Associations of Plasma Bioactive Adrenomedullin Levels with Cardiovascular Risk Factors in BRCA1/2 Mutation Carriers

Jacqueline Lammert; Maryam Basrai; Joachim Struck; Oliver Hartmann; Christoph Engel; Stephan C. Bischoff; Anika Berling-Ernst; Martin Halle; Marion Kiechle; Sabine Grill

doi:10.1055/a-1811-2164

GebFra - DGGG-Gesellschaftsausgaben, Table of Contents

CC BY-NC-ND 4.0 · Geburtshilfe Frauenheilkd 2022; 82(06): 601-609
DOI: 10.1055/a-1811-2164

GebFra Science

Original Article

Associations of Plasma Bioactive Adrenomedullin Levels with Cardiovascular Risk Factors in BRCA1/2 Mutation Carriers

Zusammenhang zwischen bioaktivem Adrenomedullin-Spiegel und kardiovaskulären Risikofaktoren bei BRCA1/2-Mutationsträgerinnen

Jacqueline Lammert

¹Department of Gynecology and Center for Hereditary Breast and Ovarian Cancer, University Hospital rechts der Isar, Technical University of Munich (TUM), Munich, Germany

,

Maryam Basrai

²Institute of Nutritional Medicine, University of Hohenheim, Stuttgart, Germany

,

Joachim Struck

³Sphingotec GmbH, Hennigsdorf, Germany

,

Oliver Hartmann

³Sphingotec GmbH, Hennigsdorf, Germany

,

Christoph Engel

⁴Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany

,

Stephan C. Bischoff

²Institute of Nutritional Medicine, University of Hohenheim, Stuttgart, Germany

,

Anika Berling-Ernst

⁵Department of Prevention and Sports Medicine, University Hospital Klinikum rechts der Isar, Technical University of Munich, Munich, Germany

,

Martin Halle

⁵Department of Prevention and Sports Medicine, University Hospital Klinikum rechts der Isar, Technical University of Munich, Munich, Germany

,

Marion Kiechle

¹Department of Gynecology and Center for Hereditary Breast and Ovarian Cancer, University Hospital rechts der Isar, Technical University of Munich (TUM), Munich, Germany

,

Sabine Grill

¹Department of Gynecology and Center for Hereditary Breast and Ovarian Cancer, University Hospital rechts der Isar, Technical University of Munich (TUM), Munich, Germany

› Author Affiliations

Abstract

Background Cardiovascular disease (CVD) is an important cause of morbidity and mortality in breast cancer survivors. Effective screening modalities to identify CVD risk are lacking in this population. Adrenomedullin (ADM) has been suggested as a biomarker for subclinical cardiac dysfunction in the general population. Levels of ADM have been proven to be responsive to lifestyle changes that lead to improved cardiovascular health. As BRCA1/2 mutation carriers are deemed to be at an increased risk for CVD, the aim of this study was to examine plasma ADM levels in a cohort of BRCA mutation carriers and to assess their association with cardiovascular risk factors.

Methods Plasma ADM concentrations were measured in 292 female BRCA1/2 mutation carriers with and without a history of breast cancer. Subjects were classified into high versus low ADM levels based on the median ADM level in the entire cohort (13.8 pg/mL). Logistic regression models were used to estimate the odds ratios (OR) of having elevated ADM levels by several cardiovascular risk factors.

Results Of all women (median age: 43 years), 57.5% had a previous diagnosis of breast cancer. The median time between diagnosis and study entry was three years (range: 0 – 32 years). Women presenting with metabolic syndrome had 22-fold increased odds of having elevated ADM levels (p < 0.001). Elevated ADM levels were associated with lower cardiorespiratory fitness (OR = 0.88, p < 0.001) and several parameters of obesity (p < 0.001). ADM levels were higher in women who have ever smoked (OR = 1.72, p = 0.02). ADM levels were not associated with a previous diagnosis of breast cancer (p = 0.28).

Conclusions This is the first study in BRCA mutation carriers that has linked circulating ADM levels to traditional cardiovascular risk factors. The long-term clinical implications of these findings are yet to be determined.

