [ABSTRACT FROM AUTHOR]

Increased aortic stiffness has been recognized as a predictor of adverse cardiovascular outcomes in some clinical conditions, such as in patients with arterial hypertension and end-stage renal disease, in population-based samples and, more recently, in type 2 diabetic patients. Patients with type 2 diabetes have higher aortic stiffness than non-diabetic individuals, and increased aortic stiffness has been correlated to the presence of micro- and macrovascular chronic diabetic complications. We aimed to review the current knowledge on the relationships between aortic stiffness and diabetic complications, their possible underlying physiopathological mechanisms, and their potential applications to clinical type 2 diabetes management. [ABSTRACT FROM AUTHOR]

BACKGROUND C-reactive protein (CRP) is a biomarker of systemic low-grade inflammation and a cardiovascular risk predictor in several clinical conditions. However, its prognostic value has never been examined in patients with resistant hypertension. METHODS In a prospective study, 476 patients with resistant hypertension had CRP levels measured at baseline, together with other clinical laboratory variables, including ambulatory blood pressures (BPs). Primary end points were a composite of major fatal or nonfatal cardiovascular events, all-cause mortality, and cardiovascular mortality. Multiple Cox regression assessed the associations between CRP levels and end points. RESULTS Median CRP was 3.8 mg/l (interquartile range: 2.0-7.2 mg/l). After a median follow-up of 9 years, 103 major cardiovascular events occurred, and 120 patients died, 62 from cardiovascular causes. Patients with CRP levels above the median value had a doubled excess risk of major cardiovascular events (95% confidence interval: 1.29-3.06; P = 0.002) and an 86% higher risk of cardiovascular death (95% confidence interval: 1.07-3.25; P = 0.029), after adjustments for potential confounders including traditional cardiovascular risk factors and ambulatory BP and dipping pattern. A high CRP equally predicted coronary (hazard ratio: 2.04; 95% confidence interval: 1.10-3.76; P = 0.023) and cerebrovascular events (hazard ratio: 2.72; 95% confidence interval: 1.30-5.67; P = 0.007). In interaction and sensitivity analyses, CRP levels were stronger predictors of worse cardiovascular outcomes in younger and obese patients, and in those with uncontrolled ambulatory BPs and with the nondipping pattern. CONCLUSIONS In patients with resistant hypertension, elevated serum CRP levels is predictive of worse cardiovascular prognosis above and beyond other cardiovascular risk factors, including ambulatory BP levels and dipping patterns. [ABSTRACT FROM AUTHOR]

Background & Aims Type 2 diabetes mellitus (T2 DM) is a risk factor for cardiovascular disease ( CVD) and advanced stages of non-alcoholic fatty liver disease ( NAFLD). The aim was to evaluate the association between aortic stiffness, a preclinical CVD marker, with advanced liver fibrosis identified by transient elastography ( TE) in T2 DM outpatients with NAFLD. Methods This longitudinal study included 291 T2 DM patients with NAFLD detected by ultrasonography, who had two carotid-femoral pulse wave velocity (cf- PWV) measurements and a TE examination (Fibroscan®) performed over a median follow-up of 7 years. Advanced liver fibrosis (corresponding to ≥ F3 stage) was considered as median values >7.9 kPa (M probe) or >7.2 kPa ( XL probe). Increased aortic stiffness was defined as cf- PWV >10 m/s. Results Eighty patients (27.5%) had advanced liver fibrosis. Overall, there was an increase in cf- PWV of 0.1 m/s/year (1% per year). Both a high aortic stiffness at the 2nd cf- PWV examination [odds ratios ( OR): 3.0; 95% CI: 1.3-7.2; P = 0.011] and a serial increase in aortic stiffness ( OR: 2.1; 95% CI: 1.0-4.3; P = 0.046) were associated with increased odds of having advanced liver fibrosis. Patients who presented either an increase in aortic stiffness or persisted with high values had significantly higher mean liver stiffness than those who either decreased aortic stiffness or persisted with normal cf- PWV values (mean difference: 2.1 kPa, 95% CI: 0.5-3.7 kPa, P = 0.012), after adjustments for anthropometric-demographic and clinical laboratory covariates. Conclusions In T2 DM patients with NAFLD, a high or increasing aortic stiffness predicted development of advanced liver fibrosis on TE. [ABSTRACT FROM AUTHOR]

Aims Reduced heart rate variability (HRV), an early sign of diabetic cardiovascular autonomic neuropathy (CAN), is associated with worse cardiovascular outcomes. The objective was to evaluate relationships between HRV parameters and three pre-clinical cardiovascular disease markers (left ventricular hypertrophy [LVH], aortic stiffness and carotid atherosclerosis) in type 2 diabetes. Methods In a cross-sectional study, 313 patients with type 2 diabetes performed 24-h Holter monitoring, carotid ultrasonography (intima-media thickness and plaques measurements), aortic pulse wave velocity measurement and echocardiography (left ventricular mass index [LVMI] measurement). Time-domain HRV parameters were the standard deviation of all normal RR intervals (SDNN), the standard deviation of the averaged normal RR intervals for all 5 min segments (SDANN), the root mean square of differences between adjacent R-R intervals (rMSSD), and the percentage of adjacent R-R intervals that varied by >50 ms (pNN50). Multivariate linear and logistic regressions assessed associations between HRV parameters and the three markers of pre-clinical cardiovascular disease. Results Patients with reduced HRV had longer diabetes duration, greater prevalences of microvascular complications, lower physical fitness, and higher heart rate, glycated hemoglobin, albuminuria and LVMI than patients with normal HRV. On multivariate regressions, after adjustments for several confounders, reduced SDNN and SDANN were independently associated with LVH and aortic stiffness. No HRV parameter was associated with carotid atherosclerosis. Conclusions Two reduced HRV parameters, SDNN and SDANN, which reflect cardiovascular autonomic imbalance, were associated with LVH and aortic stiffness, markers of pre-clinical cardiovascular disease. These findings may offer insights into physiopathological mechanisms linking CAN to worse cardiovascular prognosis. [ABSTRACT FROM AUTHOR]

