Cardiovascular Research

CARDIOVASCULAR RESEARCH


Päivi Lakkisto, M.D., Ph.D., Adjunct Professor, Head
Ilkka Tikkanen, M.D., Ph.D., Professor
Mika Laine, M.D., Ph.D., Adjunct Professor
Chunguang Wang, M.D., Ph.D., Adjunct Professor
Jere Paavola, M.D., Ph.D.
Hong Wang, M.Sc., Ph.D.
Heli Segersvärd, M.D.
Karri Kalervo, M.D.
Mikko Hänninen, M.D.
Tuomas Mäntylä, M.D.
Suneeta Narumanchi, M.Sc. 
Katariina Immonen, B.Sc., Laboratory Technician
Riikka Kosonen, M.Sc., Laboratory Technician
Sanni Perttunen, B.Sc., Laboratory Technician


Our research group studies mechanisms of end-organ damage in cardiovascular and renal diseases. In addition, we evaluate the cardiovascular and renal protective properties of new cardiovascular drugs and treatments. During recent years, the group’s research has focused on exploring the molecular mechanisms of cardiac injury and repair after myocardial infarction and in heart failure, to identify potential targets for cardiovascular medicines and novel biomarkers. In these studies, a translational approach is applied, combining methods and findings of both basic science and clinical research in order to improve the evaluation and treatment of cardiovascular diseases.

CURRENT PROJECTS

New molecular mechanisms and biomarkers of cardiac injury and heart failure 

The prognosis of chronic heart failure is still poor despite optimal therapy with currently available cardiovascular drugs. Thus, deeper understanding of cellular and molecular mechanisms of cardiac failure and repair is needed to advance discovery of novel drug target molecules, as well as novel biomarkers for more personalized diagnostics and outcome prediction. We use representative heart failure patient cohorts and zebrafish cardiac disease models to elucidate the molecular mechanisms regulating the development and progression of myocardial damage. 

Septins are small GTPases that are associated with actin and are important in the organization of cytoskeleton. We have shown in collaboration with Prof. Sanna Lehtonen, HU, that septin7b, is essential for the subcellular organization of cardiomyocytes and cardiac function in zebrafish. We are continuing our studies elucidating the role of septins in cardiac recovery after myocardial injury. 

MicroRNAs are short noncoding RNA molecules widely involved in the regulation of gene expression. Circulating miRNAs have emerged as potential diagnostic and prognostic biomarkers of cardiovascular disease. Cardiogenic shock (CS) is a severe state of inadequate systemic tissue perfusion due to low cardiac output, often resulting in multi-organ failure. New biomarkers to stratify CS patients according to their risk and to optimize treatment are needed. In collaboration with Adj. Prof. Veli-Pekka Harjola, HUCH, and Dr. Yvan Devaux, the Luxembourg Institute of Health, Luxembourg we have identified several potential miRNA biomarker candidates using microarray profiling. We have shown that high plasma levels of miR-423-5p, miR-21-5p and miR-320a-3p are independent predictors of mortality indicating potential of miRNAs as biomarkers for risk assessment in CS.

We are using the cardiac cryoinfarction model in adult zebrafish to study the effects of micro-RNAs on cardiac regeneration and repair. We have validated protocols for efficient delivery on Mirs and Antagomirs to the adult zebrafish. This method enables the study of molecules and pathways related to cardiac repair in a fast-growing, affordable model organism with an amazing regenerative capacity. Additionally, we have developed drug-induced cardiac hypertrophy/ heart failure models in embryonic and adult zebrafish. With easy delivery of drugs and methodology for gene silencing, including CRISPR/Cas9-mediated gene editing, our models will provide a robust platform for studying the development of cardiac hypertrophy and heart failure, as well as factors affecting recovery of cardiac function from heart failure.

The let-7c family of miRNAs is expressed during embryonic development and plays an important role in cell differentiation. We investigated the role of let-7c in heart regeneration after injury in adult zebrafish in collaboration with Prof. Heikki Ruskoaho, HU. Let-7c inhibition increased cardiomyocyte proliferation and epicardial activation, and resulted in faster recovery of cardiac function and faster fibrinolysis after cryoinjury.

