{"id":{"repo_id":"edinburgh","oai_identifier":"oai:era.ed.ac.uk:1842/41735"},"canonical_url":"https://search.dev.ndltd.org/etd/edinburgh/oai:era.ed.ac.uk:1842/41735","repository":{"repo_id":"edinburgh","name":"University of Edinburgh","base_url":"https://era.ed.ac.uk/server/oai/request"},"display":{"title":"Manganese-enhanced magnetic resonance imaging in cardiometabolic disorders","abstract":"BACKGROUND AND AIMS: Cardiometabolic disorders include cardiovascular diseases and metabolic conditions such as diabetes mellitus and represent a leading cause of morbidity and mortality worldwide. Identification of specific biological pathways driving progression of these disorders may unveil targets for preventing and treating these diseases. Dysregulated myocardial and pancreatic beta-cell calcium handling may be a key mediator and driver of these disorders. Manganese is a calcium analogue which has paramagnetic properties. Cellular uptake of manganese by voltage gated L-type calcium channels causes T1 shortening and intracellular contrast enhancement on magnetic resonance. Manganese-enhanced magnetic resonance imaging therefore represents a novel non-invasive method of assessing intracellular calcium handling. It has been used previously to assess myocardial viability and to assess myocardial calcium uptake in ischaemic and non-ischaemic cardiomyopathies. However, no prior studies have used manganese-enhanced magnetic resonance imaging to evaluate perturbations in myocardial calcium handling in patients with subclinical or clinically overt diabetic cardiomyopathy and it has never been used to assess pancreatic functional beta-cell mass in patients with type 1 diabetes. The aims of this thesis were 1) to assess the reproducibility and repeatability of manganese-enhanced magnetic resonance imaging, 2) to determine whether myocardial calcium uptake is altered in patients with either type 1 or type 2 diabetes without known cardiac disease, 3) to study the differences between myocardial calcium handling in patients with both heart failure and type 2 diabetes versus patients with heart failure without type 2 diabetes, and 4) to investigate whether manganese-enhanced magnetic resonance imaging can be used as a non-invasive and reproducible measure pancreatic beta-cell function. METHODS: In study one, we assessed the intra-observer and inter-observer repeatability and scanrescan reproducibility of cardiac manganese-enhanced magnetic resonance imaging. Twenty healthy volunteers, 20 patients with acute myocardial infarction, 18 patients with hypertrophic and 10 patients with non-ischemic dilated cardiomyopathy underwent manganese-enhanced magnetic resonance imaging. Native T1 values and myocardial manganese uptake (Ki) were assessed for intra and inter-observer repeatability. Scanrescan reproducibility was assessed in 10 healthy volunteers. In study two, we compared myocardial manganese uptake in patients with either type 1 or type 2 diabetes without cardiac disease versus healthy volunteers. Manganese-enhanced cardiac magnetic resonance imaging was performed in people with type 1 diabetes (n=19), type 2 diabetes (n=30) and healthy volunteers (n=28), all without prevalent cardiac disease. In study three, we studied the differences between myocardial manganese uptake in patients with heart failure with or without type 2 diabetes. Twenty patients with both heart failure and type 2 diabetes and 20 patients with heart failure but without a diagnosis of type 2 diabetes underwent manganese-enhanced magnetic resonance imaging. In study four, 20 people with type 1 diabetes mellitus (10 with low (≥50 pmol/L) and 10 with very low (<50 pmol/L) C-peptide concentrations) and 15 healthy volunteers underwent manganese-enhanced magnetic resonance imaging of the pancreas following an oral glucose load. Scan-rescan reproducibility was performed in 10 participants. In all the studies, cardiac and pancreatic manganese uptake (Ki) was measured using a two-compartment model, Patlak formulation. RESULTS: Intra-observer and inter-observer correlation was excellent in healthy volunteers for mean native T1 mapping (Lin’s correlation coefficient [LCC] 0.97 and 0.97 respectively) and myocardial manganese uptake (LCC: 0.99 and 0.96 respectively). Scan-rescan correlation for native T1 and myocardial manganese uptake was also excellent. Similarly, there was strong intra-observer agreement for native T1 and myocardial manganese uptake in patients with acute myocardial infarction (LCC: 0.97 and 0.97 respectively), hypertrophic (LCC: 0.98 and 0.97 respectively) and dilated cardiomyopathy (LCC: 0.99 and 0.95 respectively). In study two, we showed that myocardial manganese uptake was 23% and 22% lower in those with type 1 and 2 diabetes compared to healthy volunteers (Ki 6.43±0.77, 6.47±0.99 and 8.33±0.77 mL/100 g/min, respectively; P<0.001). There were no differences in left ventricular systolic and diastolic function (ejection fraction, global longitudinal strain, and peak early diastolic strain rate) between groups. In study three, we observed that myocardial manganese uptake was lower in patients with both heart failure and type 2 diabetes compared to patients with heart failure only (4.69±0.71 versus 5.48±0.88, p=0.03). There was no difference in left ventricular systolic function between the two groups. In study four, we demonstrated that mean pancreatic manganese uptake was 31±6 mL/100 g of tissue/min in healthy volunteers (median 32 [interquartile range 23-36] years, 6 women), falling to 23±4 and 13±5 mL/100 g of tissue/min (p≤0.002 for both) in people with type1 diabetes mellitus (52 [44-61] years, 6 women) and low or very low plasma Cpeptide concentrations respectively. Furthermore, pancreatic manganese uptake correlated strongly with plasma C-peptide concentrations in people with type1 diabetes mellitus (r=0.73, p<0.001). CONCLUSIONS: We have demonstrated excellent intra-observer and inter-observer repeatability and scanrescan reproducibility for manganese-enhanced T1 mapping and kinetic modelling. Therefore, it has potential for future clinical applications. We have shown significant dysregulation of myocardial calcium handling in patients with either type 1 or type 2 diabetes mellitus in the absence of any apparent cardiac disease. Hence, abnormal calcium uptake may be an early pathologic feature of the diabetic heart, reduced to a similar extent in both type 1 and type 2 diabetes mellitus. In patients with heart failure, we observed a greater reduction in myocardial calcium uptake in patients with both heart failure and type 2 diabetes mellitus versus patients with heart failure without type 2 diabetes. This suggests that type 2 diabetes mellitus has a profound effect on myocardial calcium handling in patients with heart failure. Finally, we showed that manganese19 enhanced magnetic resonance imaging provides a reproducible non-invasive imaging technique to assess functional beta-cell mass in people with type 1 diabetes mellitus. Overall, we have demonstrated that dysregulated myocardial calcium handling plays an important role in the pathophysiology of diabetic cardiomyopathy and beta-cell dysfunction in type 1 diabetes. Furthermore, manganese-enhanced magnetic resonance imaging is a promising novel imaging technique for the diagnosis and risk stratification of a variety of cardiometabolic disorders. It has the potential to be used as a non-invasive biomarker to monitor disease progression and tracking response to novel therapies.","abstract_html":"BACKGROUND AND AIMS: Cardiometabolic disorders include cardiovascular diseases and metabolic conditions such as diabetes mellitus and represent a leading cause of morbidity and mortality worldwide. Identification of specific biological pathways driving progression of these disorders may unveil targets for preventing and treating these diseases. Dysregulated myocardial and pancreatic beta-cell calcium handling may be a key mediator and driver of these disorders. Manganese is a calcium analogue which has paramagnetic properties. Cellular uptake of manganese by voltage gated L-type calcium channels causes T1 shortening and intracellular contrast enhancement on magnetic resonance. Manganese-enhanced magnetic resonance imaging therefore represents a novel non-invasive method of assessing intracellular calcium handling. It has been used previously to assess myocardial viability and to assess myocardial calcium uptake in ischaemic and non-ischaemic cardiomyopathies. However, no prior studies have used manganese-enhanced magnetic resonance imaging to evaluate perturbations in myocardial calcium handling in patients with subclinical or clinically overt diabetic cardiomyopathy and it has never been used to assess pancreatic functional beta-cell mass in patients with type 1 diabetes. The aims of this thesis were 1) to assess the reproducibility and repeatability of manganese-enhanced magnetic resonance imaging, 2) to determine whether myocardial calcium uptake is altered in patients with either type 1 or type 2 diabetes without known cardiac disease, 3) to study the differences between myocardial calcium handling in patients with both heart failure and type 2 diabetes versus patients with heart failure without type 2 diabetes, and 4) to investigate whether manganese-enhanced magnetic resonance imaging can be used as a non-invasive and reproducible measure pancreatic beta-cell function. METHODS: In study one, we assessed the intra-observer and inter-observer repeatability and scanrescan reproducibility of cardiac manganese-enhanced magnetic resonance imaging. Twenty healthy volunteers, 20 patients with acute myocardial infarction, 18 patients with hypertrophic and 10 patients with non-ischemic dilated cardiomyopathy underwent manganese-enhanced magnetic resonance imaging. Native T1 values and myocardial manganese uptake (Ki) were assessed for intra and inter-observer repeatability. Scanrescan reproducibility was assessed in 10 healthy volunteers. In study two, we compared myocardial manganese uptake in patients with either type 1 or type 2 diabetes without cardiac disease versus healthy volunteers. Manganese-enhanced cardiac magnetic resonance imaging was performed in people with type 1 diabetes (n=19), type 2 diabetes (n=30) and healthy volunteers (n=28), all without prevalent cardiac disease. In study three, we studied the differences between myocardial manganese uptake in patients with heart failure with or without type 2 diabetes. Twenty patients with both heart failure and type 2 diabetes and 20 patients with heart failure but without a diagnosis of type 2 diabetes underwent manganese-enhanced magnetic resonance imaging. In study four, 20 people with type 1 diabetes mellitus (10 with low (≥50 pmol/L) and 10 with very low (&lt;50 pmol/L) C-peptide concentrations) and 15 healthy volunteers underwent manganese-enhanced magnetic resonance imaging of the pancreas following an oral glucose load. Scan-rescan reproducibility was performed in 10 participants. In all the studies, cardiac and pancreatic manganese uptake (Ki) was measured using a two-compartment model, Patlak formulation. RESULTS: Intra-observer and inter-observer correlation was excellent in healthy volunteers for mean native T1 mapping (Lin’s correlation coefficient [LCC] 0.97 and 0.97 respectively) and myocardial manganese uptake (LCC: 0.99 and 0.96 respectively). Scan-rescan correlation for native T1 and myocardial manganese uptake was also excellent. Similarly, there was strong intra-observer agreement for native T1 and myocardial manganese uptake in patients with acute myocardial infarction (LCC: 0.97 and 0.97 respectively), hypertrophic (LCC: 0.98 and 0.97 respectively) and dilated cardiomyopathy (LCC: 0.99 and 0.95 respectively). In study two, we showed that myocardial manganese uptake was 23% and 22% lower in those with type 1 and 2 diabetes compared to healthy volunteers (Ki 6.43±0.77, 6.47±0.99 and 8.33±0.77 mL/100 g/min, respectively; P&lt;0.001). There were no differences in left ventricular systolic and diastolic function (ejection fraction, global longitudinal strain, and peak early diastolic strain rate) between groups. In study three, we observed that myocardial manganese uptake was lower in patients with both heart failure and type 2 diabetes compared to patients with heart failure only (4.69±0.71 versus 5.48±0.88, p=0.03). There was no difference in left ventricular systolic function between the two groups. In study four, we demonstrated that mean pancreatic manganese uptake was 31±6 mL/100 g of tissue/min in healthy volunteers (median 32 [interquartile range 23-36] years, 6 women), falling to 23±4 and 13±5 mL/100 g of tissue/min (p≤0.002 for both) in people with type1 diabetes mellitus (52 [44-61] years, 6 women) and low or very low plasma Cpeptide concentrations respectively. Furthermore, pancreatic manganese uptake correlated strongly with plasma C-peptide concentrations in people with type1 diabetes mellitus (r=0.73, p&lt;0.001). CONCLUSIONS: We have demonstrated excellent intra-observer and inter-observer repeatability and scanrescan reproducibility for manganese-enhanced T1 mapping and kinetic modelling. Therefore, it has potential for future clinical applications. We have shown significant dysregulation of myocardial calcium handling in patients with either type 1 or type 2 diabetes mellitus in the absence of any apparent cardiac disease. Hence, abnormal calcium uptake may be an early pathologic feature of the diabetic heart, reduced to a similar extent in both type 1 and type 2 diabetes mellitus. In patients with heart failure, we observed a greater reduction in myocardial calcium uptake in patients with both heart failure and type 2 diabetes mellitus versus patients with heart failure without type 2 diabetes. This suggests that type 2 diabetes mellitus has a profound effect on myocardial calcium handling in patients with heart failure. Finally, we showed that manganese19 enhanced magnetic resonance imaging provides a reproducible non-invasive imaging technique to assess functional beta-cell mass in people with type 1 diabetes mellitus. Overall, we have demonstrated that dysregulated myocardial calcium handling plays an important role in the pathophysiology of diabetic cardiomyopathy and beta-cell dysfunction in type 1 diabetes. Furthermore, manganese-enhanced magnetic resonance imaging is a promising novel imaging technique for the diagnosis and risk stratification of a variety of cardiometabolic disorders. It has the potential to be used as a non-invasive biomarker to monitor disease progression and tracking response to novel therapies.","abstract_has_math":false,"creators":["Joshi, Shruti Shree"],"institution":"The University of Edinburgh","degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":["Newby, David","Dweck, Marc"],"committee_chairs":[],"committee_members":[],"year":2024,"date_issued":"2024-05-03","date_published":"2024-05-03","updated_at":"2026-07-24T02:14:20Z","subjects":["diabetes","manganese-enhanced magnetic resonance imaging","heart muscle abnormalities","manganese contrast agent","calcium movement"],"languages":["en"],"rights":[],"rights_urls":[],"identifier_entries":[{"key":"dc:identifier.uri","label":"Identifier URI","values":["http://dx.doi.org/10.7488/era/4458"],"render_values":[{"text":"http://dx.doi.org/10.7488/era/4458","href":"http://dx.doi.org/10.7488/era/4458","code":true}]}]},"links":{"outbound_url":"https://hdl.handle.net/1842/41735","outbound_label":"Handle","outbound_source":"dc:identifier.uri"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Newby, David","Dweck, Marc"]},{"key":"dc:creator","label":"Author","values":["Joshi, Shruti Shree"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.accessioned","label":"Dc Date Accessioned","values":["2024-05-03T12:24:08Z"]},{"key":"dc:date.available","label":"Dc Date Available","values":["2024-05-03T12:24:08Z"]},{"key":"dc:date.issued","label":"Date","values":["2024-05-03"]},{"key":"dc:publisher","label":"Institution","values":["The University of Edinburgh"]},{"key":"dc:type","label":"Dc Type","values":["Thesis or Dissertation"]},{"key":"dc:type.qualificationlevel","label":"Dc Type Qualificationlevel","values":["Doctoral"]},{"key":"dc:type.qualificationname","label":"Dc Type Qualificationname","values":["PhD Doctor of Philosophy"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["diabetes","manganese-enhanced magnetic resonance imaging","heart muscle abnormalities","manganese contrast agent","calcium movement"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language.iso","label":"Language (ISO)","values":["en"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://hdl.handle.net/1842/41735","http://dx.doi.org/10.7488/era/4458"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["BACKGROUND AND AIMS: Cardiometabolic disorders include cardiovascular diseases and metabolic conditions such as diabetes mellitus and represent a leading cause of morbidity and mortality worldwide. Identification of specific biological pathways driving progression of these disorders may unveil targets for preventing and treating these diseases. Dysregulated myocardial and pancreatic beta-cell calcium handling may be a key mediator and driver of these disorders. Manganese is a calcium analogue which has paramagnetic properties. Cellular uptake of manganese by voltage gated L-type calcium channels causes T1 shortening and intracellular contrast enhancement on magnetic resonance. Manganese-enhanced magnetic resonance imaging therefore represents a novel non-invasive method of assessing intracellular calcium handling. It has been used previously to assess myocardial viability and to assess myocardial calcium uptake in ischaemic and non-ischaemic cardiomyopathies. However, no prior studies have used manganese-enhanced magnetic resonance imaging to evaluate perturbations in myocardial calcium handling in patients with subclinical or clinically overt diabetic cardiomyopathy and it has never been used to assess pancreatic functional beta-cell mass in patients with type 1 diabetes. The aims of this thesis were 1) to assess the reproducibility and repeatability of manganese-enhanced magnetic resonance imaging, 2) to determine whether myocardial calcium uptake is altered in patients with either type 1 or type 2 diabetes without known cardiac disease, 3) to study the differences between myocardial calcium handling in patients with both heart failure and type 2 diabetes versus patients with heart failure without type 2 diabetes, and 4) to investigate whether manganese-enhanced magnetic resonance imaging can be used as a non-invasive and reproducible measure pancreatic beta-cell function. METHODS: In study one, we assessed the intra-observer and inter-observer repeatability and scanrescan reproducibility of cardiac manganese-enhanced magnetic resonance imaging. Twenty healthy volunteers, 20 patients with acute myocardial infarction, 18 patients with hypertrophic and 10 patients with non-ischemic dilated cardiomyopathy underwent manganese-enhanced magnetic resonance imaging. Native T1 values and myocardial manganese uptake (Ki) were assessed for intra and inter-observer repeatability. Scanrescan reproducibility was assessed in 10 healthy volunteers. In study two, we compared myocardial manganese uptake in patients with either type 1 or type 2 diabetes without cardiac disease versus healthy volunteers. Manganese-enhanced cardiac magnetic resonance imaging was performed in people with type 1 diabetes (n=19), type 2 diabetes (n=30) and healthy volunteers (n=28), all without prevalent cardiac disease. In study three, we studied the differences between myocardial manganese uptake in patients with heart failure with or without type 2 diabetes. Twenty patients with both heart failure and type 2 diabetes and 20 patients with heart failure but without a diagnosis of type 2 diabetes underwent manganese-enhanced magnetic resonance imaging. In study four, 20 people with type 1 diabetes mellitus (10 with low (≥50 pmol/L) and 10 with very low (<50 pmol/L) C-peptide concentrations) and 15 healthy volunteers underwent manganese-enhanced magnetic resonance imaging of the pancreas following an oral glucose load. Scan-rescan reproducibility was performed in 10 participants. In all the studies, cardiac and pancreatic manganese uptake (Ki) was measured using a two-compartment model, Patlak formulation. RESULTS: Intra-observer and inter-observer correlation was excellent in healthy volunteers for mean native T1 mapping (Lin’s correlation coefficient [LCC] 0.97 and 0.97 respectively) and myocardial manganese uptake (LCC: 0.99 and 0.96 respectively). Scan-rescan correlation for native T1 and myocardial manganese uptake was also excellent. Similarly, there was strong intra-observer agreement for native T1 and myocardial manganese uptake in patients with acute myocardial infarction (LCC: 0.97 and 0.97 respectively), hypertrophic (LCC: 0.98 and 0.97 respectively) and dilated cardiomyopathy (LCC: 0.99 and 0.95 respectively). In study two, we showed that myocardial manganese uptake was 23% and 22% lower in those with type 1 and 2 diabetes compared to healthy volunteers (Ki 6.43±0.77, 6.47±0.99 and 8.33±0.77 mL/100 g/min, respectively; P<0.001). There were no differences in left ventricular systolic and diastolic function (ejection fraction, global longitudinal strain, and peak early diastolic strain rate) between groups. In study three, we observed that myocardial manganese uptake was lower in patients with both heart failure and type 2 diabetes compared to patients with heart failure only (4.69±0.71 versus 5.48±0.88, p=0.03). There was no difference in left ventricular systolic function between the two groups. In study four, we demonstrated that mean pancreatic manganese uptake was 31±6 mL/100 g of tissue/min in healthy volunteers (median 32 [interquartile range 23-36] years, 6 women), falling to 23±4 and 13±5 mL/100 g of tissue/min (p≤0.002 for both) in people with type1 diabetes mellitus (52 [44-61] years, 6 women) and low or very low plasma Cpeptide concentrations respectively. Furthermore, pancreatic manganese uptake correlated strongly with plasma C-peptide concentrations in people with type1 diabetes mellitus (r=0.73, p<0.001). CONCLUSIONS: We have demonstrated excellent intra-observer and inter-observer repeatability and scanrescan reproducibility for manganese-enhanced T1 mapping and kinetic modelling. Therefore, it has potential for future clinical applications. We have shown significant dysregulation of myocardial calcium handling in patients with either type 1 or type 2 diabetes mellitus in the absence of any apparent cardiac disease. Hence, abnormal calcium uptake may be an early pathologic feature