Davide Grassi

Cocoa Reduces Blood Pressure and Insulin Resistance and Improves Endothelium-Dependent Vasodilation in Hypertensives

Consumption of flavanol-rich dark chocolate (DC) has been shown to decrease blood pressure (BP) and insulin resistance in healthy subjects, suggesting similar benefits in patients with essential hypertension (EH). Therefore, we tested the effect of DC on 24-hour ambulatory BP, flow-mediated dilation (FMD), and oral glucose tolerance tests (OGTTs) in patients with EH. After a 7-day chocolate-free run-in phase, 20 never-treated, grade I patients with EH (10 males; 43.7±7.8 years) were randomized to receive either 100 g per day DC (containing 88 mg flavanols) or 90 g per day flavanol-free white chocolate (WC) in an isocaloric manner for 15 days. After a second 7-day chocolate-free period, patients were crossed over to the other treatment. Noninvasive 24-hour ambulatory BP, FMD, OGTT, serum cholesterol, and markers of vascular inflammation were evaluated at the end of each treatment. The homeostasis model assessment of insulin resistance (HOMA-IR), quantitative insulin sensitivity check index (QUICKI), and insulin sensitivity index (ISI) were calculated from OGTT values. Ambulatory BP decreased after DC (24-hour systolic BP −11.9±7.7 mm Hg, P<0.0001; 24-hour diastolic BP −8.5±5.0 mm Hg, P<0.0001) but not WC. DC but not WC decreased HOMA-IR (P<0.0001), but it improved QUICKI, ISI, and FMD. DC also decreased serum LDL cholesterol (from 3.4±0.5 to 3.0±0.6 mmol/L; P<0.05). In summary, DC decreased BP and serum LDL cholesterol, improved FMD, and ameliorated insulin sensitivity in hypertensives. These results suggest that, while balancing total calorie intake, flavanols from cocoa products may provide some cardiovascular benefit if included as part of a healthy diet for patients with EH.

Flavonoids, vascular function and cardiovascular protection.

A large body of evidence supports that the dietary intake of polyphenols - particularly of flavonoids and the specific class of flavonoids named flavanols - might be able to exert some beneficial vascular effects and reduce the risk for cardiovascular morbidity and mortality. The review of epidemiological and mechanistic studies supports the role of flavonoids, particularly cocoa and tea flavanols, in protecting the cardiovascular system against cardiovascular disease. Nevertheless, flavonoids are an heterogeneous group of natural molecules differently represented in fruit and vegetables and definitive data on cardiovascular benefits are lacking. The weakness of the available data include few and very small studies, no crossover designed studies and a wide range of dose and type of flavonoids tested. Thus, although flavonoid-rich foods and beverages are likely to protect cardiovascular system, further research is needed to characterize the mechanism of action on flavanol-rich foods. Long-term clinical trials are also needed to definitively clarify the benefits deriving from long-term consumption of flavanol-rich foods, particularly focussing on the lowest effective levels as well as synergism or antagonistic actions between different classes of flavonoids commonly found in foods.

Benefits in Cognitive Function, Blood Pressure, and Insulin Resistance Through Cocoa Flavanol Consumption in Elderly Subjects With Mild Cognitive Impairment The Cocoa, Cognition, and Aging (CoCoA) Study

Flavanol consumption is favorably associated with cognitive function. We tested the hypothesis that dietary flavanols might improve cognitive function in subjects with mild cognitive impairment. We conducted a double-blind, parallel arm study in 90 elderly individuals with mild cognitive impairment randomized to consume once daily for 8 weeks a drink containing ≈990 mg (high flavanols), ≈520 mg (intermediate flavanols), or ≈45 mg (low flavanols) of cocoa flavanols per day. Cognitive function was assessed by Mini Mental State Examination, Trail Making Test A and B, and verbal fluency test. At the end of the follow-up period, Mini Mental State Examination was similar in the 3 treatment groups (P=0.13). The time required to complete Trail Making Test A and Trail Making Test B was significantly (P<0.05) lower in subjects assigned to high flavanols (38.10±10.94 and 104.10±28.73 seconds, respectively) and intermediate flavanols (40.20±11.35 and 115.97±28.35 seconds, respectively) in comparison with those assigned to low flavanols (52.60±17.97 and 139.23±43.02 seconds, respectively). Similarly, verbal fluency test score was significantly (P<0.05) better in subjects assigned to high flavanols in comparison with those assigned to low flavanols (27.50±6.75 versus 22.30±8.09 words per 60 seconds). Insulin resistance, blood pressure, and lipid peroxidation also decreased among subjects in the high-flavanol and intermediate-flavanol groups. Changes of insulin resistance explained ≈40% of composite z score variability through the study period (partial r2=0.4013; P<0.0001). To the best of our knowledge, this is the first dietary intervention study demonstrating that the regular consumption of cocoa flavanols might be effective in improving cognitive function in elderly subjects with mild cognitive impairment. This effect appears mediated in part by an improvement in insulin sensitivity.

