- 2018 - Pilot Grant
Background and Significance
Cardiovascular Disease (CVD) remains a significant cause of morbidity and mortality in the United States and worldwide.(1,2) Psychosocial stress has long been linked with increased risk for atherosclerosis and CVD events.(3-5) Moreover, after correcting for risk factors, stress has an attributable risk that is on par with that of other major cardiovascular risk factors, including smoking and diabetes (3,4). However, until relatively recently, the mechanistic link between chronic stress and CVD was not well-characterized in humans.
Inflammation is an important feature of both stress and atherosclerosis. Atherosclerosis is driven by active inflammation that results in monocyte migration to the vessel wall.(6,7) Animal studies suggest that stress, through stimulation of sympathetic nerves that terminate in the bone marrow, prompts increased production and release of inflammatory cells that subsequently increase arterial inflammation, a key pathobiological stimulus for progression of CVD. (8-10) Likewise, human studies repeatedly linked stress to increased levels of inflammatory markers (11-14). However, an observation of a neural-hematopoietic-arterial link was only recently observed in humans.
Our group recently employed advanced imaging techniques to gain insights into the link between stress and CVD in humans. The amygdala links higher-level processing of anxiety and stress with physiologic responses in the body. High resting amygdalar metabolic activity, which associates with self- reported stress and anxiety (15), can be assessed by amygdalar uptake of radiolabeled glucose [18fluorodeoxy-glucose (FDG)] detected using positron emission tomography (PET). In a landmark study of 293 individuals, published recently in the Lancet (15), we demonstrated that resting amygdalar activity (by FDG-PET/CT) robustly predicts future CVD risk; each standard deviation increase in the amygdalar signal independently associated with a 60% increase in future CVD risk. Further, we observed that the link between amygdalar activity and CVD was mediated by upregulated bone marrow activity and increased arterial inflammation in series (figure 1). Accordingly, the recent work suggests that stress may link to CVD through upregulation of an amygdalar-hematopoietic-arterial axis.
Stress reduction (SR), reduces perceived stress,1(6,17) systemic inflammatory biomarkers (e.g., CRP, IL-6, etc.),(18-21) gene expression related to the inflammatory response,(18,22) and parameters of metabolic health.(23) Furthermore, meditation and stress reduction may reduce carotid intimal medial thickness and clinical events in individuals with CVD when implemented with usual care.(24,25) Moreover, SR has been shown to alter brain structure and function, including reductions in amygdalar grey matter density and amygdalar activation in response to emotional stimuli in a non-meditative
state. (26,27) However, a key knowledge gap remains: whether reduction of chronic stress will attenuate amygdalar-hematopoietic-arterial activity. Indeed, the question of a possible beneficial effect of stress reduction on CVD (and the mechanism mediating that benefit) were recently highlighted as key questions in a recent American Heart Association (AHA) consensus statement.(28) Accordingly, herein, we propose to take the natural next step to study these gaps. Our central hypothesis is that stress reduction reduces stress- associated neural activity and systemic inflammation, resulting in reduced arterial inflammation. We propose a pilot study to test the hypotheses that SR results in a reduction in arterial inflammation (compared to usual care) and that the reduced arterial inflammation is the result of a reduction in amygdalar-hematopoietic activity, in series. To test these hypotheses, we will leverage an NIH program project grant investigating associations between stress-related neural activity, immune system activation, and arterial inflammation, in 240 individuals who will be undergoing PET/magnetic resonance (PET/MR) imaging. Subjects will undergo full psychometric analysis, along with cutting- edge body and brain PET/MRI, brain functional MRI, and inflammatory biomarkers. The current proposal represents a longitudinal extension of that project, wherein individuals with moderate baseline stress and evidence of increased arterial inflammation (N=21) will be randomized to an 8-week stress reduction program (vs. usual care).
- Benjamin EJ, Blaha MJ, Chiuve SE, et al. Heart Disease and Stroke Statistics-2017 Update: A Report From the American Heart Association. 2017;135(10):e146-e603.
