Costantino Mancusi

Classes of antihypertensive medications and blood pressure control in relation to metabolic risk factors.

Objective Metabolic syndrome (MetS) is associated with uncontrolled blood pressure (BP), despite use of aggressive therapy. This study was performed to assess whether the use of different classes of antihypertensive drugs might influence this association. Methods We evaluated risk of uncontrolled BP (BP ≥ 140/90 mmHg under antihypertensive treatment) at the time of the last available visit, after a mean follow-up of 5 years in 4612 hypertensive patients without prevalent cardiovascular disease (43% women, 53 ± 11 years) from the Campania Salute Network. Results At the time of the first visit, prevalence of MetS was associated with 43% increased risk of follow-up uncontrolled BP, independent of significant confounders and without a significant impact of specific classes of antihypertensive medications. At the time of the last available visit, patients with MetS had more often uncontrolled BP, despite more aggressive treatment. After adjusting for demographics, risk factors and number of antihypertensive medications, risk of uncontrolled BP was reduced with increased prescription of diuretics [DRTs; odds ratio (OR) 0.73, 95% confidence interval (CI) 0.62–0.86], renin–angiotensin system blockers [RAS-blockers (Angiotensin-converting enzyme-inhibitors or angiotensin receptor blockers); OR 0.77, 95% CI 0.66–0.91] and statins (OR 0.79, 95% 0.68–0.92, all P < 0.05), without significant impact of the other classes of medications. Conclusion Despite the use of increased number of medications, hypertensive patients with MetS are at higher risk of uncontrolled BP. Among classes of antihypertensive medications, increased prescriptions of DRTs, RAS-blockers and also statins decrease the probability of poor BP control.

Left Ventricular Hypertrophy Regression During Antihypertensive Treatment in an Outpatient Clinic (the Campania Salute Network)

Background Regression of left ventricular (LV) hypertrophy (LVH) has been a goal in clinical trials. This study tests the external validity of results of clinical trials on LVH regression using a large registry from a tertiary care center, to identify phenotypes less likely to achieve regression of LVH. Methods and Results Patients from the Campania Salute Network, free of prevalent cardiovascular disease, but with echocardiographic LVH (defined as LV mass index [LVMi] >47 g/m2.7 in women and >50 g/m2.7 in men) were included. During a median follow‐up of 67 months, clear‐cut regression of LVH was documented in 14% of patients (13±8% reduction of initial LVMi) or 23% when also considering those with a reduction of LVMi ≥5 g/m2.7. Patients with persistent LVH were older with longer duration of hypertension, suboptimal blood pressure (BP) control, larger body mass index, LV mass, and carotid intima‐media thickness and included more women and subjects with diabetes mellitus, isolated systolic hypertension, and metabolic syndrome (all P<0.05). Number and class of antihypertensive drugs during follow‐up did not differ between groups. In multiple logistic regression analysis, older age, female sex, obesity, higher baseline LVMi and carotid intima‐media thickness, and suboptimal BP control were significant covariates of persistent LVH (all P≤0.01), independent of diabetes, duration of hypertension, isolated systolic hypertension, follow‐up time and number and class of antihypertensive drugs. Conclusions Early initiation of antihypertensive treatment, aggressive BP control, and attention to metabolic aspects are critical to avoid irreversible LVH.

Impact of isolated systolic hypertension on normalization of left ventricular structure during antihypertensive treatment (the LIFE study)

Abstract Objective. We tested the impact of isolated systolic hypertension (ISH) on normalization of left ventricular (LV) structure during antihypertensive treatment. Methods. Baseline and annual echocardiograms were recorded in 873 hypertensive patients with electrocardiographic signs of LV hypertrophy during 4.8 years randomized losartan- or atenolol-based antihypertensive treatment in the Losartan Intervention For Endpoint (LIFE) reduction in hypertension study and classified as having ISH (n = 128) if systolic BP ≥ 160 mmHg and diastolic BP < 90 mmHg, or non-ISH divided into two groups by systolic BP ≥ 160 mmHg (non-ISH ≥ 160 mmHg) (n = 645) and systolic BP < 160 mm Hg (n = 100) (non-ISH < 160 mmHg), respectively. Results. Patients with ISH were older, with higher prevalence of diabetes than non-ISH groups and higher pulse pressure/stroke volume index (all p < 0.05). Baseline systolic blood pressure (BP) differed between groups and was highest in the non-ISH ≥ 160 mmHg group (p < 0.05). Systolic BP reduction was less in the ISH group (p < 0.05). LV geometry did not differ between ISH and non-ISH ≥ 160 mmHg groups at baseline, but ISH had more residual LV hypertrophy of concentric type at the last study visit (p < 0.05). In multivariate analysis, less reduction of LV mass was predicted by ISH (β = − 0.07) independent of significant associations with baseline LVMi (β = 0.52) and atenolol-based treatment (β = − 0.08) and clinical confounders (all p < 0.05). Conclusions. ISH is associated with impaired normalization of LV mass during systematic antihypertensive treatment. The findings may help explain the higher cardiovascular event rate previously reported in ISH patients.

