Endogenous Regeneration Mechanisms of the Heart

Objectives

We like to advance the knowledge on endogenous regenerative capacity of the heart in response to ischemic heart disease, cancer and chemotherapy induced cardiac damage, pregnancy associated heart failure and catecholamine-induced cardiac cell death. Hereby, we focus on the cross talk among cardiac cells, the potential of secreted factors, non-coding RNAs and small molecule therapies. Moreover, we carefully analyze the regenerative potential of the adult heart with regard to the cardiac micromilieu. More recently, we embarked into preventive research using epidemiological studies to analyze the role physical exercise and of secreted factors by the gut microbiome for the regenerative potential of the cardiovascular system.

Milestones: 

  • Understand the pathophysiology of lost regenerative capacity of the heart with regard to the microcirculation, cardiac fat deposition and comorbidities such as cancer, catecholamine stress and pregnancy stress.
  • Identify novel biomarkers to access the regenerative potential of the heart and identify novel therapeutic targets to improve endogenous cardiac regeneration, for example by improving the cardiac microenvironment. 
  • Evaluate the influence of development and sex as well as genomics, proteomics and metabolomics with regard to the endogenous regeneration.
  • Reflect all of these in translational studies using epidemiological and clinical data from patient registries (PPCM registry) and cohort studies (Rebirth Active men and women) as well as biobank material data.

Research Focus

The regenerative capacity of an organ depends on how good its endogenous repair mechanisms function is. In the adult heart endogenous regeneration ability is in general low and consists mainly on improved vascularization and specific fibroblast phenotypes. Those are coordinated by complex inter- and intracellular signaling networks involving myocytes, endothelial cells, fibroblasts and progenitor cells. Paracrine mediators released by these cardiac cells acting locally and systemically, orchestrate endogenous healing and regeneration of the injured heart. In REBIRTH 1, we discovered several chemokines, cytokines, and growth factors (e.g., CCL2, EPO, 16kDa Prolactin) as critical paracrine modulators of cardiac healing, regeneration and remodeling. In REBIRTH 2 we discovered that specific pathomechanisms such as catecholamine stress, inflammation, cancer or sedentary lifestyle limit the regenerative capacity of the heart and of the entire cardiovascular system. We discovered that metabolic impairment and insulin signaling play crucial roles hereby. Moreover, we also discovered that specific biomarkers, for example the plasminogen activator inhibitor-1 (PAI-1) and certain microRNAs indicate the risk for disease and may serve at the same time as therapeutic targets to prevent cardiovascular damage and improve regeneration. Moreover, we discovered that the genetic background respectively mutation in cardiac genes are modulators of the regenerative capacity.

Finally, we completed investigator initiated clinical studies on peripartum cardiomyopathy proving the efficacy of adding the prolactin blocker bromocriptine to standard heart failure medication as an efficient therapy to promote healing and to prevent peripartum cardiomyopathy in patients at risk. These observations will be included this year in the new guidelines on treatment of PPCM.

Finally, from our involvement in the regenerative training strategies we learned how powerful physical exercise can enhance regenerative capacity and that factors like systemic inflammation are limiting it.

Main future aims are to investigate genetic and epigenetic risk factors and the influence of comorbidities for acute and longterm damage of the cardiovascular system. Biomarkers to predict longterm damage and small molecular approaches to improve regeneration will be developed.

Furthermore, we include the effect of comorbidities, i.e. cancer, metabolic syndrome, in our research concept. We will also analyze the role of the development stage and gender. Finally, we modify our research concepts so that our cell culture based approaches rely also on human iPSC derived cardiac cells, that we include also living human cardiac tissue slices (which we can freeze alive). We will use animal models but mainly will reflect on patient and cohort study data and biobank material.

Collaborations

Publications

2013 - ongoing

2017

Hilfiker-Kleiner D, Haghikia A, Berliner D, Vogel-Claussen J, Schwab J, Franke A, Schwarzkopf M, Ehlermann P, Pfister R, Michels G, Westenfeld R, Stangl V, Kindermann I, Kuhl U, Angermann CE, Schlitt A, Fischer D, Podewski E, Bohm M, Sliwa K, Bauersachs J. Bromocriptine for the treatment of peripartum cardiomyopathy: a multicentre randomized study. Eur Heart J. 2017/09/25 ed2017. p. 2671-9.