- Writing C, Smith SC, Jr., Collins A, et al. Our time: a call to save preventable death from cardiovascular disease (heart disease and stroke). Global heart. 2012;7(4):297-305.
- Rosengren A, Hawken S, Ôunpuu S, et Association of psychosocial risk factors with risk of acute myocardial infarction in 11 119 cases and 13 648 controls from 52 countries (the INTERHEART study): case-control study. The Lancet. 2004;364(9438):953-962.
- Nabi H, Kivimaki M, Batty GD, et al. Increased risk of coronary heart disease among individuals reporting adverse impact of stress on their health: the Whitehall II prospective cohort study. Eur Heart J. 2013;34(34):2697-2705.
- Robinson KL, McBeth J, Macfarlane GJ. Psychological distress and premature mortality in the general population: a prospective study. Annals of epidemiology. 2004;14(7):467-472.
- Libby P. Inflammation in atherosclerosis. Arteriosclerosis, thrombosis, and vascular biology. 2012;32(9):2045- 2051.
- Mantovani A, Garlanda C, Locati M. Macrophage diversity and polarization in atherosclerosis: a question of balance. Arteriosclerosis, thrombosis, and vascular biology. 2009;29(10):1419-1423.
- Heidt T, Sager HB, Courties G, et al. Chronic variable stress activates hematopoietic stem cells. Nat. 2014;20(7):754-758.
- Zhang T, Chen Y, Liu H, Zhou Z, Zhai Y, Yang J. Chronic unpredictable stress accelerates atherosclerosis through promoting inflammation in apolipoprotein E knockout mice. Thrombosis research. 2010;126(5):386-392.
- Nahrendorf M, Swirski Lifestyle effects on hematopoiesis and atherosclerosis. Circ Res. 2015;116(5):884-894.
- Emami H, Singh P, MacNabb M, et al. Splenic metabolic activity predicts risk of future cardiovascular events: demonstration of a cardiosplenic axis in humans. JACC Cardiovasc Imaging. 2015;8(2):121-130.
- Steptoe A, Hamer M, Chida Y. The effects of acute psychological stress on circulating inflammatory factors in humans: a review and meta-analysis. Brain, behavior, and immunity. 2007;21(7):901-912.
- Dutta P, Courties G, Wei Y, et al. Myocardial infarction accelerates atherosclerosis. 2012;487(7407):325- 329.
- Kim EJ, Kim S, Kang DO, Seo HS. Metabolic activity of the spleen and bone marrow in patients with acute myocardial infarction evaluated by 18f-fluorodeoxyglucose positron emission tomograpic imaging. Circulation Cardiovascular imaging. 2014;7(3):454-460.
- Ahmed Tawakol, Amorina Ishai, Richard A.P. Takx, et al. Resting Amygdalar Activity Predicts Cardiovascular Events: Evidence for a Neural-Hematopoietic-Arterial Axis. in press.
- Klatt MD, Buckworth J, Malarkey WB. Effects of low-dose mindfulness-based stress reduction (MBSR-ld) on working adults. Health education & behavior : the official publication of the Society for Public Health Education. 2009;36(3):601-614.
- Jensen CG, Vangkilde S, Frokjaer V, Hasselbalch SG. Mindfulness training affects attention–or is it attentional effort? Journal of experimental psychology General. 2012;141(1):106-123.
- Creswell JD, Irwin MR, Burklund LJ, et al. Mindfulness-Based Stress Reduction training reduces loneliness and pro-inflammatory gene expression in older adults: a small randomized controlled trial. Brain, behavior, and immunity. 2012;26(7):1095-1101.
- Gallegos AM, Lytle MC, Moynihan JA, Talbot Mindfulness-based stress reduction to enhance psychological functioning and improve inflammatory biomarkers in trauma-exposed women: A pilot study. Psychological trauma : theory, research, practice and policy. 2015;7(6):525-532.
