Pulmonary artery hypertension (PAH) is characterised by increased pulmonary vascular resistance (PVR) resulting in elevated pressure in the pulmonary artery supplying the pulmonary circulation. Disease of the right ventricle (RV) often manifests as a result of PAH placing excessive pressure on the right side of the heart. Although a relatively rare disease in humans, the impact of sustained PAH is severe, with poor outcomes even in treated individuals. As PAH develops, the blood flow is restricted through the pulmonary arteries and the right ventricle hypertrophies due to the increased strain of pumping blood through the pulmonary circulation. With time, RV hypertrophy progresses to right heart failure, impacting the supply of blood to the left ventricle and systemic circulation. Although right heart failure can currently be treated, it cannot be cured. There is therefore a need for more research into the physiological changes that cause the heart to fail under pressure overload. This review aims to evaluate the monocrotaline (MCT) rat model of PAH as a means of studying the cellular mechanisms associated with the development of RV hypertrophy and right heart failure.

Pulmonary artery hypertension causes right ventricular hypertrophy which rapidly progresses to heart failure with underlying cardiac mitochondrial dysfunction. Prior to failure, there are alterations in cytosolic Ca²⁺ handling that might impact mitochondrial function in the compensatory phase of RV hypertrophy. Our aims, therefore, were (i) to measure beat-to-beat mitochondrial Ca²⁺ fluxes, and (ii) to determine mitochondrial abundance and function in non-failing, hypertrophic cardiomyocytes. Male Wistar rats were injected with either saline (CON) or monocrotaline (MCT) to induce pulmonary artery hypertension and RV hypertrophy after four weeks. Cytosolic Ca²⁺ ([Ca²⁺]_cyto) transients were obtained in isolated right ventricular (RV) cardiomyocytes, and mitochondrial Ca²⁺ ([Ca²⁺]_mito) was recorded in separate RV cardiomyocytes. The distribution and abundance of key proteins was determined using confocal and stimulated emission depletion (STED) microscopy. The RV mitochondrial function was also assessed in RV homogenates using oxygraphy. The MCT cardiomyocytes had increased area, larger [Ca²⁺]_cyto transients, increased Ca²⁺ store content, and faster trans-sarcolemmal Ca²⁺ extrusion relative to CON. The MCT cardiomyocytes also had larger [Ca²⁺]_mito transients. STED images detected increased mitochondrial protein abundance (TOM20 clusters per μm²) in MCT, yet no difference was found when comparing mitochondrial respiration and membrane potential between the groups. We suggest that the larger [Ca²⁺]_mito transients compensate to match ATP supply to the increased energy demands of hypertrophic cardiomyocytes.

Prostaglandin F2α (PGF2α) has a positively inotropic effect on right ventricular (RV) trabeculae from healthy adult rat hearts, and may therefore be therapeutically useful as a non-catecholaminergic inotrope. These provide additional contractile support for the heart without the added energetic demand of increased heart rate, and are also suitable for patients with reduced β adrenergic receptor (β-AR) responsiveness, or impaired mitochondrial energy supply. However, the response of hypertrophied rat hearts to PGF2α has not previously been examined. Our aim was therefore to determine the effect of PGF2α on isolated perfused rat hearts with RV hypertrophy following induction of pulmonary artery hypertension. Male Wistar rats (300 g) were injected with either 60 mg kg⁻¹ of monocrotaline (MCT, n = 10) or sterile saline as control (CON, n = 11). Four weeks post injection; hearts were isolated and Langendorff-perfused in sinus rhythm. Measurement of left ventricular (LV) pressure and the electrocardiogram were made and the response to 0.3 μM PGF2α was determined. PGF2α increased LV developed pressure in CON and in 60% MCT hearts, with no change in heart rate. However, 40% of MCT hearts developed arrhythmias during the peak inotropic response. For comparison, the response to 0.03 μM isoproterenol (ISO) was also investigated. Peak LV pressure developed sooner in response to ISO compared to PGF2α in both rat groups, although the inotropic response to ISO was reduced in MCT hearts. Analysis of fixed ventricular tissue confirmed that only RV myocytes were hypertrophied in MCT hearts. Our study showed that PGF2α was positively inotropic for healthy hearts, but found it generated arrhythmias in 40% of MCT hearts at the dose investigated. However, a more physiological dose of PGF2α may be a useful alternative without the added energetic cost of catecholaminergic inotropes.

Aim: Collagen VI has recently been strongly linked to poor outcomes in heart failure through increased endotrophin, a collagen VI‐derived signaling molecule linked to fibrotic remodeling in cardiovascular disease. The mutation of collagen VI can result in Ullrich congenital muscular dystrophy and Bethlem myopathy, pointing to a critical function in muscle physiology. However, the functional role of collagen VI in the heart is poorly understood. In human heart failure with reduced ejection fraction, collagen VI is increased within the remodeled T‐tubules, suggesting a possible role in tubular structure and Ca ²⁺ dynamics. Methods: To investigate this hypothesis, a global knockout of the collagen VI alpha 1 gene (Col6a1 ^−/− ) was generated in the rat. Results: T‐tubule structure and ryanodine receptor cluster organization were unchanged, but echocardiography demonstrated reduced systolic function. Consistent with this, isolated trabeculae from Col6a1 ^−/− hearts generated significantly less peak stress, confirming impaired contractile force at the tissue level. Paradoxically, isolated cardiomyocytes from the Col6a1 ^−/− rat had increased Ca ²⁺ transient amplitude and increased sarcoplasmic reticulum Ca ²⁺ load that would be expected to increase force. β‐adrenergic stimulation further increased Ca ²⁺ transient amplitude and was associated with diastolic Ca ²⁺ release events in Col6a1 ^−/− cardiomyocytes. Furthermore, β‐adrenergic stimulation of Col6a1 ^−/− trabeculae exhibited spontaneous contractions, indicating an increased susceptibility to arrhythmic activity. Conclusion: Together, these results indicate collagen VI has a role in both force transduction and Ca ²⁺ cycling in the heart.