Sieve I, Munster-Kuhnel AK, Hilfiker-Kleiner D. Regulation and function of endothelial glycocalyx layer in vascular diseases. Vascul Pharmacol. 2017/09/19 ed2017.

Thackeray JT, Pietzsch S, Stapel B, Ricke-Hoch M, Lee CW, Bankstahl JP, Scherr M, Heineke J, Scharf G, Haghikia A, Bengel FM, Hilfiker-Kleiner D. Insulin supplementation attenuates cancer-induced cardiomyopathy and slows tumor disease progression. JCI Insight. 2017/05/19 ed2017.

Nonhoff J, Ricke-Hoch M, Mueller M, Stapel B, Pfeffer T, Kasten M, Scherr M, von Kaisenberg C, Bauersachs J, Haghikia A, Hilfiker-Kleiner D. Serelaxin treatment promotes adaptive hypertrophy but does not prevent heart failure in experimental peripartum cardiomyopathy. Cardiovasc Res. 2017;113(6):598-608. Epub 2017/04/30.

Hilfiker-Kleiner D, Haghikia A, Masuko D, Nonhoff J, Held D, Libhaber E, Petrie MC, Walker NL, Podewski E, Berliner D, Bauersachs J, Sliwa K. Outcome of subsequent pregnancies in patients with a history of peripartum cardiomyopathy. Eur J Heart Fail. 2017/03/28 ed2017.

2016

Ware JS, Li J, Mazaika E, Yasso CM, DeSouza T, Cappola TP, Tsai EJ, Hilfiker-Kleiner D, Kamiya CA, Mazzarotto F, Cook SA, Halder I, Prasad SK, Pisarcik J, Hanley-Yanez K, Alharethi R, Damp J, Hsich E, Elkayam U, Sheppard R, Kealey A, Alexis J, Ramani G, Safirstein J, Boehmer J, Pauly DF, Wittstein IS, Thohan V, Zucker MJ, Liu P, Gorcsan J, 3rd, McNamara DM, Seidman CE, Seidman JG, Arany Z, Imac, Investigators I. Shared Genetic Predisposition in Peripartum and Dilated Cardiomyopathies. The New England journal of medicine. 2016;374(3):233-41.

Stapel B, Kohlhaas M, Ricke-Hoch M, Haghikia A, Erschow S, Knuuti J, Silvola JM, Roivainen A, Saraste A, Nickel AG, Saar JA, Sieve I, Pietzsch S, Muller M, Bogeski I, Kappl R, Jauhiainen M, Thackeray JT, Scherr M, Bengel FM, Hagl C, Tudorache I, Bauersachs J, Maack C, Hilfiker-Kleiner D. Low STAT3 expression sensitizes to toxic effects of beta-adrenergic receptor stimulation in peripartum cardiomyopathy. European heart journal. 2016.

Lux M, Andree B, Horvath T, Nosko A, Manikowski D, Hilfiker-Kleiner D, Haverich A, Hilfiker A. In vitro maturation of large-scale cardiac patches based on a perfusable starter matrix by cyclic mechanical stimulation. Acta biomaterialia. 2016;30:177-87.

Hartmann D, Fiedler J, Sonnenschein K, Just A, Pfanne A, Zimmer K, Remke J, Foinquinos A, Butzlaff M, Schimmel K, Maegdefessel L, Hilfiker-Kleiner D, Lachmann N, Schober A, Froese N, Heineke J, Bauersachs J, Batkai S, Thum T. MicroRNA-Based Therapy of GATA2-Deficient Vascular Disease. Circulation. 2016;134(24):1973-90.

2015

Haghikia A, Rontgen P, Vogel-Claussen J, Schwab J, Westenfeld R, Ehlermann P, Berliner D, Podewski E, Hilfiker-Kleiner D, Bauersachs J. Prognostic implication of right ventricular involvement in peripartum cardiomyopathy: a cardiovascular magnetic resonance study. ESC heart failure. 2015;2(4):139-49.

