Clinical trial NCT01947712: Effect of Polyphenols on Peripheral Vascular Disease.
Official title: Effect of Dark Chocolate on Endothelial Function and Oxidative Stress in Patients With Peripheral Vascular Disease.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Peripheral Arterial Disease
Keywords: Peripheral arterial disease
Oxidative stress
Cocoa
polyphenols
NADPH oxidase
Lead sponsor: University of Roma La Sapienza
Sponsor class: OTHER
First posted: 2013-09-20
Enrollment: 20
Sex: ALL
Minimum age (years): 20
Maximum age (years): 90
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: BASIC_SCIENCE

Brief summary: Peripheral arterial disease (PAD) is a clinical setting characterized by an exceptionally high risk for cardiovascular events. Oxidative stress seems to play a role in impairing flow-mediated dilation (FMD) and contributing to atherosclerosis in patients with PAD. Cocoa seems to exert artery dilatation via oxidative stress inhibition.

OBJECTIVES: To investigate whether in PAD patients, dark chocolate elicits artery dilatation via down-regulation of NOX2, the catalytic core of NADPH oxidase.

Detailed description: Atherosclerosis represents the major cause of worldwide death; it is a complex phenomenon that encompasses the intricate interplay of classic cardiovascular risk factors, oxidative stress and inflammation.

Peripheral artery disease (PAD) is a clinical setting that well represents the model of widespread atherosclerosis. PAD affects 20% of patients over the age of 75. Furthermore, PAD patients are at an exceptionally high risk for cardiovascular events and the majority will eventually die of a cardiac or cerebrovascular etiology.

Polyphenol could represent a novel therapeutic strategy to counteract atherosclerosis. During the last decades, a growing interest in polyphenols resulted from prospective and epidemiological studies that showed the beneficial effects of these substances on human health. In particular, polyphenols exert their beneficial effect by inhibition of NADPH oxidase (NOX2), an enzyme directly involved in atherosclerosis; thus, the activation of this enzyme leads to an enhanced production of oxidative stress and inflammatory processes.

The objective of this study is to evaluate the effect of polyphenols on oxidative stress and inflammation and on surrogate markers of atherosclerosis in PAD patients. Polyphenols, inhibiting NOX2-mediated oxidative stress and immune-mediated process, could represent a novel therapy to reduce the high risk of cardiovascular events in PAD.

Eligibility criteria: Inclusion Criteria:

Every PAD patient to be enrolled in the study had:

1. claudication (defined as leg pain on walking, disappearing within 10 minutes of standing, of presumed atherosclerotic origin) and
2. ankle/brachial index (ABI), that was assessed as ankle/arm systolic blood pressure ratio by Doppler ultrasonography \<0.90 on the worst leg at rest.

Patients had to be in stable conditions without abrupt changes of ABI (\>20%) in the last month before the enrolment.

Exclusion Criteria:

Subjects were excluded from the study if they had liver insufficiency, serious renal disorders (serum creatinine\>2.8 mg/dL), acute stroke, acute myocardial infarction, deep venous thrombosis or if they were current smokers or were taking antioxidants.

Primary outcomes:
measure: endothelial function assessed by flow mediated dilation (FMD)
timeFrame: 2 hours after (dark or milk) chocolate ingestion
measure: endothelial function assessed by flow mediated dilation (FMD)
timeFrame: after 30 days of (dark or milk) chocolate ingestion
Secondary outcomes:
measure: Oxidative stress markers
timeFrame: 2 hours after (dark or milk) chocolate ingestion
measure: Maximal walking distance
timeFrame: 2 hours after (dark or milk) chocolate ingestion
measure: Ankle Brachial Index (ABI)
timeFrame: 2 hours after (dark or milk) chocolate ingestion
measure: Oxidative stress markers
timeFrame: after 30 days of (dark or milk) chocolate ingestion
measure: Maximal walking distance
timeFrame: after 30 days of (dark or milk) chocolate ingestion
measure: Ankle Brachial Index (ABI)
timeFrame: after 30 days of (dark or milk) chocolate ingestion
Other outcomes:
Locations:
city: Rome
country: Italy
facility: Sapienza University of Rome, I Clinica Medica, Research Tower
Study officials:
affiliation: Sapienza University
name: Francesco Violi, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Loffredo L, Carnevale R, Cangemi R, Angelico F, Augelletti T, Di Santo S, Calabrese CM, Della Volpe L, Pignatelli P, Perri L, Basili S, Violi F. NOX2 up-regulation is associated with artery dysfunction in patients with peripheral artery disease. Int J Cardiol. 2013 Apr 30;165(1):184-92. doi: 10.1016/j.ijcard.2012.01.069. Epub 2012 Feb 14.
citation: Carnevale R, Loffredo L, Pignatelli P, Nocella C, Bartimoccia S, Di Santo S, Martino F, Catasca E, Perri L, Violi F. Dark chocolate inhibits platelet isoprostanes via NOX2 down-regulation in smokers. J Thromb Haemost. 2012 Jan;10(1):125-32. doi: 10.1111/j.1538-7836.2011.04558.x.
citation: Loffredo L, Carnevale R, Perri L, Catasca E, Augelletti T, Cangemi R, Albanese F, Piccheri C, Nocella C, Pignatelli P, Violi F. NOX2-mediated arterial dysfunction in smokers: acute effect of dark chocolate. Heart. 2011 Nov;97(21):1776-81. doi: 10.1136/heartjnl-2011-300304. Epub 2011 Jul 31.
citation: Loffredo L, Perri L, Catasca E, Pignatelli P, Brancorsini M, Nocella C, De Falco E, Bartimoccia S, Frati G, Carnevale R, Violi F. Dark chocolate acutely improves walking autonomy in patients with peripheral artery disease. J Am Heart Assoc. 2014 Jul 2;3(4):e001072. doi: 10.1161/JAHA.114.001072.