Differential effect of obesity on prevalence of cardiac and carotid target organ damage in hypertension (the Campania Salute Network)

BACKGROUND Whether increasing body mass index (BMI) is independently associated with parallel increased prevalence of hypertensive vascular and cardiac target organ damage (TOD) needs further clarification. METHODS We analyzed 8815 hypertensive patients without prevalent cardiovascular disease, participating in the Campania Salute Network, grouped into BMI classes (normal 20-24.9kg/m2, overweight 25-29.9kg/m2 and obese ≥30kg/m2). Vascular and cardiac TOD was defined as ultrasound plaque (intima-media thickness>1.5mm) in >1 of the common or internal carotid arteries and echocardiographic left ventricular (LV) hypertrophy (LVH) (LV mass/height2.7>47g/m2.7 in women and >50g/m2.7 in men), respectively. RESULTS A majority of patients were either overweight (49%) or obese (27%). In spite of more use of combination therapy, the obese group had higher blood pressure (BP) and prevalence of TOD. In multivariate logistic analyses, obesity was associated with a 6.9 times higher prevalence of LVH (95% confidence interval [CI] 5.84-8.17, p=0.0001), independent of significant associations with female sex, age, diabetes mellitus, office systolic BP, antihypertensive and antiplatelet treatment. In contrast, only a 17% increased prevalence of carotid plaques (OR=1.17; 95% CI 1.02-1.33, p=0.02) was found in obese patients independent of significant effect of male sex, older age and higher clinic systolic BP, an association that disappeared once effect of metabolic risk factors and related therapy was also considered. CONCLUSIONS In hypertensive patients participating in the Campania Salute Project, concomitant obesity was associated with a modestly increased prevalence of carotid plaques and a pronounced increase in prevalent LVH.

Aortic root dimension and arterial stiffness in arterial hypertension: the Campania Salute Network.

Objectives: The relation between aortic root dimension (ARD) and measures of arterial stiffness is uncertain. Accordingly, we studied the relation between ARD and an estimate of arterial stiffness in 12 392 hypertensive patients (age 53 ± 12 years, 43% women) free of prevalent cardiovascular disease and with ejection fraction at least 50%, from the Campania Salute Network Registry. Methods: Echocardiographic ARD was measured and compared with the value predicted by age, sex and height by using a z-score. Arterial stiffness was assessed by the pulse pressure/stroke index. The highest population tertile of pulse pressure/stroke index was considered ‘high arterial stiffness’. Results: High arterial stiffness was more common in women than in men (P < 0.001) and associated with older age, diabetes, longer duration of hypertension and less frequent smoking habit (all P less than 0.01). Patients with high arterial stiffness had smaller ARD, higher carotid intima–media thickness and plasma cholesterol, and lower BMI and glomerular filtration rate (all P less than 0.01). In multivariable logistic analysis, high arterial stiffness was associated with both lower ARD z-score [OR 0.83 (95% confidence interval 0.79–0.88)] and higher carotid intima–media thickness [OR 1.36 (95% confidence interval 1.26–1.47); both P less than 0.0001], independent of significant associations with age, female sex, body size, DBP, heart rate, duration of hypertension, diabetes and smoking habit. Conclusion: Small ARD, together with atherosclerotic modifications of conduit arteries, is associated with increased 2-element Windkessel model of arterial stiffness in hypertension, independently of the significant effect of confounders.

