Table 2.

Sixteen Articles with BDNF-related Dependent Variables and Cardiovascular-related Independent Variables

First Author	Year	Study Purpose/ Hypothesis^a	Design/ Follow-up	Quality Rating^b	Sample	Setting	Primary Dependent Variable^a	BDNF-related Findings^c
Metabolic syndrome
Chaldakov	2004	To study the cardiovascular and metabolic biology of nerve growth factor, BDNF and mast cells.	Case control	Poor	33 adults (23 with metabolic syndrome, 10 healthy without metabolic syndrome) Age M 44.3 (2.7) 81.8% women	Clinic	Plasma BDNF levels Nerve growth factor Mast cells	Plasma BDNF levels were lower in participants with metabolic syndrome compared to participants without metabolic syndrome.
Lee	2012	To examine the relationship of metabolic syndrome, adipose tissue and biomarkers with BDNF in men.	Case control	Fair	58 men (34 with metabolic syndrome but not diabetes; 24 age-matched men without metabolic syndrome) Age M 40.2 (10.4)	Clinic	Serum BDNF levels • Collected after an overnight fast	There was no significant difference in serum BDNF levels between men with or without metabolic syndrome. There were no significant differences in the components of metabolic syndrome between those with low and those with high serum BDNF levels, except for lower systolic blood pressure in participants with high serum BDNF levels.
Coronary artery disease
Bozzini	2009	To investigate the possible roles of BDNF Val66Met, 5-HTTLPR and −1438 G/A polymorphisms in CAD in patients with and without depression.	Case control	Fair	242 adults (99 patients with CAD, 143 healthy control participants) 43.8% women 100% White	Clinic	BDNF gene	The frequency of Met/Met genotype was significantly higher in the patients with CAD compared to the control cases.
Bus	2011	To examine the determinants (sampling characteristics, socio-demographic variables, lifestyle indicators, CAD, and metabolic syndrome) of serum BDNF in a large and well-defined cohort of people without current psychiatric or neurologic diseases.	Cross-sectional	Poor	1168 adults with subthreshold depressive or anxiety symptoms, or had high risk Age M 42.5 (14.1) 65% women	Clinic	Serum BDNF levels • Collected after an overnight fast • Immediately transferred and processed within 1 hour	Higher serum BDNF levels were found in participants who were older, had higher degrees of urbanicity, current smokers, and had metabolic syndrome or CAD. Significance for both metabolic syndrome and cardiovascular disease was lost controlling for age. Eating prior to blood withdrawal resulted in a significantly lower serum BDNF levels. Sampling later in the morning resulted in lower serum BDNF levels and longer sample storage.
Sustar	2016	To evaluate the association between BDNF Val66Met (rs6265) polymorphism and CHD and/or BMI in patients with CHD and in healthy control participants. Hypothesis: Different BDNF Val66Met genotypes would be associated with CHD or with increased BMI in CHD patients and healthy control participants.	Case control	Good	704 adults (206 with CHD, 498 healthy control participants) Age M 54.2 years 100% White	Clinic	BDNF gene	There were no significant differences of BDNF genotype frequencies by sex and between adults with CHD and healthy control participants. BDNF rs6265 polymorphism was associated with BMI categories.
Myocardial infarction
Lorgis	2010	To evaluate the relationship between BDNF, functional parameters and biological markers associated with inflammatory processes and platelet activation.	Case control	Good	40 adults (20 with acute myocardial infarction, 20 age- and gender-matched with stable angina) Age Mdn 61.5 years (IQR = 54–78) 25% women	Clinic	Serum BDNF levels • Collected in the morning after an overnight fast	Median serum BDNF levels were significantly higher in the myocardial infarction group than in the stable angina group. In patients with myocardial infarction, a significant correlation was found between BDNF and sP-selectin.
Zhang	2015	To identify serum biomarkers, including BDNF, of patients with STEMI for use in diagnosis	Case control	Fair	20 men (10 with STEMI, 10 healthy without STEMI) Age M 54.2 (5.8)	Hospital	Serum BDNF levels	Serum BDNF levels were significantly higher in the STEMI group compared with control cases.
Heart failure
Pressler	2015	To examine the efficacy of Brain Fitness cognitive training intervention on memory in patients with heart failure, and to examine changes in serum BDNF levels between patients who were randomized to Brain Fitness and health education who were BDNF gene Met negative (homozygous Val/Val) and patients who were BDNF gene Met positive (heterozygous Val/Met and homozygous Met/Met). Hypothesis: Compared with heart failure patients in the active control health education group, heart failure patients who receive Brain Fitness have improved memory and serum BDNF levels.	RCT testing a cognitive training intervention (Brain Fitness) 12 weeks	Good	27 adults with heart failure Age M = 61.0 (11.9) 22% women 85.2% White 11.1% Black 3.7% Asian	Clinic	Serum BDNF levels BDNF gene	Serum BDNF levels significantly increased among patients who completed the intervention and decreased among patients who completed health education control at 12 weeks. There were no significant differences in memory between the groups over time. The intervention was associated with increased serum BDNF levels regardless of BDNF Met status.
