Life Extension Magazine®

Issue: Jul 2014

Cardiovascular Health

By Life Extension.

Fernblock, a nutriceutical with photoprotective properties and potential preventive agent for skin photoaging and photoinduced skin cancers.

Many phytochemicals are endowed with photoprotective properties, i.e., the capability to prevent the harmful effects of excessive exposure to ultraviolet (UV) light. These effects include photoaging and skin cancer, and immunosuppression. Photoprotection is endowed through two major modes of action: UV absorption or reflection/scattering; and tissue repair post-exposure. We and others have uncovered the photoprotective properties of an extract of the fern Polypodium leucotomos (commercial name Fernblock). Fernblock is an all-natural antioxidant extract, administered both topically (on the skin) or orally. It inhibits generation of reactive oxygen species (ROS) production induced by UV including superoxide anion. It also prevents damage to the DNA, inhibits UV-induced AP1 and NF-kB, and protects endogenous skin natural antioxidant systems, i.e., CAT, GSH, and GSSR. Its photoprotective effects at a cellular level include a marked decrease of UV-mediated cellular apoptosis and necrosis and a profound inhibition of extracellular matrix remodeling. These molecular and cellular effects translate into long-term inhibition of photoaging and carcinogenesis that, together with its lack of toxicity, postulate its use as a novel-generation photoprotective nutriceutical of phytochemical origin.

Int J Mol Sci. 2011;12(12):8466-75

Molecular mechanisms of retinoid actions in skin.

For more than 40 years, it has been appreciated that vitamin A is a critical regulator of growth and differentiation of developing and adult mammalian and avian skin. Vitamin A deficiency and hypervitaminosis A cause disruption of normal cellular homeostatic mechanisms, resulting in impairment of skin barrier function. More recent studies demonstrating all-trans retinoic acid as the major biologically active form of vitamin A, and nuclear retinoid receptors as the major mediators of all-trans retinoic acid actions, have provided exciting new insights into the molecular basis of vitamin A actions. These recent insights have been the driving force for important advances in the many areas of retinoid research made during the past 6 years. Nowhere has this new knowledge been more extensively applied than toward understanding the molecular basis of retinoid physiology and pharmacology in skin. This article will review these recent findings and attempt to synthesize their meaning to provide a view into the mechanisms whereby retinoids participate in regulation of skin function.

FASEB J. 1996 Jul;10(9):1002-13

Molecular Mechanisms of UV-Induced Apoptosis and Its Effects on Skin Residential Cells: The Implication in UV-Based Phototherapy.

The human skin is an integral system that acts as a physical and immunological barrier to outside pathogens, toxicants, and harmful irradiations. Environmental ultraviolet rays (UV) from the sun might potentially play a more active role in regulating several important biological responses in the context of global warming. UV rays first encounter the uppermost epidermal keratinocytes causing apoptosis. The molecular mechanisms of UV-induced apoptosis of keratinocytes include direct DNA damage (intrinsic), clustering of death receptors on the cell surface (extrinsic), and generation of ROS. When apoptotic keratinocytes are processed by adjacent immature Langerhans cells (LCs), the inappropriately activated Langerhans cells could result in immunosuppression. Furthermore, UV can deplete LCs in the epidermis and impair their migratory capacity, leading to their accumulation in the dermis. Intriguingly, receptor activator of NF-kB (RANK) activation of LCs by UV can induce the pro-survival and anti-apoptotic signals due to the upregulation of Bcl-xL, leading to the generation of regulatory T cells. Meanwhile, a physiological dosage of UV can also enhance melanocyte survival and melanogenesis. Analogous to its effect in keratinocytes, a therapeutic dosage of UV can induce cell cycle arrest, activate antioxidant and DNA repair enzymes, and induce apoptosis through translocation of the Bcl-2 family proteins in melanocytes to ensure genomic integrity and survival of melanocytes. Furthermore, UV can elicit the synthesis of vitamin D, an important molecule in calcium homeostasis of various types of skin cells contributing to DNA repair and immunomodulation. Taken together, the above-mentioned effects of UV on apoptosis and its related biological effects such as proliferation inhibition, melanin synthesis, and immunomodulations on skin residential cells have provided an integrated biochemical and molecular biological basis for phototherapy that has been widely used in the treatment of many dermatological diseases.

Int J Mol Sci. 2013 Mar 20;14(3):6414-35

Skin barrier in atopic dermatitis.

The skin represents the largest organ of the body and provides a vital interface between the body and the environment. Hereditary and acquired alterations of structural proteins and lipids of the stratum corneum and epidermal tight junctions leading to a diminished skin barrier function are major causative factors for a number of skin diseases, in particular atopic dermatitis (AD). This review summarizes current knowledge on the role of the skin barrier in AD with regard to pathogenesis and treatment, on the relationship between skin barrier abnormalities and immune aberrations, and on potential therapies aimed at repair of the skin barrier. Furthermore recent advances in the genetics of AD will be addressed.

Front Biosci (Landmark Ed). 2014 Jan 1;19:542-56

Photoprotection: part I. Photoprotection by naturally occurring, physical, and systemic agents.

The acute and chronic consequences of ultraviolet radiation on human skin are reviewed. An awareness of variations in naturally occurring photoprotective agents and the use of glass, sunglasses, and fabric can lead to effective protection from the deleterious effects of ultraviolet radiation. New systemic agents, including Polypodium leucotomos, afamelanotide, and antioxidants have potential as photoprotective agents.

J Am Acad Dermatol. 2013 Dec;69(6):853.
e1-12; quiz 865-6

UV-induced free radicals in the skin detected by ESR spectroscopy and imaging using nitroxides.

Reactive free radicals and reactive oxygen species (ROS) induced by ultraviolet irradiation in human skin are strongly involved in the occurrence of skin damages like aging and cancer. In the present work an ex vivo method for the detection of free radicals/ROS in human skin biopsies during UV irradiation is presented. This method is based on the Electron Spin Resonance (ESR) spectroscopy and imaging and uses the radical trapping properties of nitroxides. The nitroxides 2,2,6,6-Tetramethylpiperidine-1-oxyl (TEMPO), 3-Carba moyl-2,2,5,5-tetramethyl pyrrolidine-1-oxyl (PCM), and 3-Carboxy-2,2,5,5-tetramethylpyrrolidine-1-oxyl (PCA), were investigated for their applicability of trapping reactive free radicals and reactive oxygen species in skin during UV irradiation. As a result of the trapping process the nitroxides were reduced to the EPR silent hydroxylamins. The reduction rate of TEMPO was due to both the UV radiation and the enzymatic activity of the skin. The nitroxides PCM and PCA are sufficiently stable in the skin and are solely reduced by UV-generated free radicals/ROS. The nitroxide PCA was used for imaging the spatial distribution of UV-generated free radicals/ROS. As a result of the homogeneous distribution of PCA in the skin, it was possible to estimate the penetration of UVA and UVB irradiation: The UV irradiation decreased the PCA intensity corresponding to its irradiance and penetration into the skin. This reduction was shown to be caused mainly by UVA radiation (320-400 nm).

Free Radic Biol Med. 2003 Jul 1;35(1):59-67

Photoprotection of human skin beyond ultraviolet radiation.