Objective: To investigate mortality rates and predictors of mortality in Brazilian type 2 diabetic patients.Research Design and Methods: A prospective follow-up study was carried out with 471 type 2 diabetic outpatients. Primary end points were all-cause, diabetes-related, and cardiovascular deaths. Excess mortality in this cohort was evaluated by calculating standardized mortality ratios (SMRs) in relation to those of the Rio de Janeiro population. Predictors of mortality were assessed by Kaplan-Meier survival curves and by uni- and multivariate Cox survival analyses.Results: During a median follow-up of 57 months (range 2-84 months), 121 (25.7%) patients died, 91 (75.2%) from diabetes-related causes and 44 (36.4%) from cardiovascular diseases. After adjusting for age and sex, the all-cause SMR was 3.36 (95% confidence interval [CI] 2.81-4.02) and the cardiovascular SMR was 3.28 (CI 2.44-4.41). In the Cox multivariate analysis, the predictors of mortality were older age, increased 24-h proteinuria, preexisting vascular disease, presence of frequent ventricular premature contractions and prolonged maximum heart rate-corrected QT interval on baseline electrocardiogram, and decreased serum HDL cholesterol. The use of beta-blockers was a protective factor. In Kaplan-Meier curves, these variables were capable of distinguishing subgroups of patients with significantly different prognoses.Conclusions: Brazilian type 2 diabetic patients had a more than threefold excess mortality than the general population, largely because of increased cardiovascular mortality risk. Several clinical, laboratory, and electrocardiographic predictors of mortality were identified that could possibly be modified to decrease the mortality burden of type 2 diabetes in Brazil. [ABSTRACT FROM AUTHOR]

The prognostic importance of electrocardiographic ventricular repolarization QT parameters (maximum rate-corrected QT interval—QTcmax, QT interval dispersion–QTd, and QTcd), in relation to other risk markers, on cardiovascular and cardiac mortality, and on total fatal or nonfatal cardiovascular events, was evaluated prospectively in 471 type 2 diabetic outpatients. During a median follow-up of 57 months (range: 2–84), 121 (25.7%), patients died, 44 (36.3% of them) from cardiovascular causes and 106 (22.5%) fatal or nonfatal cardiovascular events were observed. In Cox proportional hazards multivariate analysis, both QTd and QTcmax were independent predictors of cardiovascular and cardiac mortality (hazard ratio [HR]: 1.34, 95% confidence interval [95% CI]: 1.12–1.59, for each 10-ms increments in QTd and HR: 1.17, 95% CI: 1.03–1.21 for 10-ms increments in QTcmax, for cardiovascular mortality). They were also predictors of total fatal or nonfatal cardiac and cardiovascular events (HR: 1.18, 95% CI: 1.05–1.33 for QTd and HR: 1.09, 95% CI: 1.04–1.15 for QTcmax). Additional independent prognostic markers for total cardiovascular events were the presence of previous cardiac disease, cerebral or peripheral vascular disease, age, male gender, known diabetes duration, heart rate, and serum triglycerides. Excluding patients with prior cardiac disease did not change significantly the prognostic performance of QTd but decreased that of QTcmax. In conclusion, QT interval parameters give additional prognostic information in patients with type 2 diabetes mellitus, beyond that obtained from traditional risk factors. QT interval dispersion seems a better prognostic marker than maximum QT interval, particularly in patients without previous cardiac diseases. [Copyright &y& Elsevier]

Background: The prognostic importance of carotid atherosclerosis in individuals with diabetes is unsettled. We aimed to evaluate the relationships between parameters of carotid atherosclerosis and the future occurrence of micro- and cardiovascular complications in individuals with type 2 diabetes. Methods: Ultrasonographic parameters of carotid atherosclerosis, intima-media thickness (CIMT) and plaques, were measured at baseline in 478 participants who were followed-up for a median of 10.8 years. Multivariate Cox analysis was used to examine the associations between carotid parameters and the occurrence of microvascular (retinopathy, renal, and peripheral neuropathy) and cardiovascular complications (total cardiovascular events [CVEs] and cardiovascular mortality), and all-cause mortality. The improvement in risk stratification was assessed by using the C-statistic and the integrated discrimination improvement (IDI) index. Results: During follow-up, 116 individuals had a CVE and 115 individuals died (56 from cardiovascular diseases); 131 newly-developed or worsened diabetic retinopathy, 156 achieved the renal composite outcome (94 newly developed microalbuminuria and 78 deteriorated renal function), and 83 newly-developed or worsened peripheral neuropathy. CIMT, either analysed as a continuous or as a categorical variable, and presence of plaques predicted CVEs occurrence and renal outcomes, but not mortality or other microvascular complications. Individuals with an increased CIMT and plaques had a 1.5- to 1.8-fold increased risk of CVEs and a 1.6-fold higher risk of renal outcome. CIMT and plaques modestly improved cardiovascular risk discrimination over classic risk factors, with IDIs ranging from 7.8 to 8.4%; but more markedly improved renal risk discrimination, with IDIs from 14.8 to 18.5%. Conclusions: Carotid atherosclerosis parameters predicted cardiovascular and renal outcomes, and improved renal risk stratification. Ultrasonographic carotid imaging may be useful in type 2 diabetes management. [ABSTRACT FROM AUTHOR]