Obesity and hypertensive heart disease: focus on body composition and sex differences

There is evidence that hypertension is frequently associated with overweight/obesity even in kids and adolescents. Either conditions influence development of left ventricular (LV) hypertrophy (LVH), through different biological and hemodynamic mechanisms: obesity is conventionally thought to elicit a coherent growth of LV chamber dimensions and myocardial wall thickness (eccentric LV geometry), whereas a more accentuated increase in wall-thickness (concentric LV geometry) is attributed to hypertension. While during youth these differences are visible, proportion of LV concentric geometry, the most harmful LV geometric pattern, sharply raises in obese individuals during middle age, and becomes the most frequent geometric patterns among obese-hypertensive individuals. Two conditions with elevated hemodynamic impact, severe obstructive sleep apnea and masked hypertension contribute to the development of such a geometric pattern, but non-hemodynamic factors, and specifically body composition, also influence prevalence of concentric LV geometry. Contrasting a general belief, it has been observed that adipose mass strongly influences LV mass, particularly in women, especially when fat-free mass is relatively deficient. Thus, though blood pressure control is mandatory for prevention and reduction of LVH in obese hypertensive patients, without reduction of visceral adiposity regression of LVH is difficult. Future researches should be addressed on (1) assessing whether LVH resulting from alteration of body composition carries the same prognosis as pressure overload LVH; (2) defining tissue characterization of the hypertrophic heart in obese-hypertensive patients; (3) evaluating whether assessment of hemodynamic loading conditions and biological markers can help defining management of the association of obesity with hypertension.

Higher pulse pressure and risk for cardiovascular events in patients with essential hypertension: The Campania Salute Network:

Background Increased pulse pressure is associated with structural target organ damage, especially in elderly patients, increasing cardiovascular risk. Design In this analysis, we investigated whether high pulse pressure retains a prognostic effect also when common markers of target organ damage are taken into account. Methods We analysed an unselected cohort of treated hypertensive patients from the Campania Salute Network registry (n = 7336). Participants with available cardiac and carotid ultrasound were required to be free of prevalent cardiovascular disease, with ejection fraction ≥50%, and no more than stage III Chronic Kidney Disease. The median follow-up was 41 months and end-point was occurrence of major cardiovascular events (i.e. fatal and non-fatal stroke or myocardial infarction and sudden death). Based on current guidelines, pulse pressure ≥60 mm Hg was classified as high pulse pressure (n = 2356), at the time of the initial visit, whereas pulse pressure <60 mm Hg was considered normal (n = 4980). Results High pulse pressure patients were older, more likely to be women and diabetic, while receiving more antihypertensive medications than normal pulse pressure (all p < 0.0001). High pulse pressure exhibited greater prevalence of left ventricular hypertrophy, and carotid plaque than normal pulse pressure (all p < 0.0001). In Cox regression, high pulse pressure patients had 57% increased hazard of major cardiovascular events, compared to normal pulse pressure (hazard ratio = 1.57; 95% confidence interval: 1.12–2.22, p = 0.01), an effect that was independent of significant prognostic impact of older age, male sex, diabetes, left ventricular hypertrophy, carotid plaque and less prescription of anti-renin–angiotensin system therapy. Conclusions High pulse pressure is a functional marker of target organ damage, predicting cardiovascular events in hypertensive patients, even independently of well-known structural markers of target organ damage.

Depressed myocardial energetic efficiency is associated with increased cardiovascular risk in hypertensive left ventricular hypertrophy

Background and purpose: Myocardial mechano-energetic efficiency (MEE) can be easily approximated by the ratio of stroke work [i.e. SBP times stroke volume (SV)] to a rough estimate of energy consumption, the ‘double product’ [SBP times heart rate (HR)], which can be simplified as SV/HR. We evaluated whether MEE is associated with adverse prognosis in relation to the presence of left ventricular hypertrophy (LVH). Methods: Hypertensive participants of the Campania Salute Network (n = 12 353) without prevalent coronary or cerebrovascular disease and with ejection fraction more than 50% were cross-sectionally and longitudinally analyzed, over a median follow-up of 31 months. MEE was estimated by echocardiographic SV (z-derived)/(HR × 0.6). Results: Due to the close relation with left ventricular mass (LVM) (P < 0.0001), MEE was normalized for LVM (MEEi) and divided into quartiles. The lowest quartile of MEEi (<0.29 ml/s per g) was considered ‘low MEEi’. MEEi was greater in women than in men (P < 0.0001). Progressively lower MEEi was associated with older age, male sex, obesity, diabetes, LVH, concentric geometry, inappropriate LVM and diastolic dysfunction, more use of antihypertensive therapy, and higher BP (all P < 0.002). In Cox regression, after controlling for LVH, age, sex, and average follow-up SBP, low MEEi exhibited increased hazard of composite fatal and nonfatal cardiovascular end-points (P < 0.01), independently of antihypertensive therapy and associated cardiovascular risk factors. Conclusion: A simple estimate of low myocardial mechano-energetic efficiency is associated with altered metabolic profile, LVH, concentric left ventricular geometry, and diastolic dysfunction and predicts cardiovascular end-points, independently of age, sex, LVH antihypertensive therapy, and cardiovascular risk factors.

