Research Focus

Heart disease is the leading cause of death in women (~1 in 3), yet for decades it has been studied mostly in men. However, it remains unclear whether when placed under stress, whether from physiological demands such as exercise and pregnancy or from disease such as high blood pressure, obesity, diabetes, or a leaky heart valve, do women’s hearts adapt similar to men’s or do they tip toward harmful, disease-causing (maladaptive) remodeling by a different pathway, or on a different timeline? These fundamental questions drive Dr. Lakin’s laboratory, whose program aims to determine whether the heart’s response to stress is sex- and chamber-unique, whether the nature and time course of that response differ, and what this means for when and how to intervene.

Indeed, the heart’s four chambers are not alike, with the two upper chambers (the atria) being thin-walled, low-pressure chambers that fill and prime the heart, while the two lower chambers (the ventricles) are thicker, high-pressure pumps that drive blood to the body. Because they differ so fundamentally in structure, wall stress, and electrical behaviour, the atria and ventricles are expected to sense and respond to hemodynamic loading in distinct ways. With every heartbeat, each chamber must accommodate the stretch and pressure of blood filling and emptying the heart. Under sustained pressure or volume overload, the chambers remodel in proportion to the stress they experience. Whether that remodeling is adaptive (keeping the heart healthy) or maladaptive (disease-causing) appears to be chamber- and sex-unique, unfolding over unique time courses. Defining these thresholds (i.e., the tipping points at which adaptation becomes disease) is fundamental to revealing unique windows in which to intervene.

A common thread runs through many of cardiovascular conditions: they raise the heart’s filling pressures and the tissue to stretch. While modest stretch can be beneficial, sustained or excessive stretch drives hypertrophy, fibrosis, and the infiltration of inflammatory and immune cells that underlie disease. How the heart senses and transduces that stretch, and whether it does so differently across chambers and between the sexes, is central to the lab’s work. As women’s hearts tend to be smaller and remodel concentrically (thicker, stiffer walls) rather than eccentrically (enlarged chambers), reaching abnormal filling pressures at lower workloads than men, which may serve as a fundamental structural starting point that may set women on a different path in response to hemodynamic overload.

A defining focus of the lab is the two-way conversation between the heart’s mechanical environment and the inflammatory–immune axis, an area Dr. Lakin calls mechano-immunology. Indeed, immune and inflammatory cells are not merely first responders to injury but are active participants that can either help the heart adapt or drive it toward failure. By tracing how mechanical stress is converted into a protective or a damaging response, and how the nature and time course of that response differ by sex and chamber, the lab works to understand the pathogenesis of two of the most common, fastest-growing, and hardest-to-treat heart conditions: atrial fibrillation (AF), the most common supraventricular rhythm disorder, and heart failure with preserved ejection fraction (HFpEF), in which the heart pumps normally but cannot relax and fill as it should. Both conditions are linked to elevated filling pressures, increasingly impacting women and frequently occur together.

Ultimately, the goal is to translate these discoveries into sex-specific care with better-defined therapeutic windows and more personalized medicine.

Why is this work important?

Cardiovascular disease is the leading cause of death worldwide and claims the lives of one in three women. Two of its fastest-growing forms, atrial fibrillation (AF) and HFpEF, are closely linked, increasingly common, and still lack effective, targeted treatments. Indeed, AF cases are projected to rise roughly 2.5-fold by 2060, and HFpEF by nearly 50% by 2030, as the population ages. Both conditions disproportionately affect women, yet women have made up only ~20–25% of participants in the clinical trials that track disease progression and test the therapies used to treat them. As a result, the biology that makes women’s hearts respond differently remains understudied, and many treatments used today were developed and validated largely in males. Compounding this, the atria and ventricles differ fundamentally in their structural, functional, and electrical properties and are tightly interdependent, so a stress felt in one chamber reshapes the other, resulting in sex- and chamber-unique remodeling that differs in both nature and time course.