- Malarkey WB, Jarjoura D, Klatt M. Workplace based mindfulness practice and inflammation: a randomized. Brain, behavior, and immunity. 2013;27(1):145-154.
- Sanada K, Alda Diez M, Salas Valero M, et al. Effects of mindfulness-based interventions on biomarkers in healthy and cancer populations: a systematic review. BMC complementary and alternative medicine. 2017;17(1):125.
- Bhasin MK, Dusek JA, Chang BH, et al. Relaxation response induces temporal transcriptome changes in energy metabolism, insulin secretion and inflammatory pathways. PLoS One. 2013;8(5):e62817.
- Paul-Labrador M, Polk D, Dwyer JH, et al. Effects of a randomized controlled trial of transcendental meditation on components of the metabolic syndrome in subjects with coronary heart disease. Arch Intern Med. 2006;166(11):1218-1224.
- Fields JZ, Walton KG, Schneider RH, et al. Effect of a multimodality natural medicine program on carotid atherosclerosis in older subjects: a pilot trial of Maharishi Vedic Medicine. The American journal of cardiology. 2002;89(8):952-958.
- Blumenthal JA, Sherwood A, Smith PJ, et Enhancing Cardiac Rehabilitation With Stress Management Training: A Randomized, Clinical Efficacy Trial. Circulation. 2016;133(14):1341-1350.
- Desbordes G, Negi LT, Pace TW, Wallace BA, Raison CL, Schwartz EL. Effects of mindful-attention and compassion meditation training on amygdala response to emotional stimuli in an ordinary, non-meditative state. Frontiers in human neuroscience. 2012;6:292.
- Holzel BK, Carmody J, Evans KC, et Stress reduction correlates with structural changes in the amygdala. Social cognitive and affective neuroscience. 2010;5(1):11-17.
- Levine GN, Lange RA, Bairey-Merz CN, et al. Meditation and Cardiovascular Risk Reduction: A Scientific Statement From the American Heart Association. Journal of the American Heart Association. 2017;6(10).
- Oler JA, Fox AS, Shelton SE, et Amygdalar and hippocampal substrates of anxious temperament differ in their heritability. Nature. 2010;466(7308):864-868.
- Fox AS, Oler JA, Shelton SE, et al. Central amygdala nucleus (Ce) gene expression linked to increased trait-like Ce metabolism and anxious temperament in young primates. Proc Natl Acad Sci U S A. 2012;109(44):18108-18113.
- Tawakol A, Ishai A, Takx RA, et Relation between resting amygdalar activity and cardiovascular events: a longitudinal and cohort study. Lancet. 2017;389(10071):834-845.
- Cohen S, Kamarck T, Mermelstein R. A global measure of perceived stress. Journal of health and social
- Heidt T, Sager HB, Courties G, et al. Chronic variable stress activates hematopoietic stem cells. Nat
- Swirski FK, Nahrendorf M. Leukocyte behavior in atherosclerosis, myocardial infarction, and heart
- Swirski FK, Nahrendorf M, Etzrodt M, et al. Identification of splenic reservoir monocytes and their deployment to inflammatory sites. 2009;325(5940):612-616.
- Jaiswal S, Natarajan P, Silver AJ, et al. Clonal Hematopoiesis and Risk of Atherosclerotic Cardiovascular
N Engl J Med. 2017;377(2):111-121.
- Rudd JH, Myers KS, Bansilal S, et al. (18)Fluorodeoxyglucose positron emission tomography imaging of atherosclerotic plaque inflammation is highly reproducible: implications for atherosclerosis therapy J Am Coll Cardiol. 2007;50(9):892-896.
- Abdelbaky A, Tawakol A. Noninvasive Positron Emission Tomography Imaging of Coronary Arterial
Curr Cardiovasc Imaging Rep. 2011;4(1):41-49.