Haghikia A, Kaya Z, Schwab J, Westenfeld R, Ehlermann P, Bachelier K, Oettl R, von Kaisenberg CS, Katus HA, Bauersachs J, Hilfiker-Kleiner D. Evidence of autoantibodies against cardiac troponin I and sarcomeric myosin in peripartum cardiomyopathy. Basic research in cardiology. 2015;110(6):60.

Hilfiker-Kleiner D. 'Social freezing' of women's eggs. Eur Heart J. 2015 Apr 1;36(13):773. (no REBIRTH-acknowledgement)

Ware J S, M R C P, Li J, Mazaika E, Yasso C M, DeSouza T, Cappola T, Tsai E J, Hilfiker-Kleiner D, Kamiya C A, Mazzarotto F, Cook S A, Halder I, Prasad S K, Pisarcik J, Hanley-Yanez K, Alharethi R, Damp J, Hsich E, Elkayam U, Sheppard R, Kealey A, Alexis J, Ramani G, Safirstein J, Boehmer J, Pauly D F, Wittstein I S, Thohan V, Zucker M J, Liu P, Gorcsan J, McNamara D M, Seidman C E, Seidman J G, Arany Z. Shared Genetic Etiology of Peripartum and Dilated Cardiomyopathies. N Engl J Med. 2015 Nov. Excepted for publication.

Westhoff-Bleck M, Hilfiker-Kleiner D. Marfan Syndrome and Pregnancy:Monitoring and Management. Eur Heart J. 2015;36(18):1066-7. Epub 2015/07/08.

Sliwa K, Hilfiker-Kleiner D. Cord Blood Samples: A Less Explored Tool in Early Diagnosis of Neonatal Cardiovascular Disease. J Am Coll Cardiol. 2015;66(8):940-2.

Schiffer M, Teng B, Gu C, Shchedrina VA, Kasaikina M, Pham VA, Hanke N, Rong S, Gueler F, Schroder P, Tossidou I, Park JK, Staggs L, Haller H, Erschow S, Hilfiker-Kleiner D, Wei C, Chen C, Tardi N, Hakroush S, Selig MK, Vasilyev A, Merscher S, Reiser J, Sever S. Pharmacological Targeting of Actin-Dependent Dynamin Oligomerization Ameliorates Chronic Kidney Disease in Diverse Animal Models. Nat Med. 2015;21(6):601-9.

Lux M, Andree B, Horvath T, Nosko A, Manikowski D, Hilfiker-Kleiner D, Haverich A, Hilfiker A. In Vitro Maturation of Large-Scale Cardiac Patches Based on a Perfusable Starter Matrix by Cyclic Mechanical Stimulation. Acta Biomater. 2015.

Hilfiker-Kleiner D, Westhoff-Bleck M, Gunter HH, von Kaisenberg CS, Bohnhorst B, Hoeltje M, Kuehn C. A Management Algorithm for Acute Heart Failure in Pregnancy. The Hannover Experience. Eur Heart J. 2015;36(13):769-70.

Hilfiker-Kleiner D, Haghikia A, Nonhoff J, Bauersachs J. Peripartum Cardiomyopathy: Current Management and Future Perspectives. Eur Heart J. 2015;36(18):1090-7.

Hilfiker-Kleiner D. Pregnancy Hormones in Cardiovascular Disease. Eur Heart J. 2015;36(18):1064-6.

Haghikia A, Podewski E, Berliner D, Sonnenschein K, Fischer D, Angermann CE, Bohm M, Rontgen P, Bauersachs J, Hilfiker-Kleiner D. Rationale and Design of a Randomized, Controlled Multicentre Clinical Trial to Evaluate the Effect of Bromocriptine on Left Ventricular Function in Women with Peripartum Cardiomyopathy. Clin Res Cardiol. 2015;104(11):911-7.

Haghikia A, Kaya Z, Schwab J, Westenfeld R, Ehlermann P, Bachelier K, Oettl R, von Kaisenberg CS, Katus HA, Bauersachs J, Hilfiker-Kleiner D. Evidence of Autoantibodies against Cardiac Troponin I and Sarcomeric Myosin in Peripartum Cardiomyopathy. Basic Res Cardiol. 2015;110(6):60.