This work matters because it addresses two questions at the root of the problem. First, how do heart cells within the distinct structural, functional, and electrical environment of each chamber sense and transduce the physical stress of elevated filling pressures and stretch, and how does that shape cardiac remodeling? Second, what is the nature and time course of that remodeling, and where are the windows to intervene? By answering these questions through the underexplored lens of the mechanical environment and the inflammatory–immune axis, and with sex as a central variable, Dr. Lakin’s work hopes to reveal new drug targets, earlier ways to identify who is at risk, and treatments tailored to the individual. For women in particular, whom have been historically underrepresented in the trials that shape care, it promises more accurate diagnosis and more effective, sex-specific treatment.

What techniques and equipment are used in this laboratory?

The laboratory pairs whole-animal physiology with cellular, molecular, and immune profiling, utilizing mouse models through to human/clinical populations, to study disease processes from the intact heart down to individual cell populations through sex- and chamber-specific lenses. Drawing on Dr. Lakin’s established expertise and the ICS and Rady core facilities, the program’s methods will include:

• Clinically relevant rodent disease and exercise models: aortic and mitral regurgitation (AR and MR; volume/filling-pressure overload), a “two-hit” HFpEF model (high-fat diet + L-NAME), and graded exercise training (voluntary and resistance free-wheel, swim, treadmill).
• In vivo cardiac electrophysiology: intracardiac octapolar catheterization (right jugular) with programmed electrical stimulation to assess atrial and ventricular arrhythmia inducibility; surface and telemetric ECG.
• Ex vivo optical mapping: isolated whole-heart and atrial voltage and calcium mapping (conduction velocity, action-potential duration) to probe arrhythmia mechanisms.
• Invasive and telemetric hemodynamics: right- and left-ventricular pressure–volume loops (open- and closed-chest), solid-state pressure catheterization, and telemetry, which are central to filling-pressure and diastolic phenotyping.
• Echocardiography: non-invasive structural and functional imaging of the atria and ventricles.
• Immune and molecular profiling: spectral flow cytometry of cardiac and systemic immune infiltrates (monocyte-dependent CCR2⁺/MHCII⁺ and tissue-resident TLF⁺ macrophages), RNA sequencing / transcriptomics, isolated-cardiomyocyte calcium dynamics, histology, immunohistochemistry, and morphometry.
• Transgenic and pharmacological modulation of inflammation: whole-body, cell-specific (endothelial, macrophage) and tissue-specific (atrial cardiomyocyte) Tnf gene ablation, and inhibitors.
• Autonomic assessment: heart-rate variability with pharmacological autonomic blockade.

These studies draw on the University of Manitoba / Rady and ICS core platforms, including Central Animal Care Services, the Small Animal & Materials Core, Flow Cytometry, Histology Services, and the Imaging Facility,  alongside in-lab electrophysiology, optical-mapping, and hemodynamics capabilities.

About Dr. Lakin

Dr. Robert Lakin is an exercise physiologist and cardiovascular scientist with more than 15 years of experience in integrative and translational research. He completed his M.Sc. and Ph.D. in exercise and cardiovascular physiology at the University of Toronto under the mentorship of Dr. Jack Goodman, followed by postdoctoral training and a subsequent research-associate appointment in the laboratory of Dr. Peter Backx at York University. His work bridges whole-animal physiology, cardiac electrophysiology, and immunology to understand how mechanical stress and inflammation shape the heart through sex- and chamber-specific lenses.

His research program focuses on women’s heart health and the sex-specific mechanisms that cause cardiovascular disease to develop and progress differently in women. Building on his training in exercise physiology, he studies how the heart’s chambers sense and transduce pressure and volume overload, from physiological stress such as exercise to disease stimuli such as valvular heart disease or TAC-mediated pressure overload, focusing on how inflammation and immune cells drive the chamber-unique remodeling that underlies atrial fibrillation (AF) and HFpEF. A distinctive thread throughout his program is timing to understand when the heart shifts from healthy adaptation toward disease, and therefore when and how to intervene.

Coming to Winnipeg was a natural fit. The ICS is one of Canada’s preeminent cardiovascular research institutes and a national leader in women’s heart health, with a dedicated discovery platform, strong community connections, and an on-site link to the province’s cardiac-care programs that carries discoveries from the laboratory toward patients. Dr. Lakin is thrilled to contribute to improving the lives of women living with heart disease in Manitoba and across Canada.

For more information, please contact:

Dr. Robert Lakin
Tel. (204) 235-3662