Zusammenfassung

Hintergrund Herz-Kreislauf-Erkrankungen (HKE) sind eine wichtige Ursache für Morbidität und Mortalität bei Brustkrebsüberlebenden. Es fehlt aber an effektiven Früherkennungsuntersuchungen, welche die HKE-Risiken in dieser Population identifizieren könnten. Adrenomedullin (ADM) wurde bereits als möglicher Biomarker für subklinische Herzerkrankungen in der Allgemeinbevölkerung vorgeschlagen. Es hat sich gezeigt, dass Lebensstiländerungen, die zu einer Verbesserung der kardiovaskulären Gesundheit führen, sich in ADM-Plasmakonzentrationen widerspiegeln. Da Trägerinnen von BRCA1/2-Mutationen ein erhöhtes HKE-Risiko haben, zielt diese Studie darauf ab, die ADM-Plasmakonzentrationen in einer Gruppe von BRCA-Mutationsträgerinnen zu messen und den Zusammenhang mit HKE-Risikofaktoren zu untersuchen.

Methoden ADM-Plasmakonzentrationen wurden in 292 BRCA1/2-Mutationsträgerinnen mit oder ohne frühere Brustkrebsdiagnose gemessen. Basierend auf der medianen ADM-Konzentration der Gesamtgruppe (13,8 pg/ml) wurden die untersuchten Frauen gemäß ihrer ADM-Konzentrationen in 2 Gruppen (hohe bzw. niedrige ADM-Konzentration) eingeteilt. Logistische Regressionsmodelle wurden verwendet, um das Chancenverhältnis (OR) verschiedener kardiovaskulärer Risikofaktoren in Abhängigkeit der Höhe der ADM-Konzentration zu schätzen.

Ergebnisse Bei 57,5% der Frauen (Durchschnittsalter: 43 Jahre) wurde zuvor Brustkrebs diagnostiziert. Die mediane Zeit zwischen der Krebsdiagnose und die Aufnahme in dieser Studie betrug 3 Jahre (Spanne: 0 – 32 Jahre). Frauen mit metabolischem Syndrom hatten eine 22-fach höhere Wahrscheinlichkeit eines erhöhten ADM-Spiegels (p < 0,001). Erhöhte ADM-Spiegel waren mit niedriger kardiorespiratorischer Fitness (OR = 0,88, p < 0,001) sowie verschiedenen Übergewichtsparametern (p < 0,001) assoziiert. Der ADM-Spiegel war höher bei Frauen, die rauchten bzw. früher geraucht hatten (OR = 1,72, p = 0,02). Es gab kein Zusammenhang zwischen ADM-Konzentrationen und einer früheren Brustkrebsdiagnose (p = 0,28).

Schlussfolgerungen Dies ist die erste Studie von BRCA-Mutationsträgerinnen, welche die Verbindung zwischen ADM-Plasmakonzentrationen und traditionellen kardiovaskulären Risikofaktoren untersucht. Die langfristigen klinischen Implikationen der Befunde müssen noch ermittelt werden.