Dutzmann J, Daniel JM, Bauersachs J, Hilfiker-Kleiner D, Sedding DG. Emerging Translational Approaches to Target Stat3 Signalling and Its Impact on Vascular Disease. Cardiovasc Res. 2015;106(3):365-74.

Duncker D, Bauersachs J, Hilfiker-Kleiner D, Veltmann C. Underestimated Risk for Life-Threatening Ventricular Arrhythmias in Newly Diagnosed Peripartum Cardiomyopathy? Eur Heart J. 2015;36(18):1067-8.

2014

Vukadinovic-Nikolic Z, Andree B, Dorfman SE, Pflaum M, Horvath T, Lux M, Venturini L, Bar A, Kensah G, Lara AR, Tudorache I, Cebotari S, Hilfiker-Kleiner D, Haverich A, Hilfiker A. Generation of Bioartificial Heart Tissue by Combining a Three-Dimensional Gel-Based Cardiac Construct with Decellularized Small Intestinal Submucosa. Tissue Engineering Part A. 2014;20(3-4):799-809.

van Spaendonck-Zwarts KY, Posafalvi A, van den Berg MP, Hilfiker-Kleiner D, Bollen IAE, Sliwa K, Alders M, Almomani R, van Langen IM, van der Meer P, Sinke RJ, van der Velden J, Van Veldhuisen DJ, van Tintelen JP, Jongbloed JDH. Titin Gene Mutations Are Common in Families with Both Peripartum Cardiomyopathy and Dilated Cardiomyopathy. European Heart Journal. 2014;35(32):2165-73.

Tarone G, Balligand JL, Bauersachs J, Clerk A, De Windt L, Heymans S, Hilfiker-Kleiner D, Hirsch E, Iaccarino G, Knoll R, Leite-Moreira AF, Lourenco AP, Mayr M, Thum T, Tocchetti CG. Targeting Myocardial Remodelling to Develop Novel Therapies for Heart Failure a Position Paper from the Working Group on Myocardial Function of the European Society of Cardiology. European Journal of Heart Failure. 2014;16(5):494-508.

Springer J, Tschirner A, Haghikia A, von Haehling S, Lal H, Grzesiak A, Kaschina E, Palus S, Ptsch M, von Websky K, Hocher B, Latouche C, Jaisser F, Morawietz L, Coats AJS, Beadle J, Argiles JM, Thum T, Flodes G, Doehner W, Hilfiker-Kleiner D, Force T, Anker SD. Prevention of Liver Cancer Cachexia-Induced Cardiac Wasting and Heart Failure. European Heart Journal. 2014;35(14):932-+.

Sliwa K, Hilfiker-Kleiner D, Mebazaa A, Petrie MC, Maggioni AP, Regitz-Zagrosek V, Schaufelberger M, Tavazzi L, van Veldhuisen DJ, Roos-Hesslink JW, Shah AJ, Seferovic PM, Elkayam U, van Spaendonck-Zwarts K, Bachelier-Walenta K, Mouquet F, Kraigher-Krainer E, Hall R, Ponikowski P, McMurray JJV, Pieske B. Eurobservational Research Programme: A Worldwide Registry on Peripartum Cardiomyopathy (Ppcm) in Conjunction with the Heart Failure Association of the European Society of Cardiology Working Group on Ppcm. European Journal of Heart Failure. 2014;16(5):583-91.

Scherr M, Elder A, Battmer K, Barzan D, Bomken S, Ricke-Hoch M, Schroder A, Venturini L, Blair HJ, Vormoor J, Ottmann O, Ganser A, Pich A, Hilfiker-Kleiner D, Heidenreich O, Eder M. Differential Expression of Mir-17 Similar to 92 Identifies Bcl2 as a Therapeutic Target in Bcr-Abl-Positive B-Lineage Acute Lymphoblastic Leukemia. Leukemia. 2014;28(3):554-65.

Ricke-Hoch M, Bultmann I, Stapel B, Condorelli G, Rinas U, Sliwa K, Scherr M, Hilfiker-Kleiner D. Opposing Roles of Akt and Stat3 in the Protection of the Maternal Heart from Peripartum Stress. Cardiovascular Research. 2014;101(4):587-96.