The role of heme oxygenase-1 (HO-1) in cardiovascular diseases 

HO-1 and its reaction products, carbon monoxide (CO), biliverdin, and bilirubin have a variety of cardiovascular protective properties. The promoter region of HMOX1 contains a guanine–thymine (GT) microsatellite repeat. A long GTn repeat decreases HO-1 expression and is associated with cardiometabolic diseases and pre-eclampsia. We are collaborating with Prof. Per-Henrik Groop and the FinnDiane Study Group, HU, Helsinki University Hospital (HUCH), and the Folkhälsan Institute of Genetics, to study the role of HO-1 and HO-1 gene polymorphisms in the development of cardiovascular and renal complications in type 1 diabetes.

Figure.  Immunostaining of zebrafish heart at 3 days post fertilization showing
cell membranes (ZN-5, green) and nuclei (mef-2, red)(courtesy of Sanni Perttunen).

Clinical hypertension

High blood pressure is the leading risk factor for death worldwide. Despite the development of antihypertensive therapies during recent years, treatment results are still unsatisfactory.

Our clinical hypertension research has focused on new treatment strategies for resistant hypertension. In addition, we have participated in international collaboration to elucidate the blood pressure lowering and vascular effects of sodium glucose co-transporter 2 (SGLT2) inhibitors, novel glucose-lowering drugs with cardiovascular and renal protective properties, in the treatment of type 2 diabetes.

Clinical collaboration

Our group is participating in several collaborative clinical studies on cardiovascular and renal diseases including acute and chronic heart failure as well as acute kidney injury.


Contact info

Päivi Lakkisto, MD, PhD, Adjunct Professor
E-mail: paivi.lakkisto@helsinki.fi


Selected publications

Hänninen M, Jäntti T, Tolppanen H, Segersvärd H, Tarvasmäki T, Lassus J, Vausort M, Devaux Y, Sionis A, Tikkanen I, Harjola V-P, Lakkisto P. Association of miR-21-5p, miR-122-5p and miR-320a-3p with 90-day mortality in cardiogenic shock. Int J Mol Sci 2020; 21:E7925; doi:10.3390/ijms21217925 

Paavola J, Alakoski T, Ulvila J, Kilpiö T, Siren J, Perttunen S, Narumanchi S, Wang H, Lin R, Porvari K, Junttila J, Huikuri H, Immonen K, Lakkisto P, Magga J, Tikkanen I, Kerkelä R. Vezf1 regulates cardiac structure and contractile function. EBioMedicine 2020; Jan3;51:102608. Doi: 10.1016/j.ebiom.2019.102608 

Narumanchi S, Kalervo K, Perttunen S, Wang H, Immonen K, Kosonen R, Laine M, Ruskoaho H, Tikkanen I, Lakkisto P, Paavola J. Inhibition of let-7c regulates cardiac regeneration after cryoinjury in adult zebrafish. J Cardiovasc Dev Dis 2019 Apr 4;6(2). pii: E16. doi: 10.3390/jcdd6020016 

Jäntti T, Segersvärd H, Tarvasmäki T, Lassus J, Devaux Y, Vausort M, Pulkki K, Sionis A, Bayes-Genis A, Tikkanen I, Lakkisto P, Harjola V-P. Circulating levels of microRNA 423-5p are associated with 90-day mortality in cardiogenic shock. ESC Heart failure, 2019; 6: 98-102 

Cherney DZI, Cooper ME, Tikkanen I, Pfarr E, Johansen OE, Woerle HJ, Broedl UC, Lund SS. Pooled analysis of Phase III trials indicate contrasting influences of renal function on blood pressure, body weight, and HbA1c reductions with empagliflozin. Kidney Int 2018; 93: 231-244. 

Lalowski MM, Björk S, Finckenberg P, Soliymani R, Tarkia M, Calza G, Blokhina D, Tulokas S, Kankainen M, Lakkisto P, Baumann M, Kankuri E, Mervaala E. Characterizing the key metabolic pathways of the neonatal mouse heart using a quantitative combinatorial omics approach. Front Physiol 2018, 11:935 doi: 10.3389/fphys.2018.00365. 

Kaartokallio T, Utge S, Klemetti MM, Paananen J, Pulkki K, Romppanen J, Tikkanen I, Heinonen S, Kajantie E, Kere J, Kivinen K, Pouta A, Lakkisto P, Laivuori H. Fetal microsatellite in the heme oxygenase 1 promoter is associated with severe and early-onset preeclampsia. Hypertension 2018; 71: 95-102. 