Photoprotection of human skin by means of sunscreens or daily skin-care products is traditionally centered around the prevention of acute (e.g. sunburn) and chronic (e.g. skin cancer and photoaging) skin damage that may result from exposure to ultraviolet rays (UVB and UVA). Within the last decade, however, it has been appreciated that wavelengths beyond the ultraviolet spectrum, in particular visible light and infrared radiation, contribute to skin damage in general and photoaging of human skin in particular. As a consequence, attempts have been made to develop skin care/sunscreen products that not only protect against UVB or UVA radiation but provide photoprotection against visible light and infrared radiation as well. In this article, we will briefly review the current knowledge about the mechanisms responsible for visible light/infrared radiation-induced skin damage and then, based on this information, discuss strategies that have been successfully used or may be employed in the future to achieve photoprotection of human skin beyond ultraviolet radiation. In this regard we will particularly focus on the use of topical antioxidants and the challenges that result from the task of showing their efficacy.

Photodermatol Photoimmunol Photomed. 2014 Apr-Jun;30(2-3):167-74

Radical protection by sunscreens in the infrared spectral range.

One essential reason for skin ageing is the formation of free radicals by excessive or unprotected sun exposure. Recently, free radical generation in skin has been shown to appear not only after irradiation in the UV wavelength range but also in the infrared (IR) spectral range. Sunscreens are known to protect against radicals generated by UV radiation; however, no data exist for those generated by IR radiation. This paper has investigated four different, commercially available sunscreens and one COLIPA standard with regard to radical formation in the skin after IR irradiation, using electron paramagnetic resonance spectroscopy. The use of sunscreens has led to reduced amounts of radicals compared to untreated skin. Furthermore, absorption and scattering properties and the radical protection factor of the formulations were determined to investigate their influence on the radical protection of the skin. None of these formulations contained an optical absorber in the IR range. The protection efficiency of the sunscreens was shown as being induced by the high scattering properties of the sunscreens, as well as the antioxidants contained in the formulations.

Photochem Photobiol. 2011 Mar-Apr;87(2): 452-6

Creatine supplementation in Parkinson disease: a placebo-controlled randomized pilot trial.

Mitochondrial dysfunction plays a major role in the pathogenesis of Parkinson disease (PD). Creatine (Cr) is an ergogenic compound that exerts neuroprotective effects in animal models of PD. We conducted a 2-year placebo-controlled randomized clinical trial on the effect of Cr in 60 patients with PD. Cr improved patient mood and led to a smaller dose increase of dopaminergic therapy but had no effect on overall Unified Parkinson’s Disease Rating Scale scores or dopamine transporter SPECT.

Neurology. 2006 Oct 10;67(7):1262-4

Oral creatine supplementation attenuates L-DOPA-induced dyskinesia in 6-hydroxydopamine-lesioned rats.

L-DOPA-induced dyskinesia (LID) is among the motor complications that arise in Parkinson patients after a prolonged treatment with levodopa (L-DOPA). Since previous transcriptome and proteomic studies performed in the rat model of LID suggested important changes in striatal energy-related components, we hypothesize that oral creatine supplementation could prevent or attenuate the occurrence of LID. In this study, 6-hydroxydopamine-lesioned rats received a 2% creatine-supplemented diet for 1 month prior to L-DOPA therapy. During the 21 days of L-DOPA treatment, significant reductions in abnormal involuntary movements (AIMs) have been observed in the creatine-supplemented group, without any worsening of parkinsonism. In situ hybridization histochemistry and immunohistochemistry analysis of the striatum also showed a reduction in the levels of prodynorphin mRNA and FosB/DeltaFosB-immunopositive cells in creatine-supplemented diet group, an effect that was dependant on the development of AIMs. Further investigation of the bioenergetics’ status of the denervated striatum revealed significant changes in the levels of creatine both after L-DOPA alone and with the supplemented diet. In conclusion, we demonstrated that combining L-DOPA therapy with a diet enriched in creatine could attenuate LID, which may represent a new way to control the motor complications associated with L-DOPA therapy.

Behav Brain Res. 2009 Jan 30;197(1):90-6

The role of creatine in the management of amyotrophic lateral sclerosis and other neurodegenerative disorders.

Creatine is consumed in the diet and endogenously synthesised in the body. Over the past decade, the ergogenic benefits of synthetic creatine monohydrate have made it a popular dietary supplement, particularly among athletes. The anabolic properties of creatine also offer hope for the treatment of diseases characterised by weakness and muscle atrophy. Moreover, because of its cellular mechanisms of action, creatine offers potential benefits for diseases involving mitochondrial dysfunction. Recent data also support the hypothesis that creatine may have a neuroprotective effect. Amyotrophic lateral sclerosis (ALS) is characterised by progressive degeneration of motor neurons, resulting in weakening and atrophy of skeletal muscles. In patients with this condition, creatine offers potential benefits in terms of facilitating residual muscle contractility as well as improving neuronal function. It may also help stabilise mitochondrial dysfunction, which plays a key role in the pathogenesis of ALS. Indeed, the likely multifactorial aetiology of ALS means the combined pharmacodynamic properties of creatine offer promise for the treatment of this condition. Evidence from available animal models of ALS supports the utility of treatment with creatine in this setting. Limited data available in other neuromuscular and neurodegenerative diseases further support the potential benefit of creatine monohydrate in ALS. However, few randomised, controlled trials have been conducted. To date, two clinical trials of creatine monohydrate in ALS have been completed without demonstration of significant improvements in overall survival or a composite measure of muscle strength. These trials have also posed unanswered questions about the optimal dosage of creatine and its beneficial effects on muscle fatigue, a measure distinct from muscle strength. A large, multicentre, clinical trial is currently underway to further investigate the efficacy of creatine monohydrate in ALS and address these unresolved issues. Evidence to date shows that creatine supplementation has a good safety profile and is well tolerated by ALS patients. The purpose of this article is to provide a short, balanced review of the literature concerning creatine monohydrate in the treatment of ALS and related neurodegenerative diseases. The pharmacokinetics and rationale for the use of creatine are described along with available evidence from animal models and clinical trials for ALS and related neurodegenerative or neuromuscular diseases.

CNS Drugs. 2004;18(14):967-80

Effects of creatine supplementation on exercise performance and muscular strength in amyotrophic lateral sclerosis: preliminary results.

Creatine supplementation in humans has been reported to enhance power and strength both in normal subjects and in patients with various neuromuscular diseases. The purpose of this study was to examine the effects of supplementation on exercise performance and maximal voluntary isometric muscular contraction (MVIC) in Amyotrophic Lateral Sclerosis (ALS) patients. We report the results obtained in 28 patients with probable/definite ALS. In each patient we acquired the dynamometric measurement of MVIC in 10 muscle groups of upper and lower limbs and a measure of fatigue by means of an high-intensity intermittent protocol in elbow flexors and knee extensors muscles. All patients completed the protocols at the baseline and after supplementation of 20 g per day for 7 days and after supplementation of 3 g per day for 3 and 6 months. MVIC increased after 7 days of supplementation in 20 patients (70%) in knee extensors and in 15 (53%) of them also in elbow flexors. A statistically significant difference between pre and post-treatment mean values of MVIC was found both in elbow flexors (P<0.05) and knee extensors (p<0.04). The analysis of the slopes of fatigue test showed a statistically significant improvement after 7 days of supplementation in 11 patients (39%) in elbow flexors and in 9 patients (32%) also in knee extensors muscles. During the 6-month follow-up period all the examined parameters showed a linear progressive decline. In conclusion, our preliminary results have demonstrated that supplementation temporary increases maximal isometric power in ALS patients so it may be of potential benefit in situations such as high intensity activity and it can be proposed as a symptomatic treatment.

