Siiri E Iismaa

• PhD Molecular Genetics
• Senior Researcher at Victor Chang Cardiac Research Institute

Background Spontaneous coronary artery dissection (SCAD) is a rare cause of acute myocardial infarction, predominantly affecting younger women with few traditional cardiac risk factors. The condition is characterised by relatively high rates of recurrence. Recent qualitative studies demonstrate that SCAD survivors often experience fears about the f...

Background Mild cognitive impairment (often subjectively referred to as "brain fog") and cognitive fatigue are common sequelae after acute coronary syndrome. However, little is known about the nature and impact of these experiences in spontaneous coronary artery dissection (SCAD) survivors. Purpose To understand if and how brain fog and cognitive...

Background Heart attacks caused by spontaneous coronary artery dissection (SCAD) are traumatic events. While stressful, traumatic events can also be catalysts for positive growth. Aims This study investigated the nature, prevalence, and correlates of posttraumatic growth (PTG) after SCAD. Methods A mixed-methods approach was used. Part 1 involved...

Aims Brain fog and fatigue are common issues after acute coronary syndrome. However, little is known about the nature and impact of these experiences in spontaneous coronary artery dissection (SCAD) survivors. The aims of this study were to understand the experiences of brain fog and the coping strategies used after SCAD. Methods and results Parti...

[This corrects the article DOI: 10.1371/journal.pone.0296224.].

Aims Spontaneous coronary artery dissection (SCAD) is recognised as a particularly stressful cause of heart attack. However few studies have documented the prevalence of post-SCAD anxiety and depressive symptoms, or identified patients most at risk. This study documents the prevalence and correlates of post-SCAD anxiety and depressive symptoms. Me...

Importance Spontaneous coronary artery dissection (SCAD) is a poorly understood cause of acute coronary syndrome that predominantly affects women. Evidence to date suggests a complex genetic architecture, while a family history is reported for a minority of cases. Objective To determine the contribution of rare and common genetic variants to SCAD...

Introduction Recent studies suggest that acute myocardial infarction due to spontaneous coronary artery dissection (SCAD) carries significant psychosocial burden. This survey-based quantitative study builds on our earlier qualitative investigation of the psychosocial impacts of SCAD in Australian SCAD survivors. The study aimed to document the prev...

Background Spontaneous coronary artery dissection (SCAD) affects mainly women with a mean age of 51 years.(1) Predicted damaging variants in connective tissue disease (CTD) genes have been found in a subset of patients with SCAD, however in some cases the typical phenotype associated with these conditions is lacking. Variants in the COL3A1 gene, on...

Despite the high prevalence of heart failure in the western world, there are few effective treatments. Fibulin-3 is a protein involved in extracellular matrix (ECM) structural integrity, however its role in the heart is unknown. We have demonstrated, using single cell RNA-seq, that fibulin-3 was highly expressed in quiescent murine cardiac fibrobla...

Transglutaminase 2 (TG2) plays a role in cellular processes that are relevant to wound healing, but to date no studies of wound healing in TG2 knockout mice have been reported. Here, using 129T2/SvEmsJ (129)- or C57BL/6 (B6)-backcrossed TG2 knockout mice, we show that TG2 facilitates murine wound healing in a strain-dependent manner. Early healing...

Despite the high prevalence of heart failure in the western world, there are few effective treatments. Fibulin-3 is a protein involved in extracellular matrix (ECM) structural integrity, however its role in the heart is unknown. We have demonstrated, using single cell RNA-seq, that fibulin-3 was highly expressed in quiescent murine cardiac fibrobla...

Spontaneous coronary artery dissection (SCAD) is an understudied cause of myocardial infarction primarily affecting women. It is not known to what extent SCAD is genetically distinct from other cardiovascular diseases, including atherosclerotic coronary artery disease (CAD). Here we present a genome-wide association meta-analysis (1,917 cases and 9...

Purpose: Spontaneous coronary artery dissection (SCAD) is an increasingly recognized cause of acute myocardial infarction (AMI), particularly in younger women without classic cardiac risk factors. Spontaneous coronary artery dissection is considered to be particularly stressful; however, few studies have quantified SCAD survivor stress levels. Thi...