Cocoa flavanol consumption improves cognitive function, blood pressure control, and metabolic profile in elderly subjects: the Cocoa, Cognition, and Aging (CoCoA) Study—a randomized controlled trial

Background: Recent evidence has indicated that flavanol consumption may have many health benefits in humans, including improved cognitive activities. Objective: The aim was to evaluate the effect of flavanol consumption on cognitive performance in cognitively intact elderly subjects. Design: This was a double-blind, controlled, parallel-arm study conducted in 90 elderly individuals without clinical evidence of cognitive dysfunction who were randomly assigned to consume daily for 8 wk a drink containing 993 mg [high flavanol (HF)], 520 mg [intermediate flavanol (IF)], or 48 mg [low flavanol (LF)] cocoa flavanols (CFs). Cognitive function was assessed at baseline and after 8 wk by using the Mini-Mental State Examination (MMSE), the Trail Making Test (TMT) A and B, and the Verbal Fluency Test (VFT). Results: The changes in MMSE score in response to the 3 different treatments were not different. In contrast, there was a positive impact of the intervention on specific aspects of cognitive function. Mean changes (±SEs) in the time required to complete the TMT A and B after consumption of the HF (−8.6 ± 0.4 and −16.5 ± 0.8 s, respectively) and IF (−6.7 ± 0.5 and −14.2 ± 0.5 s, respectively) drinks significantly (P < 0.0001) differed from that after consumption of the LF drinks (−0.8 ± 1.6 and −1.1 ± 0.7 s, respectively). Similarly, VFT scores significantly improved among all treatment groups, but the magnitude of improvement in the VFT score was significantly (P < 0.0001) greater in the HF group (7.7 ± 1.1 words/60 s) than in the IF (3.6 ± 1.2 words/60 s) and LF (1.3 ± 0.5 words/60 s) groups. Significantly different improvements in insulin resistance (P < 0.0001), blood pressure (P < 0.0001), and lipid peroxidation (P = 0.001) were also observed for the HF and IF groups in comparison with the LF group. Changes in insulin resistance explained ∼17% of changes in composite z score (partial r2 = 0.1703, P < 0.0001). Conclusions: This dietary intervention study provides evidence that regular CF consumption can reduce some measures of age-related cognitive dysfunction, possibly through an improvement in insulin sensitivity. These data suggest that the habitual intake of flavanols can support healthy cognitive function with age. This trial was registered at www.controlled-trials.com as ISRCTN68970511.

Black tea consumption dose-dependently improves flow-mediated dilation in healthy males.

Objectives Flavonoids may protect against cardiovascular disease. Tea is a major source of dietary flavonoids. Studies indicate black tea improves endothelial function but data on arterial haemodynamics, blood pressure (BP) and insulin resistance are equivocal. Inconsistency may be due to flaws in study design or flavonoid doses tested. Further, no study has evaluated the dose–response curve. Our study aimed to test the effects of various doses of black tea on vascular function, BP and insulin resistance. Methods According to a randomized, double-blind, controlled, cross-over design, 19 healthy men were assigned to receive either five treatments with a twice daily intake of black tea (0, 100, 200, 400 and 800 mg tea flvanoids/day) in five periods lasting 1 week each. Results Black tea dose dependently increased flow-mediated dilation (FMD) from 7.8% (control) to 9.0, 9.1, 9.6 and 10.3% after the different flavonoid doses, respectively (P = 0.0001). Already 100 mg/day (less than 1 cup of tea) increased FMD compared with control (P = 0.0113). FMD improvement after 800 mg/day was significant compared with control (P < 0.0001) but also to 100 mg/day (P = 0.0121) and 200 mg/day (P = 0.0275). Black tea intake decreased office systolic (−2.6 mmHg, P = 0.0007) and diastolic (−2.2 mmHg, P = 0.006) BP as well as stiffness index (P = 0.0159) without changes in other parameters studied. Conclusion Our study is the first showing black tea ingestion dose dependently improved FMD and decreased peripheral arterial stiffness in healthy volunteers. Our data suggest that worldwide all tea drinkers could benefit from protective cardiovascular effects exerted by tea.