- Fayad ZA, Mani V, Woodward M, et al. Safety and efficacy of dalcetrapib on atherosclerotic disease using novel non-invasive multimodality imaging (dal-PLAQUE): a randomised clinical trial. 2011;378(9802):1547- 1559.
- Fayad ZA, Mani V, Woodward M, et al. Rationale and design of dal-PLAQUE: a study assessing efficacy and safety of dalcetrapib on progression or regression of atherosclerosis using magnetic resonance imaging and 18F- fluorodeoxyglucose positron emission tomography/computed tomography. Am Heart J. 2011;162(2):214-221 e212.
- Figueroa AL, Subramanian SS, Cury RC, et al. Distribution of inflammation within carotid atherosclerotic plaques with high-risk morphological features: a comparison between positron emission tomography activity, plaque morphology, and histopathology. Circulation Cardiovascular imaging. 2012;5(1):69-77.
- Hiari N, Rudd JH. FDG PET imaging and cardiovascular inflammation. Current cardiology reports. 2011;13(1):43- 48.
- Joshi F, Rosenbaum D, Bordes S, Rudd JH. Vascular imaging with positron emission tomography. Journal of internal medicine. 2011;270(2):99-109.
- Menezes LJ, Kotze CW, Hutton BF, et al. Vascular inflammation imaging with 18F-FDG PET/CT: when to image?
Journal of nuclear medicine : official publication, Society of Nuclear Medicine. 2009;50(6):854-857.
- Rudd JH, Narula J, Strauss HW, et al. Imaging atherosclerotic plaque inflammation by fluorodeoxyglucose with positron emission tomography: ready for prime time? Journal of the American College of Cardiology. 2010;55(23):2527-2535.
- Tawakol A, Finn Imaging inflammatory changes in atherosclerosis multimodal imaging hitting stride. JACC Cardiovascular imaging. 2011;4(10):1119-1122.
- Tawakol A, Migrino RQ, Bashian GG, et al. In vivo 18F-fluorodeoxyglucose positron emission tomography imaging provides a noninvasive measure of carotid plaque inflammation in patients. J Am Coll Cardiol. 2006;48(9):1818-1824.
- Yun M, Jang S, Cucchiara A, Newberg AB, Alavi 18F FDG uptake in the large arteries: a correlation study with the atherogenic risk factors. Seminars in Nuclear Medicine. 2002;32(1):70-76.
- Wu YW, Kao HL, Chen MF, et al. Characterization of plaques using 18F-FDG PET/CT in patients with carotid atherosclerosis and correlation with matrix metalloproteinase-1. Journal of nuclear medicine : official publication, Society of Nuclear Medicine. 2007;48(2):227-233.
- Tahara N, Yamagishi S, Takeuchi M, et al. Positive association between serum level of glyceraldehyde-derived advanced glycation end products and vascular inflammation evaluated by [(18)F]fluorodeoxyglucose positron emission tomography. Diabetes Care. 2012;35(12):2618-2625.
- Myers KS, Rudd JH, Hailman EP, et al. Correlation between arterial FDG uptake and biomarkers in peripheral artery disease. JACC Cardiovasc Imaging. 2012;5(1):38-45.
- Bucerius J, Mani V, Moncrieff C, et al. Impact of noninsulin-dependent type 2 diabetes on carotid wall 18F- fluorodeoxyglucose positron emission tomography uptake. J Am Coll Cardiol. 2012;59(23):2080-2088.
- Kim TN, Kim S, Yang SJ, et al. Vascular inflammation in patients with impaired glucose tolerance and type 2 diabetes: analysis with 18F-fluorodeoxyglucose positron emission tomography. Circ Cardiovasc Imaging. 2010;3(2):142-148.
- Rominger A, Saam T, Wolpers S, et 18F-FDG PET/CT identifies patients at risk for future vascular events in an otherwise asymptomatic cohort with neoplastic disease. J Nucl Med. 2009;50(10):1611-1620.