Pressler	2017	To characterize major allelic frequency of 2 variants in APOE gene in patients with heart failure, and evaluate differences in memory and serum BDNF levels based on APOE ε 4 allele(s).	One-group pre-post design testing a cognitive training intervention 8 weeks 12 weeks	Fair	26 adults with heart failure Age M 60.8 (12.1)	Clinic	Serum BDNF levels	There were no significant differences in serum BDNF levels between those who had the APOEε4 allele and those who did not. None of the participants who had APOE ε 4 present had the BDNF Met allele.
Takashio	2015	To evaluate plasma BDNF levels in patients with heart failure and age- and gender-matched control participants. Hypothesis: Plasma BDNF levels would be decreased in patients with heart failure.	Case control	Fair	242 heart failure patients, 80 case control participants Age M 71 (12) 34% women	Hospital	Plasma BDNF levels	Plasma BDNF levels were significantly lower in patients with heart failure and lower in patients with heart failure with NYHA class III than class I.
Stroke
Lasek-Bal	2015	To assess the role of BDNF concentration in the course of ischemic stroke and its effect on post-stroke disability prognosis.	Longitudinal 90 days	Good	87 adults with ischemic stroke Age M 71.7 (11.8) 48.3% women	Hospital	Serum BDNF levels • On the first day of stroke	There were no significant differences between adults who had mild vs. moderate/severe neurological deficits on the first day post-stroke. Serum BDNF levels were significantly lower in adults with lower functional status at 90 days after the onset of stroke.
Stanne	2016	To investigate whether circulating concentrations of BDNF are altered in the acute phase of ischemic stroke and whether they are associated with short- or long-term functional outcomes. Hypothesis: Circulating BDNF concentrations are lowered in the acute phase of ischemic stroke and low BDNF concentrations are associated with poor short- and long-term functional outcomes	Case control	Fair	491 adults after stroke, 513 case control participants (1004 total) Age Mdn 58.5 (IQR = 51–64) 36% women 100% White	Clinic	• Serum BDNF levels	Serum BDNF levels were significantly lower in adults after ischemic stroke compared with healthy control participants. Serum BDNF levels were not significantly associated with 3-month outcomes. In adults after ischemic stroke, those with the lowest tertile of BDNF had an increased risk of experiencing poor outcomes both at follow-up at 2 and 7 years.
Other
Costa	2014	To evaluate the acute effect of aerobic exercise on the BDNF levels in adults with Chagas heart disease and the relationship between BDNF and ventricular dysfunction and exercise intensity.	Case control	Fair	30 patients with Chagas heart disease (16 non-dilated, 14 dilated) Age M 47.9 (8.7) 33.0 % women	Clinic	Serum BDNF levels • Collected immediately after exercise	There was a significant decrease in serum BDNF levels after acute exercise across groups. The non-dilated group showed a significant decrease in serum BDNF levels. Patients who completed exercise at a high intensity had a significant decrease in serum BDNF levels compared to patients at moderate intensity.
Ejiri	2005	To examine neurotrophin plasma levels in development of CAD and compare the levels in coronary circulation in with stable and unstable angina and without CAD	Cross-sectional	Fair	107 adults (45 with stable angina, 38 with unstable angina, 24 without CAD) Age M 64.8 36% women	Hospital	Plasma BDNF levels • Obtained from human coronary arteries	The difference in BDNF levels between the coronary sinus and aorta was significantly greater in adults with unstable angina group compared with adults the stable angina and adults without CAD.
Sanchez-DeToledo	2014	To determine the utility of non-invasive bedside neuromonitoring, including serum biomarkers (including serum BDNF), in identifying children at risk from adverse neurological outcome after heart surgery. Hypothesis: Two non-invasive neurological monitoring tools (including serum BDNF) would predict short-term adverse neurological outcomes.	Longitudinal 16 hours, 12 months	Good	36 children undergoing heart surgery with cardiopulmonary bypass Age Mdn 8 months (IQR = 1–20)	Hospital	Serum BDNF levels • Collected at baseline, immediately after and 16 hours after surgery	There were no significant differences in the levels of serum BDNF at baseline and immediately after and 16 hours after surgery between children with adverse neurological outcomes and children with good neurological outcomes at 12 months after surgery.
Schutte	2016	To investigate associations between cardiometabolic risk markers, cortisol and cortisol:BDNF ratio in a bi-ethnic cohort	Cross-sectional	Fair	406 adults Age M 44.7 (9.5) 50.7% women 51.5% White 58.5% African	Clinic	Cortisol:serum BDNF ratio	Cortisol levels were lower in African men. BDNF was lower in African women compared to White women. In Africans (particularly men), higher cortisol:BDNF ratios were significantly associated with hyperglycemia, elevated 24-hour blood pressure, and silent ischemia.

As reported in the study publications.

Quality ratings were determined by the National Heart, Lung, and Blood Institute Study Quality Assessment Tools, with the appropriate tool chosen by the design.

Adjusted model findings reported as available.

Note. BDNF = brain-derived neurotrophic factor. CAD = coronary artery disease. NYHA = New York Heart Association Classification. STEMI = ST-Elevation Myocardial Infarction. BMI = body mass index. CHD = coronary heart disease