J Neurol Sci. 2001 Oct 15;191(1-2):139-44

Creatine supplementation and cognitive performance in elderly individuals.

The purpose of this study was to examine the effect of creatine supplementation on the cognitive performance of elderly people. Participants were divided into two groups, which were tested on random number generation, forward and backward number and spatial recall, and long-term memory tasks to establish a baseline level. Group 1 (n = 15) were given 5 g four times a day of placebo for 1 week, followed by the same dosage of creatine for the second week. Group 2 (n = 17) were given placebo both weeks. Participants were retested at the end of each week. Results showed a significant effect of creatine supplementation on all tasks except backward number recall. It was concluded that creatine supplementation aids cognition in the elderly.

Neuropsychol Dev Cogn B Aging Neuropsychol Cogn. 2007 Sep;14(5):517-28

The influence of creatine supplementation on the cognitive functioning of vegetarians and omnivores.

Creatine when combined with P forms phosphocreatine that acts as a reserve of high-energy phosphate. Creatine is found mostly in meat, fish and other animal products, and the levels of muscle creatine are known to be lower in vegetarians. Creatine supplementation influences brain functioning as indicated by imaging studies and the measurement of oxygenated Hb. Given the key role played by creatine in the provision of energy, the influence of its supplementation on cognitive functioning was examined, contrasting the effect in omnivores and vegetarians. Young adult females (n 128) were separated into those who were and were not vegetarian. Randomly and under a double-blind procedure, subjects consumed either a placebo or 20 g of creatine supplement for 5 d. Creatine supplementation did not influence measures of verbal fluency and vigilance. However, in vegetarians rather than in those who consume meat, creatine supplementation resulted in better memory. Irrespective of dietary style, the supplementation of creatine decreased the variability in the responses to a choice reaction-time task.

Br J Nutr. 2011 Apr;105(7):1100-5

Oral creatine monohydrate supplementation improves brain performance: a double-blind, placebo-controlled, cross-over trial.

Creatine supplementation is in widespread use to enhance sports-fitness performance, and has been trialled successfully in the treatment of neurological, neuromuscular and atherosclerotic disease. Creatine plays a pivotal role in brain energy homeostasis, being a temporal and spatial buffer for cytosolic and mitochondrial pools of the cellular energy currency, adenosine triphosphate and its regulator, adenosine diphosphate. In this work, we tested the hypothesis that oral creatine supplementation (5 g d(-1) for six weeks) would enhance intelligence test scores and working memory performance in 45 young adult, vegetarian subjects in a double-blind, placebo-controlled, cross-over design. Creatine supplementation had a significant positive effect (p < 0.0001) on both working memory (backward digit span) and intelligence (Raven’s Advanced Progressive Matrices), both tasks that require speed of processing. These findings underline a dynamic and significant role of brain energy capacity in influencing brain performance.

Proc Biol Sci. 2003 Oct 22;270(1529):2147-50

Creatine supplementation and cognitive performance in elderly individuals.

The purpose of this study was to examine the effect of creatine supplementation on the cognitive performance of elderly people. Participants were divided into two groups, which were tested on random number generation, forward and backward number and spatial recall, and long-term memory tasks to establish a baseline level. Group 1 (n = 15) were given 5 g four times a day of placebo for 1 week, followed by the same dosage of creatine for the second week. Group 2 (n = 17) were given placebo both weeks. Participants were retested at the end of each week. Results showed a significant effect of creatine supplementation on all tasks except backward number recall. It was concluded that creatine supplementation aids cognition in the elderly.

Neuropsychol Dev Cogn B Aging Neuropsychol Cogn. 2007 Sep;14(5):517-28

The effects of creatine loading and gender on anaerobic running capacity.

Creatine (Cr) loading consists of short-term, high-dosage Cr supplementation and has been shown to increase intramuscular total Cr content. Increases in body weight (BW) have been shown to result from Cr loading, with differences by gender, and increased BW may impact weight-bearing exercise. The critical velocity (CV) test is used to quantify the relationship between total running distance and time to exhaustion. The CV test provides the variable, anaerobic running capacity (ARC), which is an estimate of the anaerobic energy reserves in muscle. The purpose of this study was to examine the effects of gender and Cr loading on ARC. Fifty moderately trained men and women volunteered to participate in this randomized, double-blinded, placebo (PL)-controlled, repeated-measures study. After a familiarization session, a 3-day testing procedure was conducted. A maximal oxygen consumption test VO(2)max) on a treadmill was performed on day 1 to establish the maximum velocity (Vmax) at VO(2)max and to record BW. Days 2 and 3 involved treadmill running at varying percentages of Vmax. Participants were randomly assigned to either the Cr or PL group and received 20 packets of the Cr supplement (1 packet = 5 g Cr citrate, 18 g dextrose) or 20 packets of the PL (1 packet = 18 g dextrose). After consuming 4 packets daily for 5 consecutive days, the 3-day testing procedure was repeated. The male Cr loading group exhibited a 23% higher (p = 0.003) ARC compared to the PL group. Nonsignificant BW increases were found for the Cr groups. These findings suggest that Cr loading may be an effective strategy for improving ARC in men, but not in women, and revealed only nonsignificant increases in BW. Creatine loading may be used before competition by athletes to provide improvements in high-intensity, short-duration activities.

J Strength Cond Res. 2010 Jul;24(7):1826-33

Creatine supplementation in chronic heart failure increases skeletal muscle creatine phosphate and muscle performance.

BACKGROUND: Cardiac creatine levels are depressed in chronic heart failure. Oral supplementation of creatine to healthy volunteers has been shown to increase physical performance. AIM: To evaluate the effects of creatine supplementation on ejection fraction, symptom-limited physical endurance and skeletal muscle strength in patients with chronic heart failure. METHODS: With a double-blind, placebo-controlled design 17 patients (age 43-70 years, ejection fraction < 40) were supplemented with creatine 20 g daily for 10 days. Before and on the last day of supplementation ejection fraction was determined by radionuclide angiography as was symptom-limited 1-legged knee extensor and 2-legged exercise performance on the cycle ergometer. Muscle strength as unilateral concentric knee extensor performance (peak torque, Nm at 180 degrees/s) was also evaluated. Skeletal muscle biopsies were taken for the determination of energy-rich phosphagens. RESULTS: Ejection fraction at rest and at work did not change. Performance before creatine supplementation did not differ between placebo and creatine groups. While no change was seen in the placebo group compared to baseline, creatine supplementation increased skeletal muscle total creatine and creatine phosphate by 17 +/- 4% (P < 0.05) and 12 +/- 4% (P < 0.05), respectively. Increments were seen only in patients with < 140 mmol total creatine/kg d.w. (P < 0.05). One-legged performance (21%, P < 0.05), 2-legged performance (10%, P < 0.05), and peak torque, Nm (5%, P < 0.05) increased. Both peak torque and 1-legged performance increased linearly with increased skeletal muscle phosphocreatine (P < 0.05). The increments in 1-legged, 2-legged and peak torque were significant compared to the placebo group, (P < 0.05). CONCLUSIONS: One week of creatine supplementation to patients with chronic heart failure did not increase ejection fraction but increased skeletal muscle energy-rich phosphagens and performance as regards both strength and endurance. This new therapeutic approach merits further attention.