- Arauz A, Hoyos L, Zenteno M, Mendoza R, Alexanderson E. Carotid plaque inflammation detected by 18F- fluorodeoxyglucose-positron emission Pilot study. Clin Neurol Neurosurg. 2007;109(5):409-412.
- Figueroa AL, Abdelbaky A, Truong QA, et al. Measurement of arterial activity on routine FDG PET/CT images improves prediction of risk of future CV events. JACC Cardiovasc Imaging. 2013;6(12):1250-1259.
- Tahara N, Kai H, Ishibashi M, et al. Simvastatin attenuates plaque inflammation: evaluation by fluorodeoxyglucose positron emission tomography. J Am Coll Cardiol. 2006;48(9):1825-1831.
- Tawakol A, Fayad ZA, Mogg R, et al. Intensification of statin therapy results in a rapid reduction in atherosclerotic inflammation: results of a multicenter fluorodeoxyglucose-positron emission tomography/computed tomography feasibility study. J Am Coll Cardiol. 2013;62(10):909-917.
- Wu YW, Kao HL, Huang CL, et al. The effects of 3-month atorvastatin therapy on arterial inflammation, calcification, abdominal adipose tissue and circulating biomarkers. Eur J Nucl Med Mol Imaging. 2012;39(3):399- 407.
- Mizoguchi M, Tahara N, Tahara A, et al. Pioglitazone attenuates atherosclerotic plaque inflammation in patients with impaired glucose tolerance or diabetes a prospective, randomized, comparator-controlled study using serial FDG PET/CT imaging study of carotid artery and ascending aorta. JACC Cardiovasc Imaging. 2011;4(10):1110-1118.
- Kuo B, Bhasin M, Jacquart J, et al. Genomic and clinical effects associated with a relaxation response mind-body intervention in patients with irritable bowel syndrome and inflammatory bowel disease. PLoS One. 2015;10(4):e0123861.
- Bhasin MK, Denninger JW, Huffman JC, et al. Specific Transcriptome Changes Associated with Blood Pressure Reduction in Hypertensive Patients After Relaxation Response Training. J Altern Complement Med.
- Weathers FW, Keane TM, Davidson JR. Clinician-administered PTSD scale: a review of the first ten years of research. Depression and anxiety. 2001;13(3):132-156.
- Wilson JP, Keane TM. Assessing psychological trauma and PTSD. Guilford Press;
- Adkins JW, Weathers FW, McDevitt-Murphy M, Daniels JB. Psychometric properties of seven self-report measures of posttraumatic stress disorder in college students with mixed civilian trauma exposure. Journal of anxiety disorders. 2008;22(8):1393-1402.
- McDonald MK, Borntrager CF, Rostad W. Measuring trauma: considerations for assessing complex and non-PTSD Criterion A childhood trauma. Journal of trauma & dissociation : the official journal of the International Society for the Study of Dissociation. 2014;15(2):184-203.
- Kontaxakis V, Konstantakopoulos G. From DSM-1 to DSM-5. 2015;26(1):13-16.
- Gaztanaga J, Farkouh M, Rudd JH, et al. A phase 2 randomized, double-blind, placebo-controlled study of the effect of VIA-2291, a 5-lipoxygenase inhibitor, on vascular inflammation in patients after an acute coronary syndrome. 2015;240(1):53-60.
- Fayad ZA, Mani V, Woodward M, et al. Safety and efficacy of dalcetrapib on atherosclerotic disease using novel non-invasive multimodality imaging (dal-PLAQUE): a randomised clinical trial. The Lancet. 2011;378(9802):1547- 1559.
- Emami H, Vucic E, Subramanian S, et al. The effect of BMS-582949, a P38 mitogen-activated protein kinase (P38 MAPK) inhibitor on arterial inflammation: a multicenter FDG-PET trial. 2015;240(2):490-496.
- Tawakol A, Ishai A, Takx RAP, et al. Relation between resting amygdalar activity and cardiovascular events: a longitudinal and cohort study. The Lancet. 2017;389(10071):834-845.