Cardiometabolic risk in overweight subjects with or without relative fat-free mass deficiency: The Strong Heart Study

BACKGROUND AND AIM Sarcopenia is a condition mainly due to loss of fat-free mass (FFM) in elderly individuals. RFFMD, however, is also frequent in obese subjects due to abnormal body composition. Objective of this study was to evaluate the impact of relative fat-free mass deficiency (RFFMD) on cardiometabolic (CM) risk in obese normoglycemic individuals. METHODS AND RESULTS Overweight/obese American Indians from the Strong Heart Study population, without diabetes and with FBG ≤ 110 mg/dL and with GFR >60 mg/mL/1.73 m(2) were selected for this analysis (n = 742). RFFMD was defined on the basis of a multivariable equation previously reported. Fasting glucose and 2 h-OGTT were measured together with urine albumin/creatinine excretion, laboratory and anthropometric parameters. In addition to lower FFM and greater adipose mass, participants with RFFMD had higher body mass index, waist circumference, C-reactive protein, fibrinogen, insulin resistance and urinary albumin/creatinine than participants with normal FFM (all p < 0.001); they also had a greater prevalence of hypertension, impaired glucose tolerance (IGT) or OGTT-diabetes than participants with normal FFM (all p < 0.003) and a near 2-fold greater probability of significant proteinuria (p < 0.01). RFFMD was more frequent in women than in men: significant sex-RFFMD interactions were found for BMI and waist circumference (both p < 0.0001). CONCLUSIONS RFFMD in overweight/obese normoglycemic individuals is associated with greater probability of hypertension, abnormalities of glucose tolerance and proteinuria. Assessment of RFFRMD might, therefore, help stratifying cardiometabolic risk among normoglycemic individuals with overweight/obesity.

Effect of diabetes and metabolic syndrome on myocardial mechano-energetic efficiency in hypertensive patients. The Campania Salute Network

Reduced myocardial mechano-energetic efficiency (MEE), estimated as stroke volume/heart rate ratio per g of left ventricular (LV) mass (LVM), and expressed in μl s−1 g−1 (MEEi), is a strong predictor of cardiovascular (CV) events, independently of LV hypertrophy and other confounders, including type II diabetes (DM). Decreased MEEi is more frequent in patients with diabetes. In the present analysis we evaluated the interrelation among MEEi, DM and metabolic syndrome (MetS) in the setting of arterial hypertension. Hypertensive patients from the Campania Salute Network, free of prevalent CV disease and with ejection fraction >50% (n=12 503), were analysed. Coexistence of MetS and DM was ordinally categorized into 4 groups: 8235 patients with neither MetS nor DM (MetS−/DM−); 502 without MetS and with DM (MetS−/DM+); 3045 with MetS and without DM (MetS+/DM−); and 721 with MetS and DM (MetS+/DM+). After controlling for sex, systolic blood pressure, body mass index, relative wall thickness (RWT), antihypertensive medications and type of antidiabetic therapy, MEEi was 333 μl s−1 g−1 in MetS−/DM−, 328 in MetS−/DM+, 326 in MetS+/DM− and 319 in MetS+/DM+ (P for trend <0.0001). In pairwise comparisons (Sidak-adjusted), all conditions, except MetS−/DM+, were significantly different from MetS−/DM− (all P<0.02). No statistical difference was detected between MetS−/DM+ and MetS+/DM−. Both MetS and DM are associated with decreased MEEi in hypertensive patients, independently to each other, but the reduction is statistically less evident for MetS−/DM+. MetS+/DM+ patients have the lowest levels of MEEi, consistent with the alterations of energy supply associated with the combination of insulin resistance with insulin deficiency.