Cardiovasc Res. 1995 Sep;30(3):413-8

Acute effects of coffee on endothelial function in healthy subjects.

BACKGROUND/OBJECTIVES: Coffee is the most widely consumed beverage in the world, but its effect on the cardiovascular system has not been fully understood. Coffee contains caffeine and antioxidants, which may influence endothelial function, both of which have not yet been investigated. The objective of this study was to investigate the acute effects of coffee on endothelial function measured by brachial artery flow-mediated dilation (FMD). SUBJECTS/METHODS: A total of 20 (10 males and 10 females) healthy non-obese subjects underwent a double-blind, crossover study. Subjects ingested one cup of caffeinated (CC) and one cup of decaffeinated (DC) Italian espresso coffee in random order at 5- to 7-day intervals. RESULTS: Following CC ingestion, FMD decreased progressively and significantly (mean+/-s.e.m.: 0 min, 7.7+/-0.6; 30 min, 6.3+/-0.7; 60 min, 6.0+/-0.8%; ANOVA (analysis of variance), P<0.05), but it did not significantly increase after DC ingestion (0 min, 6.9+/-0.6; 30 min, 8.1+/-0.9; 60 min, 8.5+/-0.9%; P=0.115). Similarly, CC significantly increased both systolic and diastolic blood pressure; this effect was not observed after DC ingestion. Blood glucose concentrations remained unchanged after ingestion of both CC and DC, but insulin (0 min, 15.8+/-0.9; 60 min, 15.0+/-0.8 muU/ml; P<0.05) and C-peptide (0 min, 1.25+/-0.09; 60 min, 1.18+/-0.09 ng/ml; P<0.01) blood concentrations decreased significantly only after CC ingestion. CONCLUSIONS: CC acutely induced unfavorable cardiovascular effects, especially on endothelial function. In the fasting state, insulin secretion is also likely reduced after CC ingestion. Future studies will determine whether CC has detrimental clinically relevant effects, especially in unhealthy subjects.

Eur J Clin Nutr. 2010 May;64(5):483-9

Effects of habitual coffee consumption on cardiometabolic disease, cardiovascular health, and all-cause mortality.

Coffee, after water, is the most widely consumed beverage in the United States, and is the principal source of caffeine intake among adults. The biological effects of coffee may be substantial and are not limited to the actions of caffeine. Coffee is a complex beverage containing hundreds of biologically active compounds, and the health effects of chronic coffee intake are wide ranging. From a cardiovascular (CV) standpoint, coffee consumption may reduce the risk of type 2 diabetes mellitus and hypertension, as well as other conditions associated with CV risk such as obesity and depression; but it may adversely affect lipid profiles depending on how the beverage is prepared. Regardless, a growing body of data suggests that habitual coffee consumption is neutral to beneficial regarding the risks of a variety of adverse CV outcomes including coronary heart disease, congestive heart failure, arrhythmias, and stroke. Moreover, large epidemiological studies suggest that regular coffee drinkers have reduced risks of mortality, both CV and all-cause. The potential benefits also include protection against neurodegenerative diseases, improved asthma control, and lower risk of select gastrointestinal diseases. A daily intake of ∼2 to 3 cups of coffee appears to be safe and is associated with neutral to beneficial effects for most of the studied health outcomes. However, most of the data on coffee’s health effects are based on observational data, with very few randomized, controlled studies, and association does not prove causation. Additionally, the possible advantages of regular coffee consumption have to be weighed against potential risks (which are mostly related to its high caffeine content) including anxiety, insomnia, tremulousness, and palpitations, as well as bone loss and possibly increased risk of fractures.

J Am Coll Cardiol. 2013 Sep 17;62(12):1043-51

Coffee consumption but not green tea consumption is associated with adiponectin levels in Japanese males.

PURPOSE: Coffee is among the most widely consumed beverages in the world. Numerous epidemiological studies have reported a significant inverse association between coffee consumption and risk of type 2 diabetes mellitus, but the underlying mechanisms are still not fully understood. Therefore, we conducted an epidemiological study to clarify the relationship between coffee consumption and adiponectin levels in Japanese males. We also evaluated whether green tea consumption affected adiponectin levels. METHODS: We carried out a cross-sectional study. The subjects were 665 male employees in Japan. Coffee consumption was assessed, using a self-administered questionnaire, as the number of times per week and cups per day respondents drank, and subjects were grouped into four levels (non, 1-5 times/week, 1-2 cups/day and ≥3 cups/day). RESULTS: The means of adiponectin levels were positively associated with coffee consumption. A dose-response relationship was found between coffee consumption and circulating adiponectin levels. The relationship remained significant after adjustment for potential confounding factors (P for trend <0.05). However, green tea consumption was not significantly associated with adiponectin levels (P for trend = 0.90). CONCLUSIONS: We not only revealed that habitual coffee consumption is associated with higher adiponectin levels in Japanese males but also found a dose-dependent association between coffee consumption and adiponectin levels. Therefore, our study suggested that coffee components might play an important role in the elevation of adiponectin level.

Eur J Nutr. 2011 Jun;50(4):279-84

Association of coffee drinking with total and cause-specific mortality.

BACKGROUND: Coffee is one of the most widely consumed beverages, but the association between coffee consumption and the risk of death remains unclear. METHODS: We examined the association of coffee drinking with subsequent total and cause-specific mortality among 229,119 men and 173,141 women in the National Institutes of Health-AARP Diet and Health Study who were 50 to 71 years of age at baseline. Participants with cancer, heart disease, and stroke were excluded. Coffee consumption was assessed once at baseline. RESULTS: During 5,148,760 person-years of follow-up between 1995 and 2008, a total of 33,731 men and 18,784 women died. In age-adjusted models, the risk of death was increased among coffee drinkers. However, coffee drinkers were also more likely to smoke, and, after adjustment for tobacco-smoking status and other potential confounders, there was a significant inverse association between coffee consumption and mortality. Adjusted hazard ratios for death among men who drank coffee as compared with those who did not were as follows: 0.99 (95% confidence interval [CI], 0.95 to 1.04) for drinking less than 1 cup per day, 0.94 (95% CI, 0.90 to 0.99) for 1 cup, 0.90 (95% CI, 0.86 to 0.93) for 2 or 3 cups, 0.88 (95% CI, 0.84 to 0.93) for 4 or 5 cups, and 0.90 (95% CI, 0.85 to 0.96) for 6 or more cups of coffee per day (P<0.001 for trend); the respective hazard ratios among women were 1.01 (95% CI, 0.96 to 1.07), 0.95 (95% CI, 0.90 to 1.01), 0.87 (95% CI, 0.83 to 0.92), 0.84 (95% CI, 0.79 to 0.90), and 0.85 (95% CI, 0.78 to 0.93) (P<0.001 for trend). Inverse associations were observed for deaths due to heart disease, respiratory disease, stroke, injuries and accidents, diabetes, and infections, but not for deaths due to cancer. Results were similar in subgroups, including persons who had never smoked and persons who reported very good to excellent health at baseline. CONCLUSIONS: In this large prospective study, coffee consumption was inversely associated with total and cause-specific mortality. Whether this was a causal or associational finding cannot be determined from our data.