- Noh TS, Moon SH, Cho YS, et Relation of carotid artery 18F-FDG uptake to C-reactive protein and Framingham risk score in a large cohort of asymptomatic adults. J Nucl Med. 2013;54(12):2070-2076.
- Bucci M, Aparici CM, Hawkins R, et al. Validation of FDG uptake in the arterial wall as an imaging biomarker of atherosclerotic plaques with 18F-fluorodeoxyglucose positron emission tomography-computed tomography (FDG-PET/CT). Journal of neuroimaging : official journal of the American Society of Neuroimaging. 2014;24(2):117-123.
- Calcagno C, Cornily JC, Hyafil F, et al. Detection of neovessels in atherosclerotic plaques of rabbits using dynamic contrast enhanced MRI and 18F-FDG PET. Arteriosclerosis, thrombosis, and vascular biology. 2008;28(7):1311- 1317.
- Zhao QM, Zhao X, Feng TT, et al. Detection of vulnerable atherosclerotic plaque and prediction of thrombosis events in a rabbit model using 18F-FDG -PET/CT. PLoS One. 2013;8(4):e61140.
- Rudd JH, Myers KS, Bansilal S, et al. Atherosclerosis inflammation imaging with 18F-FDG PET: carotid, iliac, and femoral uptake reproducibility, quantification methods, and J Nucl Med. 2008;49(6):871-878.
- Ishii H, Nishio M, Takahashi H, et al. Comparison of atorvastatin 5 and 20 mg/d for reducing F-18 fluorodeoxyglucose uptake in atherosclerotic plaques on positron emission tomography/computed tomography: a randomized, investigator-blinded, open-label, 6-month study in Japanese adults scheduled for percutaneous coronary intervention. Clinical therapeutics. 2010;32(14):2337-2347.
- Shin LM, Lasko NB, Macklin ML, et Resting metabolic activity in the cingulate cortex and vulnerability to posttraumatic stress disorder. Archives of general psychiatry. 2009;66(10):1099-1107.
- Bremner JD, Vermetten E, Schmahl C, et al. Positron emission tomographic imaging of neural correlates of a fear acquisition and extinction paradigm in women with childhood sexual-abuse-related post-traumatic stress disorder. Psychological medicine. 2005;35(6):791-806.
- Zhu Y, Du R, Zhu Y, et al. PET Mapping of Neurofunctional Changes in a Posttraumatic Stress Disorder Model. J Nucl Med. 2016;57(9):1474-1477.
- Grothues F, Smith GC, Moon JC, et al. Comparison of interstudy reproducibility of cardiovascular magnetic resonance with two-dimensional echocardiography in normal subjects and in patients with heart failure or left ventricular hypertrophy. The American journal of cardiology. 2002;90(1):29-34.
- Park ER, Traeger L, Vranceanu AM, et al. The development of a patient-centered program based on the relaxation response: the Relaxation Response Resiliency Program (3RP). 2013;54(2):165-174.
- Vranceanu AM, Shaefer JR, Saadi AF, et al. The Relaxation Response Resiliency Enhancement Program in the Management of Chronic Refractory Temporomandibular Joint Disorder: Results from a Pilot Study. Journal of musculoskeletal pain. 2013;21(3):224-230.
- Vranceanu AM, Merker VL, Plotkin SR, Park ER. The relaxation response resiliency program (3RP) in patients with neurofibromatosis 1, neurofibromatosis 2, and schwannomatosis: results from a pilot study. J Neurooncol. 2014;120(1):103-109.
- Vranceanu AM, Riklin E, Merker VL, Macklin EA, Park ER, Plotkin SR. Mind-body therapy via videoconferencing in patients with neurofibromatosis: An RCT. 2016;87(8):806-814.
- Jacquart J, Miller KM, Radossi A, et al. The effectiveness of a community-based, mind-body group for symptoms of depression and anxiety. Adv Mind Body Med. 2014;28(3):6-13.