Key words

BRCA1 - BRCA2 - cardiovascular risk - breast cancer survivors

Schlüsselwörter

BRCA1 - BRCA2 - kardiovaskuläres Risiko - Brustkrebsüberlebende

Full Text

References

References
1 Sturgeon KM, Deng L, Bluethmann SM. et al. A population-based study of cardiovascular disease mortality risk in US cancer patients. Eur Heart J 2019; 40: 3889-3897
2 Blaes AH, Konety SH. Cardiovascular Disease in Breast Cancer Survivors: An Important Topic in Breast Cancer Survivorship. J Natl Cancer Inst 2021; 113: 105-106
3 Patnaik JL, Byers T, DiGuiseppi C. et al. Cardiovascular disease competes with breast cancer as the leading cause of death for older females diagnosed with breast cancer: a retrospective cohort study. Breast Cancer Res 2011; 13: R64
4 Kirkham AA, Beaudry RI, Paterson DI. et al. Curing breast cancer and killing the heart: A novel model to explain elevated cardiovascular disease and mortality risk among women with early stage breast cancer. Prog Cardiovasc Dis 2019; 62: 116-126
5 Mehta LS, Watson KE, Barac A. et al. Cardiovascular Disease and Breast Cancer: Where These Entities Intersect: A Scientific Statement From the American Heart Association. Circulation 2018; 137: e30-e66
6 Koelwyn GJ, Newman AAC, Afonso MS. et al. Myocardial infarction accelerates breast cancer via innate immune reprogramming. Nat Med 2020; 26: 1452-1458
7 Johnson CB, Davis MK, Law A. et al. Shared Risk Factors for Cardiovascular Disease and Cancer: Implications for Preventive Health and Clinical Care in Oncology Patients. Can J Cardiol 2016; 32: 900-907
8 Gernaat SAM, Ho PJ, Rijnberg N. et al. Risk of death from cardiovascular disease following breast cancer: a systematic review. Breast Cancer Res Treat 2017; 164: 537-555
9 Gernaat SAM, Boer JMA, van den Bongard DHJ. et al. The risk of cardiovascular disease following breast cancer by Framingham risk score. Breast Cancer Res Treat 2018; 170: 119-127
10 Park NJ, Chang Y, Bender C. et al. Cardiovascular disease and mortality after breast cancer in postmenopausal women: Results from the Womenʼs Health Initiative. PLoS One 2017; 12: e0184174
11 Gulati M, Mulvagh SL. The connection between the breast and heart in a woman: Breast cancer and cardiovascular disease. Clin Cardiol 2018; 41: 253-257
12 Gernaat SA, Isgum I, de Vos BD. et al. Automatic Coronary Artery Calcium Scoring on Radiotherapy Planning CT Scans of Breast Cancer Patients: Reproducibility and Association with Traditional Cardiovascular Risk Factors. PLoS One 2016; 11: e0167925
13 Abdel-Qadir H, Thavendiranathan P, Austin PC. et al. Development and validation of a multivariable prediction model for major adverse cardiovascular events after early stage breast cancer: a population-based cohort study. Eur Heart J 2019; 40: 3913-3920
14 Lyngbakken MN, Myhre PL, Rosjo H. et al. Novel biomarkers of cardiovascular disease: Applications in clinical practice. Crit Rev Clin Lab Sci 2019; 56: 33-60
15 Funke-Kaiser A, Havulinna AS, Zeller T. et al. Predictive value of midregional pro-adrenomedullin compared to natriuretic peptides for incident cardiovascular disease and heart failure in the population-based FINRISK 1997 cohort. Ann Med 2014; 46: 155-162
16 Melander O, Newton-Cheh C, Almgren P. et al. Novel and conventional biomarkers for prediction of incident cardiovascular events in the community. JAMA 2009; 302: 49-57
17 Kawano S, Kawagoe Y, Kuwasako K. et al. Gender-related alterations in plasma adrenomedullin level and its correlation with body weight gain. Endocr Connect 2015; 4: 43-49
18 Vila G, Riedl M, Maier C. et al. Plasma MR-proADM correlates to BMI and decreases in relation to leptin after gastric bypass surgery. Obesity (Silver Spring) 2009; 17: 1184-1188
19 Ohlsson T, Nilsson PM, Persson M. et al. Midregional proadrenomedullin predicts reduced blood pressure and glucose elevation over time despite enhanced progression of obesity markers. J Hypertens 2019; 37: 590-595