N Engl J Med. 2012 May 17;366(20):1891-904

Impact of acute caffeine ingestion on endothelial function in subjects with and without coronary artery disease.

Although coffee is a widely used, pharmacologically active beverage, its impact on the cardiovascular system is controversial. To explore the effect of acute caffeine ingestion on brachial artery flow-mediated dilation (FMD) in subjects without coronary artery disease (CAD; controls) and patients with CAD, we prospectively assessed brachial artery FMD in 40 controls and 40 age- and gender-matched patients with documented stable CAD on 2 separate mornings 1 week to 2 weeks apart. After overnight fasting, discontinuation of all medications for ≥12 hours, and absence of caffeine for >48 hours, participants received capsules with caffeine 200 mg or placebo. One hour after drug ingestion, participants underwent brachial artery FMD and nitroglycerin-mediated dilation (NTG) using high-resolution ultrasound. As expected, patients with CAD were more often diabetic, hypertensive, obese, dyslipidemic, and smoked more than controls (p <0.01 for all comparisons). Aspirin, Clopidogrel, angiotensin-converting enzyme inhibitors, blockers, and statins were significantly more common in patients with CAD than in controls (p <0.01 for all comparisons). At baseline, FMD, but not NTG, was significantly lower in patients with CAD compared to controls. Acute caffeine ingestion significantly increased FMD (patients with CAD 5.6 ± 5.0% vs 14.6 ± 5.0%, controls 8.4 ± 2.9% vs 18.6 ± 6.8%, p <0.001 for all comparisons) but not NTG (patients with CAD 13.0 ± 5.2% vs 13.8 ± 6.1%, controls 12.9 ± 3.9% vs 13.9 ± 5.8%, p = NS for all comparisons) and significantly decreased high-sensitivity C-reactive protein (patients with CAD 2.6 ± 1.4 vs 1.4 ± 1.2 mg/L, controls 3.4 ± 3.0 vs 1.2 ± 1.0 mg/L, p <0.001 for all comparisons) in the 2 groups compared to placebo. In conclusion, acute caffeine ingestion significantly improved endothelial function assessed by brachial artery FMD in subjects with and without CAD and was associated with lower plasma markers of inflammation.

Am J Cardiol. 2011 May 1;107(9):1255-61

Effects of habitual coffee consumption on cardiometabolic disease, cardiovascular health, and all-cause mortality.

Coffee, after water, is the most widely consumed beverage in the United States, and is the principal source of caffeine intake among adults. The biological effects of coffee may be substantial and are not limited to the actions of caffeine. Coffee is a complex beverage containing hundreds of biologically active compounds, and the health effects of chronic coffee intake are wide ranging. From a cardiovascular (CV) standpoint, coffee consumption may reduce the risk of type 2 diabetes mellitus and hypertension, as well as other conditions associated with CV risk such as obesity and depression; but it may adversely affect lipid profiles depending on how the beverage is prepared. Regardless, a growing body of data suggests that habitual coffee consumption is neutral to beneficial regarding the risks of a variety of adverse CV outcomes including coronary heart disease, congestive heart failure, arrhythmias, and stroke. Moreover, large epidemiological studies suggest that regular coffee drinkers have reduced risks of mortality, both CV and all-cause. The potential benefits also include protection against neurodegenerative diseases, improved asthma control, and lower risk of select gastrointestinal diseases. A daily intake of ∼2 to 3 cups of coffee appears to be safe and is associated with neutral to beneficial effects for most of the studied health outcomes. However, most of the data on coffee’s health effects are based on observational data, with very few randomized, controlled studies, and association does not prove causation. Additionally, the possible advantages of regular coffee consumption have to be weighed against potential risks (which are mostly related to its high caffeine content) including anxiety, insomnia, tremulousness, and palpitations, as well as bone loss and possibly increased risk of fractures.

J Am Coll Cardiol. 2013 Sep 17;62(12):1043-51

Cafestol and kahweol, two coffee specific diterpenes with anticarcinogenic activity.

Epidemiological studies have found an inverse association between coffee consumption and the risk of certain types of cancers such as colorectal cancers. Animal data support such a chemopreventive effect of coffee. Substantial research has been devoted to the identification of coffee components that may be responsible for these beneficial effects. In animal models and cell culture systems, the coffee diterpenes cafestol and kahweol (C+K) were shown to produce a broad range of biochemical effects resulting in a reduction of the genotoxicity of several carcinogens including 7,12-dimethylbenz[a]anthracene (DMBA), aflatoxin B(1) (AFB(1)), benzo[a]pyrene (B[a]P) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). Different mechanisms appear to be involved in these chemoprotective effects: an induction of conjugating enzymes (e.g. glutathione S-transferases, glucuronosyl S-transferases), an increased expression of proteins involved in cellular antioxidant defense (e.g. gamma-glutamyl cysteine synthetase and heme oxygenase-1) and an inhibition of the expression and/or activity of cytochromes P450 involved in carcinogen activation (e.g. CYP2C11, CYP3A2). In animal models, the C+K-mediated induction of conjugating and antioxidant enzymes has been observed in hepatic, intestinal and kidney tissues. In the small intestine, these inductions were shown to be mediated by Nrf2-dependent transcriptional activation. In vitro investigations obtained in cell cultures of human origin indicate that the effects and mechanisms observed in animal test systems with C+K are likely to be of relevance for humans. In human liver epithelial cell lines transfected to express AFB(1)-activating P450s, C+K treatment resulted in a reduction of AFB(1)-DNA binding. This protection was correlated with an induction of GST-mu, an enzyme known to be involved in AFB(1) detoxification. In addition, C+K was found to inhibit P450 2B6, one of the human enzymes responsible for AFB(1) activation. Altogether, the data on the biological effects of C+K provide a plausible hypothesis to explain some of the anticarcinogenic effects of coffee observed in human epidemiological studies and in animal experiments.

Food Chem Toxicol. 2002 Aug;40(8):1155-63

Coffee polyphenols modulate whole-body substrate oxidation and suppress postprandial hyperglycaemia, hyperinsulinaemia and hyperlipidaemia.

Postprandial energy metabolism, including postprandial hyperglycaemia, hyperinsulinaemia and hyperlipidaemia, is related to the risk for developing obesity and CVD. In the present study, we examined the effects of polyphenols purified from coffee (coffee polyphenols (CPP)) on postprandial carbohydrate and lipid metabolism, and whole-body substrate oxidation in C57BL/6J mice. In mice that co-ingested CPP with a lipid-carbohydrate (sucrose or starch)-mixed emulsion, the respiratory quotient determined by indirect calorimetry was significantly lower than that in control mice, whereas there was no difference in VO2 (energy expenditure), indicating that CPP modulates postprandial energy partitioning. CPP also suppressed postprandial increases in plasma glucose, insulin, glucose-dependent insulinotropic polypeptide and TAG levels. Inhibition experiments on digestive enzymes revealed that CPP inhibits maltase and sucrase, and, to a lesser extent, pancreatic lipase in a concentration-dependent manner. Among the nine kinds of polyphenols (caffeoyl quinic acids (CQA), di-CQA, feruloyl quinic acids (FQA)) contained in CPP, di-CQA showed more potent inhibitory activity than CQA or FQA on these digestive enzymes, suggesting a predominant role of di-CQA in the regulation of postprandial energy metabolism. These results suggest that CPP modulates whole-body substrate oxidation by suppressing postprandial hyperglycaemia and hyperinsulinaemia, and these effects are mediated by inhibiting digestive enzymes.