Flavonoids: Antioxidants Against Atherosclerosis

Oxidative stress results from an imbalance between excessive formation of reactive oxygen species (ROS) and/or reactive nitrogen species and limited antioxidant defences. Endothelium and nitric oxide (NO) are key regulators of vascular health. NO bioavailability is modulated by ROS that degrade NO, uncouple NO synthase, and inhibit synthesis. Cardiovascular risk conditions contribute to oxidative stress, causing an imbalance between NO and ROS, with a relative decrease in NO bioavailability. Dietary flavonoids represent a range of polyphenolic compounds naturally occurring in plant foods. Flavonoids are potentially involved in cardiovascular prevention mainly by decreasing oxidative stress and increasing NO bioavailability.

Chronic Hyperuricemia, Uric Acid Deposit and Cardiovascular Risk

Hyperuricemia is commonly associated with traditional risk factors such as dysglicemia, dyslipidemia, central obesity and abnormal blood pressure, i.e. the metabolic syndrome. Concordantly, recent studies have revived the controversy over the role of circulating uric acid, hyperuricemia, and gout as an independent prognostic factor for cardiovascular morbidity and mortality. In this regard, different studies also evaluated the possible role of xanthine inhibitors in inducing blood pressure reduction, increment in flow-mediated dilation, and improved cardiovascular prognosis in various patient settings. The vast majority of these studies have been conducted with either allopurinol or its active metabolite oxypurinol, i.e. two purine-like non-selective inhibitors of xanthine oxidase. More recently, the role of uric acid as a risk factor for cardiovascular disease and the possible protective role exerted by reduction of hyperuricemia to normal level have been evaluated by the use of febuxostat, a selective, non purine-like xanthine oxidase inhibitor. In this review, we will report current evidence on hyperuricemia in cardiovascular disease. The value of uric acid as a biomarker and as a potential therapeutic target for tailored old and novel “cardiometabolic” treatments will be also discussed.

Protective Effects of Flavanol-Rich Dark Chocolate on Endothelial Function and Wave Reflection During Acute Hyperglycemia

Nitric oxide plays a pivotal role in regulating vascular tone. Different studies show endothelial function is impaired during hyperglycemia. Dark chocolate increases flow-mediated dilation in healthy and hypertensive subjects with and without glucose intolerance; however, the effect of pretreatment with dark chocolate on endothelial function and other vascular responses to hyperglycemia has not been examined. Therefore, we aimed to investigate the effects of flavanol-rich dark chocolate administration on (1) flow-mediated dilation and wave reflections; (2) blood pressure, endothelin-1 and oxidative stress, before and after oral glucose tolerance test (OGTT). Twelve healthy volunteers (5 males, 28.2±2.7 years) randomly received either 100 g/d dark chocolate or flavanol-free white chocolate for 3 days. After 7 days washout period, volunteers were switched to the other treatment. Flow-mediated dilation, stiffness index, reflection index, peak-to–peak time, blood pressure, endothelin-1 and 8-iso-PGF2&agr; were evaluated after each treatment phase and OGTT. Compared with white chocolate, dark chocolate ingestion improved flow-mediated dilation (P=0.03), wave reflections, endothelin-1 and 8-iso-PGF2&agr; (P<0.05). After white chocolate ingestion, flow-mediated dilation was reduced after OGTT from 7.88±0.68 to 6.07±0.76 (P=0.027), 6.74±0.51 (P=0.046) at 1 and 2 h after the glucose load, respectively. Similarly, after white chocolate but not after dark chocolate, wave reflections, blood pressure, and endothelin-1 and 8-iso-PGF2&agr; increased after OGTT. OGTT causes acute, transient impairment of endothelial function and oxidative stress, which is attenuated by flavanol-rich dark chocolate. These results suggest cocoa flavanols may contribute to vascular health by reducing the postprandial impairment of arterial function associated with the pathogenesis of atherosclerosis.