Radke MB, Taft MH, Stapel B, Hilfiker-Kleiner D, Preller M, Manstein DJ. Small Molecule-Mediated Refolding and Activation of Myosin Motor Function. Elife. 2014;3.

Melk A, Tegtbur U, Hilfiker-Kleiner D, Eberhard J, Saretzki G, Eulert C, Kerling A, Nelius AK, Homme M, Strunk D, Berliner D, Rontgen P, Kuck M, Bauersachs J, Hilfiker A, Haverich A, Bara C, Stiesch M. Improvement of Biological Age by Physical Activity. International Journal of Cardiology. 2014;176(3):1187-9.

Leite-Moreira AF, Lourenco AP, Balligand JL, Bauersachs J, Clerk A, De Windt LJ, Heymans S, Hilfiker-Kleiner D, Hirsch E, Iaccarino G, Kaminski KA, Knoll R, Mayr M, Tarone G, Thum T, Tocchetti CG. Esc Working Group on Myocardial Function Position Paper: How to Study the Right Ventricle in Experimental Models. European Journal of Heart Failure. 2014;16(5):509-18.

Kiyan Y, Tkachuk S, Hilfiker-Kleiner D, Haller H, Fuhrman B, Dumler I. Oxldl Induces Inflammatory Responses in Vascular Smooth Muscle Cells Via Urokinase Receptor Association with Cd36 and Tlr4. Journal of Molecular and Cellular Cardiology. 2014;66:72-82.

Hilfiker-Kleiner D, Sliwa K. Pathophysiology and Epidemiology of Peripartum Cardiomyopathy. Nature Reviews Cardiology. 2014;11(6):364-70.

Hilfiker-Kleiner D, Arany Z. Focus on Pregnancy-Mediated Heart and Vascular Disease. Cardiovascular Research. 2014;101(4):543-4.

Haghikia A, Ricke-Hoch M, Stapel B, Gorst I, Hilfiker-Kleiner D. Stat3, a Key Regulator of Cell-to-Cell Communication in the Heart. Cardiovascular Research. 2014;102(2):281-9.

Eberhard J, Stiesch M, Kerling A, Bara C, Eulert C, Hilfiker-Kleiner D, Hilfiker A, Budde E, Bauersachs J, Kuck M, Haverich A, Melk A, Tegtbur U. Moderate and Severe Periodontitis Are Independent Risk Factors Associated with Low Cardiorespiratory Fitness in Sedentary Non-Smoking Men Aged between 45 and 65 Years. Journal of Clinical Periodontology. 2014;41(1):31-7.

Duncker D, Haghikia A, Konig T, Hohmann S, Gutleben KJ, Westenfeld R, Oswald H, Klein H, Bauersachs J, Hilfiker-Kleiner D, Veltmann C. Risk for Ventricular Fibrillation in Peripartum Cardiomyopathy with Severely Reduced Left Ventricular Function-Value of the Wearable Cardioverter/Defibrillator. Eur J Heart Fail. 2014;16(12):1331-6.

Chowdhury A, Herzog C, Hasselbach L, Khouzani HL, Zhang J, Hammerschmidt M, Rudat C, Kispert A, Gaestel M, Menon MB, Tudorache I, Hilfiker-Kleiner D, Muhlfeld C, Schmitto JD, Muller M, Theilmeier G. Expression of Fibulin-6 in Failing Hearts and Its Role for Cardiac Fibroblast Migration. Cardiovasc Res. 2014;103(4):509-20.

Belge C, Hammond J, Dubois-Deruy E, Manoury B, Hamelet J, Beauloye C, Markl A, Pouleur AC, Bertrand L, Esfahani H, Jnaoui K, Gotz KR, Nikolaev VO, Vanderper A, Herijgers P, Lobysheva I, Iaccarino G, Hilfiker-Kleiner D, Tavernier G, Langin D, Dessy C, Balligand JL. Enhanced Expression of Beta 3-Adrenoceptors in Cardiac Myocytes Attenuates Neurohormone-Induced Hypertrophic Remodeling through Nitric Oxide Synthase. Circulation. 2014;129(4):451-62.