Br J Nutr. 2012 Jun;107(12):1757-65

Coffee and endothelial function: a battle between caffeine and antioxidants?

Although coffee is largely consumed by adults in Western countries, controversy exists about its impact on the cardiovascular system. We recently demonstrated that caffeinated and decaffeinated espresso coffee have different acute effects on endothelial function in healthy subjects, measured using flow-mediated dilation (FMD) of the brachial artery. In this study, we measured the anti-oxidant capacity of two coffee substances in terms of free stable radical 2,2-diphenyl-1-picryl-hydrazyl 50% inhibition (I(50) DPPH). The caffeinated coffee had a slightly higher anti-oxidant capacity than decaffeinated espresso coffee (I(50) DPPH: 1.13±0.02 vs 1.30±0.03 µl; P<0.001). We suggest that the unfavourable effects observed after caffeinated coffee ingestion are due to caffeine and that the antioxidant activity is responsible for the increased FMD observed after decaffeinated coffee ingestion. Further clinical and epidemiological studies are needed to understand the chronic effects of coffee consumption on health.

Eur J Clin Nutr. 2010 Oct;64(10):1242-3

Consumption of a boiled Greek type of coffee is associated with improved endothelial function: the Ikaria study.

OBJECTIVE: The association of coffee consumption with cardiovascular disease remains controversial. Endothelial function is associated with cardiovascular risk. We examined the association between chronic coffee consumption and endothelium function in elderly inhabitants of the island of Ikaria. METHODS: The analysis was conducted on 142 elderly subjects (aged 66-91 years) of the Ikaria Study. Endothelial function was evaluated by ultrasound measurement of flow-mediated dilation (FMD). Coffee consumption was evaluated based on a food frequency questionnaire and was categorized as ‘low’ (< 200 ml/day), ‘moderate’ (200-450 ml/day), or ‘high’ (> 450 ml/day). RESULTS: From the subjects included in the study, 87% consumed a boiled Greek type of coffee. Moreover, 40% had a ‘low’, 48% a ‘moderate’ and 13% a ‘high’ daily coffee consumption. There was a linear increase in FMD according to coffee consumption (‘low’: 4.33 ± 2.51% vs ‘moderate’: 5.39 ± 3.09% vs ‘high’: 6.47 ± 2.72%; p = 0.032). Moreover, subjects consuming mainly a boiled Greek type of coffee had a significantly higher FMD compared with those consuming other types of coffee beverages (p = 0.035). CONCLUSIONS: Chronic coffee consumption is associated with improved endothelial function in elderly subjects, providing a new connection between nutrition and vascular health.

Vasc Med. 2013 Apr;18(2):55-62

The clinical significance of subclinical thyroid dysfunction.

Subclinical thyroid disease (SCTD) is defined as serum free T(4) and free T(3) levels within their respective reference ranges in the presence of abnormal serum TSH levels. SCTD is being diagnosed more frequently in clinical practice in young and middle-aged people as well as in the elderly. However, the clinical significance of subclinical thyroid dysfunction is much debated. Subclinical hyper- and hypothyroidism can have repercussions on the cardiovascular system and bone, as well as on other organs and systems. However, the treatment and management of SCTD and population screening are controversial despite the potential risk of progression to overt disease, and there is no consensus on the thyroid hormone and thyrotropin cutoff values at which treatment should be contemplated. Opinions differ regarding tissue effects, symptoms, signs, and cardiovascular risk. Here, we critically review the data on the prevalence and progression of SCTD, its tissue effects, and its prognostic implications. We also examine the mechanisms underlying tissue alterations in SCTD and the effects of replacement therapy on progression and tissue parameters. Lastly, we address the issue of the need to treat slight thyroid hormone deficiency or excess in relation to the patient’s age.

Endocr Rev. 2008 Feb;29(1):76-131

Plasma phospholipid trans fatty acids, fatal ischemic heart disease, and sudden cardiac death in older adults: the cardiovascular health study.

BACKGROUND: Intake of trans fatty acids is associated with increased risk of coronary heart disease. Whether different classes of trans fatty acids show similar associations is unclear. We previously reported an association of sudden cardiac death with red cell membrane trans-18:2 but not trans-18:1 fatty acids. To extend these findings, we investigated the associations of plasma phospholipid trans fatty acids with fatal ischemic heart disease (IHD) and sudden cardiac death. METHODS AND RESULTS: We conducted a case-control study nested in the Cardiovascular Health Study. We identified 214 cases of fatal IHD (fatal myocardial infarction and coronary heart disease death) between 1992 and 1998. We randomly selected 214 controls, matched to cases on demographics, prevalent cardiovascular disease, and timing of blood draw. Plasma phospholipid fatty acids were assessed in blood samples collected earlier. Higher levels of plasma phospholipid trans-18:2 fatty acids were associated with higher risk of fatal IHD (odds ratio [OR] for interquintile range 1.68, 95% confidence interval [CI] 1.21 to 2.33) after adjustment for risk factors and trans-18:1 levels. Trans-18:1 levels above the 20th percentile were associated with lower risk (OR 0.34, 95% CI 0.18 to 0.63). In analyses limited to cases of sudden cardiac death (n=95), higher levels of trans-18:2 fatty acids were associated with higher risk (OR 2.34, 95% CI 1.27 to 4.31) and higher trans-18:1 with lower risk (OR 0.18, 95% CI 0.06 to 0.54). CONCLUSIONS: Higher levels of trans-18:2 and lower levels of trans-18:1 fatty acids are associated with higher risks of fatal IHD and sudden cardiac death. If confirmed, these findings suggest that current efforts at decreasing trans fatty acid intake in foods should take into consideration the trans-18:2 content.

Circulation. 2006 Jul 18;114(3):209-15

Fish intake, contaminants, and human health: evaluating the risks and the benefits.

CONTEXT: Fish (finfish or shellfish) may have health benefits and also contain contaminants, resulting in confusion over the role of fish consumption in a healthy diet. EVIDENCE ACQUISITION: We searched MEDLINE, governmental reports, and meta-analyses, supplemented by hand reviews of references and direct investigator contacts, to identify reports published through April 2006 evaluating (1) intake of fish or fish oil and cardiovascular risk, (2) effects of methylmercury and fish oil on early neurodevelopment, (3) risks of methylmercury for cardiovascular and neurologic outcomes in adults, and (4) health risks of dioxins and polychlorinated biphenyls in fish. We concentrated on studies evaluating risk in humans, focusing on evidence, when available, from randomized trials and large prospective studies. When possible, meta-analyses were performed to characterize benefits and risks most precisely. EVIDENCE SYNTHESIS: Modest consumption of fish (eg, 1-2 servings/wk), especially species higher in the n-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), reduces risk of coronary death by 36% (95% confidence interval, 20%-50%; P<.001) and total mortality by 17% (95% confidence interval, 0%-32%; P = .046) and may favorably affect other clinical outcomes. Intake of 250 mg/d of EPA and DHA appears sufficient for primary prevention. DHA appears beneficial for, and low-level methylmercury may adversely affect, early neurodevelopment. Women of childbearing age and nursing mothers should consume 2 seafood servings/wk, limiting intake of selected species. Health effects of low-level methylmercury in adults are not clearly established; methylmercury may modestly decrease the cardiovascular benefits of fish intake. A variety of seafood should be consumed; individuals with very high consumption (> or =5 servings/wk) should limit intake of species highest in mercury levels. Levels of dioxins and polychlorinated biphenyls in fish are low, and potential carcinogenic and other effects are outweighed by potential benefits of fish intake and should have little impact on choices or consumption of seafood (women of childbearing age should consult regional advisories for locally caught freshwater fish). CONCLUSIONS: For major health outcomes among adults, based on both the strength of the evidence and the potential magnitudes of effect, the benefits of fish intake exceed the potential risks. For women of childbearing age, benefits of modest fish intake, excepting a few selected species, also outweigh risks.