20 Eggers KM, Venge P, Lindahl B. et al. Associations of mid-regional pro-adrenomedullin levels to cardiovascular and metabolic abnormalities, and mortality in an elderly population from the community. Int J Cardiol 2013; 168: 3537-3542
21 Kuchenbaecker KB, Hopper JL, Barnes DR. et al. Risks of Breast, Ovarian, and Contralateral Breast Cancer for BRCA1 and BRCA2 Mutation Carriers. JAMA 2017; 317: 2402-2416
22 Sajjad M, Fradley M, Sun W. et al. An Exploratory Study to Determine Whether BRCA1 and BRCA2 Mutation Carriers Have Higher Risk of Cardiac Toxicity. Genes (Basel) 2017; 8: 59
23 Hubner J, Katalinic A, Waldmann A. et al. Long-term Incidence and Mortality Trends for Breast Cancer in Germany. Geburtshilfe Frauenheilkd 2020; 80: 611-618
24 Metcalfe K, Gershman S, Lynch HT. et al. Predictors of contralateral breast cancer in BRCA1 and BRCA2 mutation carriers. Br J Cancer 2011; 104: 1384-1392
25 Metcalfe K, Lynch HT, Ghadirian P. et al. Risk of ipsilateral breast cancer in BRCA1 and BRCA2 mutation carriers. Breast Cancer Res Treat 2011; 127: 287-296
26 Hodgson A, Turashvili G. Pathology of Hereditary Breast and Ovarian Cancer. Front Oncol 2020; 10: 531790
27 Ditsch N, Stickeler E, Behrens A. et al. Update Breast Cancer 2021 Part 2 – Advanced Stages, Long-Term Consequences and Biomarkers. Geburtshilfe Frauenheilkd 2021; 81: 539-548
28 Schneeweiss A, Hartkopf AD, Muller V. et al. Update Breast Cancer 2020 Part 1 – Early Breast Cancer: Consolidation of Knowledge About Known Therapies. Geburtshilfe Frauenheilkd 2020; 80: 277-287
29 Gordon T, Kannel WB, Hjortland MC. et al. Menopause and coronary heart disease. The Framingham Study. Ann Intern Med 1978; 89: 157-161
30 Gordhandas S, Norquist BM, Pennington KP. et al. Hormone replacement therapy after risk reducing salpingo-oophorectomy in patients with BRCA1 or BRCA2 mutations; a systematic review of risks and benefits. Gynecol Oncol 2019; 153: 192-200
31 Arts-de Jong M, Maas AH, Massuger LF. et al. BRCA1/2 mutation carriers are potentially at higher cardiovascular risk. Crit Rev Oncol Hematol 2014; 91: 159-171
32 Gast KC, Viscuse PV, Nowsheen S. et al. Cardiovascular Concerns in BRCA1 and BRCA2 Mutation Carriers. Curr Treat Options Cardiovasc Med 2018; 20: 18
33 van Westerop LL, Arts-de Jong M, Hoogerbrugge N. et al. Cardiovascular risk of BRCA1/2 mutation carriers: A review. Maturitas 2016; 91: 135-139
34 Powell CB, Alabaster A, Armstrong MA. et al. Risk of cardiovascular disease in women with BRCA1 and BRCA2 mutations. Gynecol Oncol 2018; 151: 489-493
35 Shukla PC, Singh KK, Quan A. et al. BRCA1 is an essential regulator of heart function and survival following myocardial infarction. Nat Commun 2011; 2: 593
36 Singh KK, Shukla PC, Quan A. et al. BRCA1 is a novel target to improve endothelial dysfunction and retard atherosclerosis. J Thorac Cardiovasc Surg 2013; 146: 949-960.e4
37 Singh KK, Shukla PC, Quan A. et al. BRCA2 protein deficiency exaggerates doxorubicin-induced cardiomyocyte apoptosis and cardiac failure. J Biol Chem 2012; 287: 6604-6614
38 Kiechle M, Engel C, Berling A. et al. Lifestyle intervention in BRCA1/2 mutation carriers: study protocol for a prospective, randomized, controlled clinical feasibility trial (LIBRE-1 study). Pilot Feasibility Stud 2016; 2: 74
39 Kiechle M, Engel C, Berling A. et al. Effects of lifestyle intervention in BRCA1/2 mutation carriers on nutrition, BMI, and physical fitness (LIBRE study): study protocol for a randomized controlled trial. Trials 2016; 17: 368
40 Hebestreit K, Yahiaoui-Doktor M, Engel C. et al. Validation of the German version of the Mediterranean Diet Adherence Screener (MEDAS) questionnaire. BMC Cancer 2017; 17: 341
41 Marino R, Struck J, Maisel AS. et al. Plasma adrenomedullin is associated with short-term mortality and vasopressor requirement in patients admitted with sepsis. Crit Care 2014; 18: R34
42 Weber J, Sachse J, Bergmann S. et al. Sandwich Immunoassay for Bioactive Plasma Adrenomedullin. J Appl Lab Med 2017; 2: 222-233