2013

Veldink H, Faulhaber-Walter R, Park JK, Martens-Lobenhoffer J, Bode-Boger S, Schuett H, Haghikia A, Hilfiker-Kleiner D, Kielstein JT. Effects of Chronic Sdma Infusion on Glomerular Filtration Rate, Blood Pressure, Myocardial Function and Renal Histology in C57bl6/J Mice. Nephrology Dialysis Transplantation. 2013;28(6):1434-9.

Mueller M, Herzog C, Larmann J, Schmitz M, Hilfiker-Kleiner D, Gessner JE, Theilmeier G. The Receptor for Activated Complement Factor 5 (C5ar) Conveys Myocardial Ischemic Damage by Mediating Neutrophil Transmigration. Immunobiology. 2013;218(9):1131-8.

Hermida N, Markl A, Hamelet J, Van Assche T, Vanderper A, Herijgers P, van Bilsen M, Hilfiker-Kleiner D, Noppe G, Beauloye C, Horman S, Balligand JL. Hmgcoa Reductase Inhibition Reverses Myocardial Fibrosis and Diastolic Dysfunction through Amp-Activated Protein Kinase Activation in a Mouse Model of Metabolic Syndrome. Cardiovascular Research. 2013;99(1):44-54.

Halkein J, Tabruyn SR, Ricke-Hoch M, Haghikia A, Nguyen NQN, Scherr M, Castermans K, Malvaux L, Lambert V, Thiry M, Sliwa K, Noel A, Martial JA, Hilfiker-Kleiner D, Struman I. Microrna-146a Is a Therapeutic Target and Biomarker for Peripartum Cardiomyopathy. Journal of Clinical Investigation. 2013;123(5):2143-54.

Haghikia A, Podewski E, Libhaber E, Labidi S, Fischer D, Roentgen P, Tsikas D, Jordan J, Lichtinghagen R, von Kaisenberg CS, Struman I, Bovy N, Sliwa K, Bauersachs J, Hilfiker-Kleiner D. Phenotyping and Outcome on Contemporary Management in a German Cohort of Patients with Peripartum Cardiomyopathy. Basic Research in Cardiology. 2013;108(4).

El Hasnaoui-Saadani R, Marchant D, Pichon A, Escoubet B, Pezet M, Hilfiker-Kleiner D, Hoch M, Pham I, Quidu P, Voituron N, Journe C, Richalet JP, Favret F. Epo Deficiency Alters Cardiac Adaptation to Chronic Hypoxia. Respiratory Physiology & Neurobiology. 2013;186(2):146-54.

2006 - 2012

2012

Yndestad A, Finsen AV, Ueland T, Husberg C, Dahl CP, Oie E, Vinge LE, Sjaastad I, Sandanger O, Ranheim T, Dickstein K, Kjekshus J, Damas JK, Fiane AE, Hilfiker-Kleiner D, Lipp M, Gullestad L, Christensen G, Aukrust P. The Homeostatic Chemokine Ccl21 Predicts Mortality and May Play a Pathogenic Role in Heart Failure. Plos One. 2012;7(3).

Walenta K, Schwarz V, Schirmer SH, Kindermann I, Friedrich EB, Solomayer EF, Sliwa K, Labidi S, Hilfiker-Kleiner D, Bohm M. Circulating Microparticles as Indicators of Peripartum Cardiomyopathy. European Heart Journal. 2012;33(12):1469-79.

Lindner D, Hilbrandt M, Marggraf K, Becher PM, Hilfiker-Kleiner D, Klingel K, Pauschinger M, Schultheiss H-P, Tschöpe C, Westermann D. Protective Function of Stat3 in Cvb3-Induced Myocarditis. Cardiology Research and Practice. 2012;2012:11.

Arany Z, Patten I, Rana S, Shahul S, Rowe G, Jang C, Liu L, Hacker M, Rhee J, Mitchell J, Mahmood F, Hess P, Farrell C, Koulisis N, Khankin E, Burke S, Tudorache I, Bauersachs J, del Monte F, Hilfiker-Kleiner D, Karumanchi A. Cardiac Angiogenic Imbalance Leads to Peripartum Cardiomyopathy. Circulation Research. 2012;111(4).

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