JAMA. 2006 Oct 18;296(15):1885-99

Omega-3 fatty acids and cardiovascular disease: effects on risk factors, molecular

We reviewed available evidence for cardiovascular effects of n-3 polyunsaturated fatty acid (PUFA) consumption, focusing on long chain (seafood) n-3 PUFA, including their principal dietary sources, effects on physiological risk factors, potential molecular pathways and bioactive metabolites, effects on specific clinical endpoints, and existing dietary guidelines. Major dietary sources include fatty fish and other seafood. n-3 PUFA consumption lowers plasma triglycerides, resting heart rate, and blood pressure and might also improve myocardial filling and efficiency, lower inflammation, and improve vascular function. Experimental studies demonstrate direct anti-arrhythmic effects, which have been challenging to document in humans. n-3 PUFA affect a myriad of molecular pathways, including alteration of physical and chemical properties of cellular membranes, direct interaction with and modulation of membrane channels and proteins, regulation of gene expression via nuclear receptors and transcription factors, changes in eicosanoid profiles, and conversion of n-3 PUFA to bioactive metabolites. In prospective observational studies and adequately powered randomized clinical trials, benefits of n-3 PUFA seem most consistent for coronary heart disease mortality and sudden cardiac death. Potential effects on other cardiovascular outcomes are less-well-established, including conflicting evidence from observational studies and/or randomized trials for effects on nonfatal myocardial infarction, ischemic stroke, atrial fibrillation, recurrent ventricular arrhythmias, and heart failure. Research gaps include the relative importance of different physiological and molecular
mechanisms, precise dose-responses of physiological and clinical effects, whether fish oil provides all the benefits of fish consumption, and clinical effects of plant-derived n-3 PUFA. Overall, current data provide strong concordant evidence that n-3 PUFA are bioactive compounds that reduce risk of cardiac death. National and international guidelines have converged on consistent recommendations for the general population to consume at least 250 mg/day of long-chain n-3 PUFA or at least 2 servings/week of oily fish.

J Am Coll Cardiol. 2011 Nov 8;58(20):2047-67

Mercury exposure and risk of cardiovascular disease in two U.S. cohorts.

BACKGROUND: Exposure to methylmercury from fish consumption has been linked to a potentially increased risk of cardiovascular disease, but evidence from prior studies is equivocal. Beneficial effects of the ingestion of fish and selenium may also modify such effects. METHODS: Among subjects from two U.S. cohorts (a total of 51,529 men and 121,700 women) whose toenail clippings had been stored, we prospectively identified incident cases of cardiovascular disease (coronary heart disease and stroke) in 3427 participants and matched them to risk-set-sampled controls according to age, sex, race, and smoking status. Toenail mercury and selenium concentrations were assessed with the use of neutron-activation analysis. Other demographic characteristics, cardiovascular risk factors, fish consumption, and lifestyle habits were assessed by means of validated questionnaires. Associations between mercury exposure and incident cardiovascular disease were evaluated with the use of conditional logistic regression. RESULTS: Median toenail mercury concentrations were 0.23 µg per gram (interdecile range, 0.06 to 0.94) in the case participants and 0.25 µg per gram (interdecile range, 0.07 to 0.97) in the controls. In multivariate analyses, participants with higher mercury exposures did not have a higher risk of cardiovascular disease. For comparisons of the fifth quintile of mercury exposure with the first quintile, the relative risks were as follows: coronary heart disease, 0.85 (95% confidence interval [CI], 0.69 to 1.04; P=0.10 for trend); stroke, 0.84 (95% CI, 0.62 to 1.14; P=0.27 for trend); and total cardiovascular disease, 0.85 (95% CI, 0.72 to 1.01; P=0.06 for trend). Findings were similar in analyses of participants with low selenium concentrations or low overall fish consumption and in several additional sensitivity analyses. CONCLUSIONS: We found no evidence of any clinically relevant adverse effects of mercury exposure on coronary heart disease, stroke, or total cardiovascular disease in U.S. adults at the exposure levels seen in this study.

N Engl J Med. 2011 Mar 24;364(12):1116-25

Effects of chocolate, cocoa, and flavan-3-ols on cardiovascular health: a systematic review and meta-analysis of randomized trials.

BACKGROUND: There is substantial interest in chocolate and flavan-3-ols for the prevention of cardiovascular disease (CVD). OBJECTIVE: The objective was to systematically review the effects of chocolate, cocoa, and flavan-3-ols on major CVD risk factors. DESIGN: We searched Medline, EMBASE, and Cochrane databases for randomized controlled trials (RCTs) of chocolate, cocoa, or flavan-3-ols. We contacted authors for additional data and conducted duplicate assessment of study inclusion, data extraction, validity, and random-effects meta-analyses. RESULTS: We included 42 acute or short-term chronic (≤18 wk) RCTs that comprised 1297 participants. Insulin resistance (HOMA-IR: -0.67; 95% CI: -0.98, -0.36) was improved by chocolate or cocoa due to significant reductions in serum insulin. Flow-mediated dilatation (FMD) improved after chronic (1.34%; 95% CI: 1.00%, 1.68%) and acute (3.19%; 95% CI: 2.04%, 4.33%) intakes. Effects on HOMA-IR and FMD remained stable to sensitivity analyses. We observed reductions in diastolic blood pressure (BP; -1.60 mm Hg; 95% CI: -2.77, -0.43 mm Hg) and mean arterial pressure (-1.64 mm Hg; 95% CI: -3.27, -0.01 mm Hg) and marginally significant effects on LDL (-0.07 mmol/L; 95% CI: -0.13, 0.00 mmol/L) and HDL (0.03 mmol/L; 95% CI: 0.00, 0.06 mmol/L) cholesterol. Chocolate or cocoa improved FMD regardless of the dose consumed, whereas doses >50 mg epicatechin/d resulted in greater effects on systolic and diastolic BP. GRADE (Grading of Recommendations, Assessment, Development and Evaluation, a tool to assess quality of evidence and strength of recommendations) suggested low- to moderate-quality evidence of beneficial effects, with no suggestion of negative effects. The strength of evidence was lowered due to unclear reporting for allocation concealment, dropouts, missing data on outcomes, and heterogeneity in biomarker results in some studies. CONCLUSIONS: We found consistent acute and chronic benefits of chocolate or cocoa on FMD and previously unreported promising effects on insulin and HOMA-IR. Larger, longer-duration, and independently funded trials are required to confirm the potential cardiovascular benefits of cocoa flavan-3-ols.

Am J Clin Nutr. 2012 Mar;95(3):740-51

Flavonoid-rich cocoa consumption affects multiple cardiovascular risk factors in a meta-analysis of short-term studies.