Cocoa consumption dose-dependently improves flow-mediated dilation and arterial stiffness decreasing blood pressure in healthy individuals.

Background: Cocoa flavonoids exert beneficial vascular effects and reduce the risk of cardiovascular morbidity and mortality. Nevertheless, the involved mechanisms have not been clarified and no study has yet focused on the dose–response effects. Objectives: We aimed to investigate the effects of different doses of cocoa flavonoids on flow-mediated dilation (FMD), endothelin-1 (ET-1), pulse wave velocity (PWV), and SBP and DBP. Design: According to a randomized, double-blind, controlled, cross-over design, 20 healthy volunteers (1.5% improvement in FMD in 20 individuals: 0.99 at alpha = 0.05) were assigned to receive either five treatments with daily intake of 10 g cocoa (0, 80, 200, 500 and 800 mg cocoa flavonoids/day) in five periods lasting 1 week each. Results: Cocoa dose-dependently increased FMD from 6.2% (control) to 7.3, 7.6, 8.1 and 8.2% after the different flavonoid doses, respectively (P < 0.0001). Compared with the control, even 80 mg cocoa flavonoids per day increased FMD (P < 0.0001). Cocoa dose-dependently decreased PWV (P < 0.0001). Cocoa intake decreased office blood pressure (BP) (SBP: −4.8 ± 1.03 mmHg, P < 0.0001; DBP: −3.03 ± 1.07 mmHg, P = 0.0011). With respect to control, cocoa ingestion decreased 24-h (P = 0.05) and daytime (P = 0.038) SBP, and 24-h (P = 0.0064), daytime (P = 0.0088) and night-time (P = 0.0352) pulse pressure. Compared with the control, cocoa dose-dependently decreased ET-1 levels [from 17.1 (control) to 15.2, 14.5, 14.2 and 14.1 pg/ml, after the different flavonoid doses, respectively (P for treatment <0.05)]. Compared with the control, significant changes were observed for all doses of flavonoids (ET-1; P < 0.05). Conclusion: Our study showed for the first time that cocoa dose-dependently improved FMD and decreased PWV and ET-1 also by ameliorating office and monitored BP. Our findings are clinically relevant, suggesting cocoa, with very low calorie intake, might be reasonably incorporated into a dietary approach, representing a consistent tool in cardiovascular prevention.

Air Pollution Exposure and Blood Pressure: An Updated Review of the Literature

Both high arterial blood pressure (BP) and elevated levels of fine particulate matter (PM2.5) air pollution have been associated with an increased risk for several cardiovascular (CV) diseases, including stroke, heart failure, and myocardial infarction. Given that PM2.5 and high BP are each independently leading risk factors for premature mortality worldwide, a potential relationship between these factors would have tremendous public health repercussions. Therefore, the aim of this review is to summarize recent evidence linking air pollution and BP. Epidemiological findings demonstrate that particulate pollutants cause significant increases in BP parameters in relation to both short and long-term exposures, with robust evidence for exposures to PM2.5. Moreover, recent epidemiological studies suggest a positive association between residence within regions with higher levels of ambient PM and an increased incidence and prevalence of overt hypertension. Studies provide consistent results that elevated concentrations of pollutants increase hospital admissions and/or emergency visits for hypertensive disorders and also support that PM levels increases BP in vulnerable subsets of individuals (pregnant women, high CV risk individuals). In this context, PM-mediated BP elevations may be an important pathway which acts as a potential triggering factor for acute CV events. Mechanistic evidence illustrates plausible pathways by which acute and chronic exposures to air pollutants might disrupt hemodynamic balance favoring vasoconstriction, including autonomic imbalance and augmented release of various pro-oxidative, inflammatory and/or hemodynamically-active mediators. Together these responses may underlie PM-induced BP elevations; however, full details regarding the responsible mechanisms require further studies. As a consequence of the ubiquity of air pollution, even a small effect on raising BP and/or the prevalence of hypertension, i.e. the major risk factor for mortality and morbidity worldwide, would have enormous global public health implications.