Arterial dissections, which involve an abrupt tear in the wall of a major artery resulting in the intramural accumulation of blood, are a family of catastrophic disorders causing major, potentially fatal sequelae. Involving diverse vascular beds, including the aorta or coronary, cervical, pulmonary, and visceral arteries, each type of dissection is...

Introduction: Spontaneous coronary artery dissection (SCAD) is an understudied cause of acute myocardial infarction due to hematoma formation in coronary arteries primarily affecting women. It is not known to what extent SCAD is genetically distinct from other cardiovascular diseases, including atherosclerotic coronary artery disease (CAD). Methods...

Spontaneous coronary artery dissection (SCAD) is an increasingly recognised cause of acute myocardial infarction, particularly in younger women without classic cardiac risk factors. While recent quantitative studies have noted high anxiety and depression in SCAD survivors, the full range and extent of psychosocial impacts of SCAD is unknown. The pr...

Spontaneous coronary artery dissection (SCAD) is an understudied cause of acute myocardial infarction primarily affecting women. It is not known to what extent SCAD is genetically distinct from other cardiovascular diseases, including atherosclerotic coronary artery disease (CAD). Through a meta-analysis of genome-wide association studies including...

Pressure overload-induced cardiac hypertrophy is a maladaptive response with poor outcomes and limited treatment options. The transient receptor potential melastatin 4 (TRPM4) ion channel is key to activation of a Ca2+/calmodulin-dependent kinase II (CaMKII)-reliant hypertrophic signaling pathway after pressure overload, but TRPM4 is neither stretc...

Background Spontaneous coronary artery dissection (SCAD) is a cause of acute coronary syndrome that predominantly affects women. Its pathophysiology remains unclear but connective tissue disorders (CTD) and other vasculopathies have been observed in many SCAD patients. A genetic component for SCAD is increasingly appreciated, although few genes hav...

Primary cardiomyocytes are invaluable for understanding postnatal heart development. However, a universal method to obtain freshly purified cardiomyocytes without using different age-dependent isolation procedures and cell culture, is lacking. Here, we report the development of a standardised method that allows rapid isolation and purification of h...

Primary cardiomyocytes are invaluable for understanding postnatal heart development. However, a universal method to obtain freshly purified cardiomyocytes without using different age-dependent isolation procedures and cell culture, is lacking. Here, we report the development of a standardised method that allows rapid isolation and purification of h...

Murine surgical models play an important role in preclinical research. Mechanistic insights into myocardial regeneration after cardiac injury may be gained from cardiothoracic surgery models in 0-14-day-old mice, the cardiomyocytes of which, unlike those of adults, retain proliferative capacity. Mouse pups up to 7 days old are effectively immobiliz...

Rational: Primary cardiomyocytes (CMs) are invaluable for understanding postnatal heart development and elucidating disease mechanisms in genetic and pharmacological models, however, a method to obtain freshly purified CMs at any postnatal age, without the need for different age-dependent isolation procedures and cell culture, is lacking. Objective...

Background/Introduction SCAD typically affects women in their fifth or sixth decade with a paucity of cardiovascular risk factors.(1) It is caused by a coronary artery intramural haematoma with or without intimal tear. Resultant luminal occlusion manifests as myocardial ischaemia/infarction or death. There are two published sporadic cases of SCAD w...

Heart failure in adults is a leading cause of morbidity and mortality worldwide. It can arise from a variety of diseases, with most resulting in a loss of cardiomyocytes that cannot be replaced due to their inability to replicate, as well as to a lack of resident cardiomyocyte progenitor cells in the adult heart. Identifying and exploiting mechanis...

Pressure overload-induced cardiac hypertrophy is a maladaptive response with poor outcomes and limited treatment options. The transient receptor potential melastatin 4 (TRPM4) ion channel is key to activation of a Ca2+-calmodulin kinase II (CaMKII)-dependent hypertrophic signalling pathway after pressure overload, but TRPM4 is neither stretch-activ...