43 Pavo N, Raderer M, Hulsmann M. et al. Cardiovascular biomarkers in patients with cancer and their association with all-cause mortality. Heart 2015; 101: 1874-1880
44 Neumann JT, Tzikas S, Funke-Kaiser A. et al. Association of MR-proadrenomedullin with cardiovascular risk factors and subclinical cardiovascular disease. Atherosclerosis 2013; 228: 451-459
45 Bhandari SS, Davies JE, Struck J. et al. Influence of confounding factors on plasma mid-regional pro-adrenomedullin and mid-regional pro-A-type natriuretic peptide concentrations in healthy individuals. Biomarkers 2011; 16: 281-287
46 Sahin I, Celik O, Celik N. et al. Adrenomedullin: possible predictor of insulin resistance in women with polycystic ovary syndrome. J Endocrinol Invest 2012; 35: 553-556
47 Lim SC, Morgenthaler NG, Subramaniam T. et al. The relationship between adrenomedullin, metabolic factors, and vascular function in individuals with type 2 diabetes. Diabetes Care 2007; 30: 1513-1519
48 Torres C, Lima-Martinez MM, Rosa FJ. et al. [Epicardial adipose tissue and its association to plasma adrenomedullin levels in patients with metabolic syndrome]. Endocrinol Nutr 2011; 58: 401-408
49 Kolditz M, Seyfarth HJ, Wilkens H. et al. MR-proADM Predicts Exercise Capacity and Survival Superior to Other Biomarkers in PH. Lung 2015; 193: 901-910
50 Krintus M, Kozinski M, Braga F. et al. Plasma midregional proadrenomedullin (MR-proADM) concentrations and their biological determinants in a reference population. Clin Chem Lab Med 2018; 56: 1161-1168
51 Nomura I, Kato J, Tokashiki M. et al. Increased plasma levels of the mature and intermediate forms of adrenomedullin in obesity. Regul Pept 2009; 158: 127-131
52 Del Ry S, Cabiati M, Bianchi V. et al. Mid-regional-pro-adrenomedullin plasma levels are increased in obese adolescents. Eur J Nutr 2016; 55: 1255-1260
53 Koyama T, Kuriyama N, Uehara R. Midregional Proadrenomedullin Can Reflect the Accumulation of Visceral Adipose Tissue-A Key to Explaining the Obesity Paradox. Int J Environ Res Public Health 2020; 17: 3968
54 Cespedes Feliciano EM, Chen WY, Bradshaw PT. et al. Adipose Tissue Distribution and Cardiovascular Disease Risk Among Breast Cancer Survivors. J Clin Oncol 2019; 37: 2528-2536
55 Yuyun MF, Narayan HK, Ng LL. Prognostic significance of adrenomedullin in patients with heart failure and with myocardial infarction. Am J Cardiol 2015; 115: 986-991
56 Daukantaite D, Tellhed U, Maddux RE. et al. Five-week yin yoga-based interventions decreased plasma adrenomedullin and increased psychological health in stressed adults: A randomized controlled trial. PLoS One 2018; 13: e0200518
57 Martinez A, Vos M, Guedez L. et al. The effects of adrenomedullin overexpression in breast tumor cells. J Natl Cancer Inst 2002; 94: 1226-1237
58 Oehler MK, Fischer DC, Orlowska-Volk M. et al. Tissue and plasma expression of the angiogenic peptide adrenomedullin in breast cancer. Br J Cancer 2003; 89: 1927-1933
59 Pare M, Darini CY, Yao X. et al. Breast cancer mammospheres secrete Adrenomedullin to induce lipolysis and browning of adjacent adipocytes. BMC Cancer 2020; 20: 784
60 Liu LL, Chen SL, Huang YH. et al. Adrenomedullin inhibits tumor metastasis and is associated with good prognosis in triple-negative breast cancer patients. Am J Transl Res 2020; 12: 773-786
61 Awolaran O, Brooks SA, Lavender V. Breast cancer osteomimicry and its role in bone specific metastasis; an integrative, systematic review of preclinical evidence. Breast 2016; 30: 156-171
62 Nolan E, Vaillant F, Branstetter D. et al. RANK ligand as a potential target for breast cancer prevention in BRCA1-mutation carriers. Nat Med 2016; 22: 933-939
63 Sigl V, Owusu-Boaitey K, Joshi PA. et al. RANKL/RANK control Brca1 mutation. Cell Res 2016; 26: 761-774
64 Moebus S, Hanisch J, Bramlage P. et al. Regional differences in the prevalence of the metabolic syndrome in primary care practices in Germany. Dtsch Arztebl Int 2008; 105: 207-213