A growing body of evidence suggests that the consumption of foods rich in polyphenolic compounds, particularly cocoa, may have cardioprotective effects. No review, however, has yet examined the effect of flavonoid-rich cocoa (FRC) on all major cardiovascular risk factors or has examined potential dose-response relationships for these effects. A systematic review and meta-analysis of randomized, controlled trials was performed to evaluate the effect of FRC on cardiovascular risk factors and to assess a dose-response relationship. Inclusion and exclusion criteria as well as dependent and independent variables were determined a priori. Data were collected for: blood pressure, pulse, total cholesterol, HDL cholesterol, LDL cholesterol, TG, BMI, C-reactive protein, flow-mediated vascular dilation (FMD), fasting glucose, fasting insulin, serum isoprostane, and insulin sensitivity/resistance indices. Twenty-four papers, with 1106 participants, met the criteria for final analysis. In response to FRC consumption, systolic blood pressure decreased by 1.63 mm Hg (P = 0.033), LDL cholesterol decreased by 0.077 mmol/L (P = 0.038), and HDL cholesterol increased by 0.046 mmol/L (P = 0.037), whereas total cholesterol, TG, and C-reactive protein remained the same. Moreover, insulin resistance decreased (HOMA-IR: -0.94 points; P < 0.001), whereas FMD increased (1.53%; P < 0.001). A nonlinear dose-response relationship was found between FRC and FMD (P = 0.004), with maximum effect observed at a flavonoid dose of 500 mg/d; a similar relationship may exist with HDL cholesterol levels (P = 0.06). FRC consumption significantly improves blood pressure, insulin resistance, lipid profiles, and FMD. These short-term benefits warrant larger long-term investigations into the cardioprotective role of FRC.

J Nutr. 2011 Nov;141(11):1982-8

Red and processed meat consumption and risk of incident coronary heart disease, stroke, and diabetes mellitus: a systematic review and meta-analysis.

BACKGROUND: Meat consump-tion is inconsistently associated with development of coronary heart disease (CHD), stroke, and diabetes mellitus, limiting quantitative recommendations for consumption levels. Effects of meat intake on these different outcomes, as well as of red versus processed meat, may also vary.METHODS AND RESULTS: We performed a systematic review and meta-analysis of evidence for relationships of red (unprocessed), processed, and total meat consumption with incident CHD, stroke, and diabetes mellitus. We searched for any cohort study, case-control study, or randomized trial that assessed these exposures and outcomes in generally healthy adults. Of 1598 identified abstracts, 20 studies met inclusion criteria, including 17 prospective cohorts and 3 case-control studies. All data were abstracted independently in duplicate. Random-effects generalized least squares models for trend estimation were used to derive pooled dose-response estimates. The 20 studies included 1 218 380 individuals and 23 889 CHD, 2280 stroke, and 10 797 diabetes mellitus cases. Red meat intake was not associated with CHD (n=4 studies; relative risk per 100-g serving per day=1.00; 95% confidence interval, 0.81 to 1.23; P for heterogeneity=0.36) or diabetes mellitus (n=5; relative risk=1.16; 95% confidence interval, 0.92 to 1.46; P=0.25). Conversely, processed meat intake was associated with 42% higher risk of CHD (n=5; relative risk per 50-g serving per day=1.42; 95% confidence interval, 1.07 to 1.89; P=0.04) and 19% higher risk of diabetes mellitus (n=7; relative risk=1.19; 95% confidence interval, 1.11 to 1.27; P<0.001). Associations were intermediate for total meat intake. Consumption of red and processed meat were not associated with stroke, but only 3 studies evaluated these relationships. CONCLUSIONS: Consumption of processed meats, but not red meats, is associated with higher incidence of CHD and diabetes mellitus. These results highlight the need for better understanding of potential mechanisms of effects and for particular focus on processed meats for dietary and policy recommendations.

Circulation. 2010 Jun 1;121(21):2271-83

Non-high-density lipoprotein and very-low-density lipoprotein cholesterol and their risk predictive values in coronary heart disease.

To determine if non-high-density lipoprotein (HDL) cholesterol is a more useful predictor of coronary heart disease (CHD) risk than low-density lipoprotein (LDL) cholesterol and if very-low-density lipoprotein (VLDL) cholesterol is an independent predictor of CHD risk, data from the Framingham Heart Study (2,693 men, 3,101 women) were used for this analysis. All subjects were aged > or =30 years and free of CHD at baseline, and incident CHD was the end point (618 men, 372 women). Cox proportional-hazards models were used to assess the risk for CHD (relative risks and 95% confidence intervals) on the basis of the joint distribution of LDL cholesterol and non-HDL cholesterol (in milligrams per deciliter), as well as LDL cholesterol, non-HDL cholesterol, and VLDL cholesterol as continuous variables. After multivariate adjustment, within non-HDL cholesterol level, no association was found between LDL cholesterol and the risk for CHD, whereas within LDL cholesterol levels, a strong positive and graded association between non-HDL cholesterol and risk for CHD was observed. When the analysis was repeated within triglyceride levels (<200 vs > or =200 mg/dl), the risk pattern did not change significantly. Also, VLDL cholesterol was found to be a significant predictor of CHD risk after adjusting for LDL cholesterol at triglyceride levels of > or =200 or <200 mg/dl. In conclusion, these results suggest that non-HDL cholesterol level is a stronger predictor of CHD risk than LDL cholesterol; that is, VLDL cholesterol may play a critical role in the development of CHD

Am J Cardiol. 2006 Nov 15;98(10):1363-8

Lipoprotein subclasses and coronary artery calcium in postmenopausal women from the healthy women study.

Lipoprotein subclass levels may improve the prediction of cardiovascular disease (CAD) in individuals beyond the risk assessment provided by conventional enzymatically determined lipid levels. The objective of this study was to evaluate the associations between nuclear magnetic resonance (NMR) spectroscopy-determined lipoprotein subclasses and coronary calcification in postmenopausal women, and to determine whether the associations were independent of conventional lipid measures. Coronary artery calcification (CAC) was measured by electron beam computed tomography, and lipoprotein subclasses were determined by NMR spectroscopy (Liposcience, Inc., Raleigh, NC), in 286 healthy women (mean age = 61.7), at 8 years postmenopause. CAC was analyzed as categories 0, 1 to 99, and > or =100. The mean CAC was 53 (range, 0 to 1,175), and 54% of the women had 0 scores. Large high-density lipoprotein (HDL) was inversely associated with CAC category, but small HDL was not. All very low-density lipoprotein (VLDL) subclasses-small, medium, and large-were positively associated with CAC (p <0.01). Small low-density lipoprotein (LDL) was positively associated with CAC (p <0.01), but medium and large LDL were not. Smaller LDL particle size (p <0.01) and higher levels of LDL particles (p <0.001) were associated with higher CAC category. In separate ordinal logistic regression models, small LDL, LDL particles, and large VLDL were each positively associated (p <0.05) with higher CAC after adjustment for age, systolic blood pressure (SBP), current smoking, and conventional measures of LDL cholesterol, HDL cholesterol, and triglycerides. These results suggest that the measurement of lipoprotein subclasses may improve the prediction of CAD in postmenopausal women beyond that provided by the conventional lipid panel and CAD risk factors.

Am J Cardiol. 2002 Oct 17;90(8A):71i-76i