Pathological left ventricular hypertrophy (LVH) occurs in response to pressure overload and remains the single most important clinical predictor of cardiac mortality. The molecular pathways in the induction of pressure overload LVH are potential targets for therapeutic intervention. Current treatments aim to remove the pressure overload stimulus fo...

Objective Previously published work has indicated that transcripts encoding transglutaminase (TG)2 increase markedly in a rat model of abdominal aortic aneurysm. This study determines whether TG2 and the related transglutaminase, factor (F)XIII-A, protect against aortic aneurysm development in mice. Methods C57BL/6J wild-type, Tgm2-/- knockout, F1...

The ‘fight or flight’ response to physiological stress involves sympathetic nervous system activation, catecholamine release and adrenergic receptor stimulation. In the heart, this induces positive inotropy, previously attributed to the β1-adrenergic receptor subtype. However, the role of the α1A-adrenergic receptor, which has been suggested to be...

Cardiomyocytes of newborn mice proliferate after injury or exposure to growth factors. However, these responses are diminished after postnatal day-6 (P6), representing a barrier to building new cardiac muscle in adults. We have previously shown that exogenous thyroid hormone (T3) stimulates cardiomyocyte proliferation in P2 cardiomyocytes, by activ...

Background - Spontaneous coronary artery dissection (SCAD) occurs when an epicardial coronary artery is narrowed or occluded by an intramural hematoma. SCAD mainly affects women and is associated with pregnancy and systemic arteriopathies, particularly fibromuscular dysplasia. Variants in several genes, such as those causing connective tissue disor...

Animal models of pressure overload are valuable for understanding hypertensive heart disease. We characterised a surgical model of pressure overload-induced hypertrophy in C57BL/6J mice produced by suprarenal aortic constriction (SAC). Compared to sham controls, at one week post-SAC systolic blood pressure was significantly elevated and left ventri...

A developmental surge in thyroid hormone (T3) after postnatal day-10 (P10), in mice, results in a burst of cardiomyocyte proliferation. This finding remains controversial, which could arise from perceived homogeneity of myocardial sampling for immunoblotting and immunohistochemical studies, or from differences in enzymatic digestion efficiency for...

Memory helper T (Th) cells are crucial for secondary immune responses against infectious microorganisms but also drive the pathogenesis of chronic inflammatory diseases. Therefore, it is of fundamental importance to understand how memory T cells are generated. However, the molecular mechanisms governing memory Th cell generation remain incompletely...

The burden of cardiovascular disease in women is being increasingly appreciated. Nevertheless, both clinicians and the general public are largely unaware that cardiovascular disease is the leading cause of death worldwide in women in all countries and that outcomes after a heart attack are worse for women than men. Of note, certain types of cardiov...

α-Synuclein (α-Syn) is a key pathogenic protein in α-synucleinopathies including Parkinson disease (PD) and Dementia with Lewy Bodies. The aggregation of α-Syn is believed to be deleterious and a critical step leading to neuronal dysfunction and death. One of the factors that may contribute to the initial steps of this aggregation is crosslinking t...

Synuclein (α-Syn) is a key pathogenic protein in α-synucleinopathies including Parkinson disease (PD) and Dementia with Lewy Bodies. The aggregation of α-Syn is believed to be deleterious and a critical step leading to neuronal dysfunction and death. One of the factors that may contribute to the initial steps of this aggregation is crosslinking thr...

Background and aims: Transglutaminase (TG) 2 and Factor (F) XIII-A have both been implicated in cardiovascular protection and repair. This study was designed to differentiate between two competing hypotheses: that TG2 and FXIII-A mediate these functions in mice by fulfilling separate roles, or that they act redundantly in this respect. Methods:...

Spontaneous coronary artery dissection (SCAD) is a non-atherosclerotic form of coronary artery disease of unknown cause that predominantly affects women (>90%; mean age 44-55 years) and can be fatal. The finding of familial clustering, including the concordant involvement of monozygotic twins, and its association with the PHACTR1/EDN1 genetic locus...