Segersvärd H, Lakkisto P, Hänninen M, Forsten H, Siren J, Immonen K, Kosonen R, Sarparanta M, Laine M, Tikkanen I. Carbon monoxide releasing molecule improves structural and functional cardiac recovery after myocardial injury. Eur J Pharmacol 2018; 818: 57-66. 

Dash SN, Narumanchi S, Paavola J, Perttunen S, Wang H, Lakkisto P, Tikkanen I, Lehtonen S. Sept7b is required for the subcellular organization of cardiomyocytes and cardiac function in zebrafish. Am J Physiol Heart Circ Physiol 2017; 312: H1085-H1095. 

Gordin D, Fadl Elmula FEM, Andersson B, Gottsäter A, Elf J, Kahan T, Christensen KL, Vikatmaa P, Vikatmaa L, Bastholm Olesen T, Groop PH, Olsen MH, Tikkanen I; Nordic BAT Study Group. The effects of baroreflex activation therapy on blood pressure and sympathetic function in patients with refractory hypertension: the rationale and design of the Nordic BAT study. Blood Pressure 2017; 26: 294-302 

Siren J, Vaahersalo J, Skrifvars M, Pettilä V, Tiainen M, Tikkanen I, Lakkisto P; FINNRESUSCI Study Group. Plasma heme oxygenase-1 in patients resuscitated from out-of-hospital cardiac arrest. Shock. 2016; 45(3):320-5. 

Chilton R, Tikkanen I, Cannon CP, Crowe S, Woerle HJ, Broedl UC, Johansen OE. Effects of empagliflozin on blood pressure and markers of arterial stiffness and vascular resistance in patients with type 2 diabetes. Diabetes Obes Metab. 2015; 17:1180-1193. 

Tikkanen I, Narko K, Zeller C, Green A, Salsali A, Broedl UC, Woerle HJ; on behalf of the EMPA-REG BP Investigators. Empagliflozin Reduces Blood Pressure in Patients With Type 2 Diabetes and Hypertension. Diabetes Care. 2015; 38:420-428. 

Kaartokallio T, Klemetti MM, Timonen A, Uotila J, Heinonen S, Kajantie E, Kere J, Kivinen K, Pouta A, Lakkisto P, Laivuori H. Microsatellite polymorphism in the heme oxygenase-1 promoter is associated with nonsevere and late-onset preeclampsia. Hypertension. 2014; 64:172-77. 

Paavola J, Schliffke S, Rossetti S, Kuo IY, Yuan S, Sun Z, Harris PC, Torres VE, Ehrlich BE. Polycystin-2 mutations lead to impaired calcium cycling in the heart and predispose to dilated cardiomyopathy. J Mol Cell Cardiol 58:199-208, 2013. 

Lakkisto P, Siren J-M, Kytö V, Forsten H, Laine M, Pulkki K, Tikkanen I. Heme oxygenase-1 induction protects the heart and modulates cellular and extracellular remodeling after myocardial infarction in rats. Exp Biol Med. 2011; 236:1437-1448. 

Lakkisto P, Kytö V, Forsten H, Siren JM, Segersvärd H, Voipio-Pulkki LM, Laine M, Pulkki K, Tikkanen I. Heme oxygenase-1 and carbon monoxide promote neovascularization after myocardial infarction by modulating the expression of Hif-1a, SDF-1a and VEGF-B. Eur J Pharmacol. 2010; 635: 156-164. 

Paavola J, Viitasalo M, Laitinen-Forsblom PJ, Pasternack M, Swan H, Tikkanen I, Toivonen L, Kontula K, Laine M. Mutant ryanodine receptors in catecholaminergic polymorphic ventricular tachycardia generate delayed afterdepolarizations due to increased propensity to Ca2+ waves. Eur Heart J. 2007; 28: 1135-1142. 

Pörsti I, Fan M, Kööbi P, Jolma P, Kalliovalkama J, Vehmas TI, Helin H, Holthöfer H, Mervaala E, Nyman T, Tikkanen I. High calcium diet down-regulates kidney angiotensin-converting enzyme in experimental renal failure. Kidney Int. 2004; 66: 2155-2166.  

%d bloggers like this: