Myocardial microvascular permeability, interstitial oedema, and compromised cardiac function

Abstract

The heart, perhaps more than any other organ, is exquisitely sensitive to increases in microvascular permeability and the accumulation of myocardial interstitial oedema fluid. Whereas some organs can cope with profound increases in the interstitial fluid volume or oedema formation without a compromise in function, heart function is significantly compromised with only a few percent increase in the interstitial fluid volume. This would be of little consequence if myocardial oedema were an uncommon pathology. On the contrary, myocardial oedema forms in response to many disease states as well as clinical interventions such as cardiopulmonary bypass and cardioplegic arrest common to many cardiothoracic surgical procedures. The heart's inability to function effectively in the presence of myocardial oedema is further confounded by the perplexing fact that the resolution of myocardial oedema does not restore normal cardiac function. We will attempt to provide some insight as to how microvascular permeability and myocardial oedema formation compromise cardiac function and discuss the acute changes that might take place in the myocardium to perpetuate compromised cardiac function following oedema resolution. We will also discuss compensatory changes in the interstitial matrix of the heart in response to chronic myocardial oedema and the role they play to optimize myocardial function during chronic oedemagenic disease.

A Novel ARNT-Dependent HIF-2α Signaling as a Protective Mechanism for Cardiac Microvascular Barrier Integrity and Heart Function Post-Myocardial Infarction

“…We also demonstrated that the angiogenic activity and hypoxic resistance of cultured ECs declined in response to siRNA-mediated Hif2α inactivation, that the upregulated expression of inflammatory genes and endothelial-barrier dysfunction observed in Hif2α -deficient ECs could be mitigated via the overexpression of ARNT, and that ARNT, but not Hif2α, bound directly to the IL6 promoter and suppressed IL6 expression. Collectively, our observations are consistent with previous reports linking microvascular dysfunction to a variety of pathological processes, including inflammation, apoptosis 3, 28,29-31 , and impaired angiogenesis 32, 33 , and suggest that Hif2α/ARNT heterodimers are crucial regulators of endothelial barrier integrity and function in ischemic hearts.…”

A Novel ARNT-Dependent HIF-2α Signaling as a Protective Mechanism for Cardiac Microvascular Barrier Integrity and Heart Function Post-Myocardial Infarction

“…We also demonstrated that the angiogenic activity and hypoxic resistance of cultured ECs declined in response to siRNA-mediated Hif2α inactivation, that the upregulated expression of inflammatory genes and endothelial-barrier dysfunction observed in Hif2α -deficient ECs could be mitigated via the overexpression of ARNT, and that ARNT, but not Hif2α, bound directly to the IL6 promoter and suppressed IL6 expression. Collectively, our observations are consistent with previous reports linking microvascular dysfunction to a variety of pathological processes, including inflammation, apoptosis 3, 28,29-31 , and impaired angiogenesis 32, 33 , and suggest that Hif2α/ARNT heterodimers are crucial regulators of endothelial barrier integrity and function in ischemic hearts.…”

Longitudinal changes in myocardial T1 and T2 relaxation times related to diffuse myocardial fibrosis in aortic stenosis; before and after aortic valve replacement

“…However, if myocardial edema or inflammation is present after surgery, it will be expected to result in an increase in T 1 as well as in T 2 after surgery, while we observed an increase in T 2 in combination with a decrease in T 1 . Also, the fact that T 1 and T 2 after surgery change towards normal values indicates that the amount of edema or inflammation is relatively small 3 and 12 months after surgery, which is in accordance with Dongaonkar et al The observed decrease in LV mass after surgery may also affect the relaxation times. An LV mass reduction solely caused by a reduction of muscle tissue would result in a relative increase in fibrotic tissue, and consequently an increased T 1 .…”

The role of regional myocardial topography post‐myocardial infarction on infarct extension

“…This indicates that the IVR stretching phenomenon was independent of ED fibre strain under high infarct stiffness. Based on the published findings, an infarct containing MVO had higher stiffness due to the increased extent of myocardial oedema 38,39 . This was reflected in our parameter optimisation result (Table 2), which demonstrated higher relative stiffness ( C 0(IZ) / C 0(RZ) ) in MVO patients as compared to non‐MVO patients.…”

A Novel ARNT-Dependent HIF-2α Signaling as a Protective Mechanism for Cardiac Microvascular Barrier Integrity and Heart Function Post-Myocardial Infarction

“…We also demonstrated that the angiogenic activity and hypoxic resistance of cultured ECs declined in response to siRNA-mediated Hif2α inactivation, that the upregulated expression of inflammatory genes and endothelial-barrier dysfunction observed in Hif2α -deficient ECs could be mitigated via the overexpression of ARNT, and that ARNT, but not Hif2α, bound directly to the IL6 promoter and suppressed IL6 expression. Collectively, our observations are consistent with previous reports linking microvascular dysfunction to a variety of pathological processes, including inflammation, apoptosis 3, 28,29-31 , and impaired angiogenesis 32, 33 , and suggest that Hif2α/ARNT heterodimers are crucial regulators of endothelial barrier integrity and function in ischemic hearts.…”

Longitudinal changes in myocardial T1 and T2 relaxation times related to diffuse myocardial fibrosis in aortic stenosis; before and after aortic valve replacement

“…However, if myocardial edema or inflammation is present after surgery, it will be expected to result in an increase in T 1 as well as in T 2 after surgery, while we observed an increase in T 2 in combination with a decrease in T 1 . Also, the fact that T 1 and T 2 after surgery change towards normal values indicates that the amount of edema or inflammation is relatively small 3 and 12 months after surgery, which is in accordance with Dongaonkar et al The observed decrease in LV mass after surgery may also affect the relaxation times. An LV mass reduction solely caused by a reduction of muscle tissue would result in a relative increase in fibrotic tissue, and consequently an increased T 1 .…”

The role of regional myocardial topography post‐myocardial infarction on infarct extension

“…This indicates that the IVR stretching phenomenon was independent of ED fibre strain under high infarct stiffness. Based on the published findings, an infarct containing MVO had higher stiffness due to the increased extent of myocardial oedema 38,39 . This was reflected in our parameter optimisation result (Table 2), which demonstrated higher relative stiffness ( C 0(IZ) / C 0(RZ) ) in MVO patients as compared to non‐MVO patients.…”

A Novel ARNT-Dependent HIF-2α Signaling as a Protective Mechanism for Cardiac Microvascular Barrier Integrity and Heart Function Post-Myocardial Infarction

“…We also demonstrated that the angiogenic activity and hypoxic resistance of cultured ECs declined in response to siRNA-mediated Hif2α inactivation, that the upregulated expression of inflammatory genes and endothelial-barrier dysfunction observed in Hif2α -deficient ECs could be mitigated via the overexpression of ARNT, and that ARNT, but not Hif2α, bound directly to the IL6 promoter and suppressed IL6 expression. Collectively, our observations are consistent with previous reports linking microvascular dysfunction to a variety of pathological processes, including inflammation, apoptosis 3, 28,29-31 , and impaired angiogenesis 32, 33 , and suggest that Hif2α/ARNT heterodimers are crucial regulators of endothelial barrier integrity and function in ischemic hearts.…”

Longitudinal changes in myocardial T1 and T2 relaxation times related to diffuse myocardial fibrosis in aortic stenosis; before and after aortic valve replacement

“…However, if myocardial edema or inflammation is present after surgery, it will be expected to result in an increase in T 1 as well as in T 2 after surgery, while we observed an increase in T 2 in combination with a decrease in T 1 . Also, the fact that T 1 and T 2 after surgery change towards normal values indicates that the amount of edema or inflammation is relatively small 3 and 12 months after surgery, which is in accordance with Dongaonkar et al The observed decrease in LV mass after surgery may also affect the relaxation times. An LV mass reduction solely caused by a reduction of muscle tissue would result in a relative increase in fibrotic tissue, and consequently an increased T 1 .…”

The role of regional myocardial topography post‐myocardial infarction on infarct extension

“…This indicates that the IVR stretching phenomenon was independent of ED fibre strain under high infarct stiffness. Based on the published findings, an infarct containing MVO had higher stiffness due to the increased extent of myocardial oedema 38,39 . This was reflected in our parameter optimisation result (Table 2), which demonstrated higher relative stiffness ( C 0(IZ) / C 0(RZ) ) in MVO patients as compared to non‐MVO patients.…”