Background There is increasing evidence that patients with spontaneous coronary artery dissection (SCAD) have an underlying genetic susceptibility (Goel et al JAMA Intern Med175:821–826, 2015). Moreover, in a collaborative study involving 1,055 SCAD cases and 7,190 controls, we recently reported the first risk allele for SCAD, a variant (rs9349379-...

The ‘fight or flight’ response, involving sympathetic nervous system activation and catecholamine release, is central to survival. Resulting activation of adrenergic receptors (ARs) drives physiological responses, such as positive inotropy, which to date has been attributed solely to β 1 -AR/Gs/adenylyl cyclase/protein kinase A pathway-activation....

In humans, 9 members of the transglutaminase (TG) family have been identified, of which 8 [factor XIII (FXIII)A and TG1–TG7] catalyze post‐translational protein‐modifying reactions, and 1 does not (protein 4.2). The TG enzymatic activities considered in our discussion of human disease include deamidation of glutamine (Gln) residues, amine incorpora...

Stimulating regeneration of complex tissues and organs after injury to effect complete structural and functional repair, is an attractive therapeutic option that would revolutionize clinical medicine. Compared to many metazoan phyla that show extraordinary regenerative capacity, which in some instances persists throughout life, regeneration in mamm...

Introduction Intravascular fibrin clots and extravascular fibrin deposits are often implicated in the progression of liver fibrosis. However, evidence supporting a pathological role of fibrin in hepatic fibrosis is indirect and based largely on studies using anticoagulant drugs that inhibit activation of the coagulation protease thrombin, which has...

We have previously demonstrated that adult transgenic C57BL/6J mice with CM-restricted overexpression of the dominant negative W v mutant protein (dn-c-kit-Tg) respond to pressure overload with robust cardiomyocyte (CM) cell cycle entry. Here, we tested if outcomes after myocardial infarction (MI) due to coronary artery ligation are improved in thi...

Background: Over 100 mammalian G protein-coupled receptors are yet to be matched with endogenous ligands; these so-called orphans are prospective drug targets for the treatment of disease. GPR37L1 is one such orphan, abundant in the brain and detectable as mRNA in the heart and kidney. GPR37L1 ablation was reported to cause hypertension and left v...

In mice, the heart nearly quadruples in size from early preadolescence (postnatal day 10 [P10]) to puberty (∼P35) (Naqvi et al., 2014). Because it is widely believed that mammalian cardiomyocytes (CMs) are incapable of replication after birth, it has been assumed that early postnatal heart growth is driven solely by CM hypertrophy. Our findings que...

Hypertrophic cardiomyopathy (HCM) is caused by mutations in sarcomere protein genes, and left ventricular hypertrophy (LVH) develops as an adaptive response to sarcomere dysfunction. It remains unclear whether persistent expression of the mutant gene is required for LVH or whether early gene expression acts as an immutable inductive trigger. The ai...

Transglutaminase 2 (TG2) has been implicated in a number of physiological processes and in disease. A number of different types of genetically engineered mice have been generated to help understand the role and regulation of TG2 in physiology and pathology and to help delineate the molecular basis of its actions. This chapter will briefly review gu...

Thyroid hormone is a critical regulator of cardiac growth and development, both in fetal life and postnatally. Here we review the role of thyroid hormone in postnatal cardiac development, given recent insights into its role in stimulating a burst of cardiomyocyte proliferation in the murine heart in preadolescence; a response required to meet the m...

To determine the mechanisms by which the α1A-adrenergic receptor (AR) regulates cardiac contractility.We reported previously that transgenic mice with cardiac-restricted α1A-AR overexpression (α1A-TG) exhibit enhanced contractility but not hypertrophy, despite evidence implicating this Gαq/11-coupled receptor in hypertrophy.Contractility, calcium (...

It is widely believed that perinatal cardiomyocyte terminal differentiation blocks cytokinesis, thereby causing binucleation and limiting regenerative repair after injury. This suggests that heart growth should occur entirely by cardiomyocyte hypertrophy during preadolescence when, in mice, cardiac mass in-creases many-fold over a few weeks. Here,...

It is widely believed that perinatal cardiomyocyte terminal differentiation blocks cytokinesis, thereby causing binucleation and limiting regenerative repair after injury. This suggests that heart growth should occur entirely by cardiomyocyte hypertrophy during preadolescence when, in mice, cardiac mass increases many-fold over a few weeks. Here, w...

Transglutaminase type 2 (TG2) has been reported to be a candidate gene for maturity onset diabetes of the young (MODY) because three different mutations that impair TG2 transamidase activity have been found in 3 families with MODY. TG2 null (TG2(-/-)) mice have been reported to be glucose intolerant and have impaired glucose-stimulated insulin secr...

Migration of cells in the ocular surface underpins physiological wound healing as well as many human diseases. Transglutaminase (TG)-2 is a multifunctional cross-linking enzyme involved in migration of skin fibroblasts and wound healing, however, its functional role in epithelial migration has not been evaluated. This study investigated the importa...

Molecular deletion of transglutaminase 2 (TG2) has been shown to improve function and survival in a host of neurological conditions including stroke, Huntington's disease, and Parkinson's disease. However, unifying schemes by which these cross-linking or polyaminating enzymes participate broadly in neuronal death have yet to be presented. Unexpecte...

Using a mouse model of cardiac‐specific over‐expression of the α 1A ‐adrenergic receptor (α 1A ‐AR; α 1A ‐M 66‐fold; α 1A ‐H 166‐fold) we have recently shown that acute activation of the α 1A ‐AR results in enhanced contraction through activation of α 1A ‐AR‐operated Ca ²⁺ entry via Snapin and TRPC6. We have now defined a hypertrophic signalling pa...

We determined the extent to which cardiac overexpression of the α 1A ‐adrenergic receptor (AR) in transgenic (TG) rats affords cardioprotection, and if it is involved in first or second window ischemic preconditioning (IPC). Without IPC, infarct size, induced by coronary artery occlusion (CAO) for 30min and 3hrs reperfusion (CAR; expressed as % are...

We examined α(1A)-adrenergic receptor (AR) mediation of preconditioning in a novel α(1A)-AR cardiac transgenic (TG) rat model (α(1A)-TG). Compared with nontransgenic littermates (NTLs), in conscious α(1A)-TG rats, heart rate was reduced, contractility [left ventricle (LV) +dP/dt, ejection fraction, end-systolic elastance] was significantly enhanced...

Idiopathic pulmonary fibrosis (IPF) is a deadly progressive disease with few treatment options. Transglutaminase 2 (TG2) is a multifunctional protein, but its function in pulmonary fibrosis is unknown. To determine the role of TG2 in pulmonary fibrosis. The fibrotic response to bleomycin was compared between wild-type and TG2 knockout mice. Transgl...

Sympathetic regulation of cardiac contractility is mediated in part by α(1)-adrenergic receptors (ARs), and the α(1A)-subtype has been implicated in the pathogenesis of cardiac hypertrophy. However, little is known about α(1A)-AR signalling pathways in ventricular myocardium. The aim of this study was to determine the signalling pathway that mediat...

Caused by a polyglutamine expansion in the huntingtin protein, Huntington's disease leads to striatal degeneration via the transcriptional dysregulation of a number of genes, including those involved in mitochondrial biogenesis. Here we show that transglutaminase 2, which is upregulated in HD, exacerbates transcriptional dysregulation by acting as...

We determined whether cardiac overexpression of the alpha 1A ‐adrenergic receptor (α 1A ‐AR) affords protection against myocardial ischemia in a novel transgenic (TG) rat model where α 1A ‐ARs were overexpressed by 40‐fold in the heart. The effects of 30 min coronary artery occlusion and 3 hrs reperfusion (I/R) were examined in 7 TG and 7 WT rats....

In the heart under normal conditions the β 1 ‐adrenergic receptors (ARs) predominantly regulate cardiac contractility, with the α 1 ‐ARs playing a minor role. However, when the heart is compromised, e.g. during cardiac hypertrophy, the α 1 ‐ARs play a more prominent role. Using a model of enhanced cardiac α 1A ‐AR signaling (α 1A ‐H) we identified...