of the diabetic heart, reduced to a similar extent in both type 1 and type 2 diabetes mellitus. In patients with heart failure, we observed a greater reduction in myocardial calcium uptake in patients with both heart failure and type 2 diabetes mellitus versus patients with heart failure without type 2 diabetes. This suggests that type 2 diabetes mellitus has a profound effect on myocardial calcium handling in patients with heart failure. Finally, we showed that manganese19 enhanced magnetic resonance imaging provides a reproducible non-invasive imaging technique to assess functional beta-cell mass in people with type 1 diabetes mellitus. Overall, we have demonstrated that dysregulated myocardial calcium handling plays an important role in the pathophysiology of diabetic cardiomyopathy and beta-cell dysfunction in type 1 diabetes. Furthermore, manganese-enhanced magnetic resonance imaging is a promising novel imaging technique for the diagnosis and risk stratification of a variety of cardiometabolic disorders. It has the potential to be used as a non-invasive biomarker to monitor disease progression and tracking response to novel therapies."]},{"key":"dc:title","label":"Title","values":["Manganese-enhanced magnetic resonance imaging in cardiometabolic disorders"]}]}],"canonical_facts":{"dc:contributor.advisor":["Newby, David","Dweck, Marc"],"dc:creator":["Joshi, Shruti Shree"],"dc:date.accessioned":["2024-05-03T12:24:08Z"],"dc:date.available":["2024-05-03T12:24:08Z"],"dc:date.issued":["2024-05-03"],"dc:description.abstract":["BACKGROUND AND AIMS: Cardiometabolic disorders include cardiovascular diseases and metabolic conditions such as diabetes mellitus and represent a leading cause of morbidity and mortality worldwide. Identification of specific biological pathways driving progression of these disorders may unveil targets for preventing and treating these diseases. Dysregulated myocardial and pancreatic beta-cell calcium handling may be a key mediator and driver of these disorders. Manganese is a calcium analogue which has paramagnetic properties. Cellular uptake of manganese by voltage gated L-type calcium channels causes T1 shortening and intracellular contrast enhancement on magnetic resonance. Manganese-enhanced magnetic resonance imaging therefore represents a novel non-invasive method of assessing intracellular calcium handling. It has been used previously to assess myocardial viability and to assess myocardial calcium uptake in ischaemic and non-ischaemic cardiomyopathies. However, no prior studies have used manganese-enhanced magnetic resonance imaging to evaluate perturbations in myocardial calcium handling in patients with subclinical or clinically overt diabetic cardiomyopathy and it has never been used to assess pancreatic functional beta-cell mass in patients with type 1 diabetes. The aims of this thesis were 1) to assess the reproducibility and repeatability of manganese-enhanced magnetic resonance imaging, 2) to determine whether myocardial calcium uptake is altered in patients with either type 1 or type 2 diabetes without known cardiac disease, 3) to study the differences between myocardial calcium handling in patients with both heart failure and type 2 diabetes versus patients with heart failure without type 2 diabetes, and 4) to investigate whether manganese-enhanced magnetic resonance imaging can be used as a non-invasive and reproducible measure pancreatic beta-cell function. METHODS: In study one, we assessed the intra-observer and inter-observer repeatability and scanrescan reproducibility of cardiac manganese-enhanced magnetic resonance imaging. Twenty healthy volunteers, 20 patients with acute myocardial infarction, 18 patients with hypertrophic and 10 patients with non-ischemic dilated cardiomyopathy underwent manganese-enhanced magnetic resonance imaging. Native T1 values and myocardial manganese uptake (Ki) were assessed for intra and inter-observer repeatability. Scanrescan reproducibility was assessed in 10 healthy volunteers. In study two, we compared myocardial manganese uptake in patients with either type 1 or type 2 diabetes without cardiac disease versus healthy volunteers. Manganese-enhanced cardiac magnetic resonance imaging was performed in people with type 1 diabetes (n=19), type 2 diabetes (n=30) and healthy volunteers (n=28), all without prevalent cardiac disease. In study three, we studied the differences between myocardial manganese uptake in patients with heart failure with or without type 2 diabetes. Twenty patients with both heart failure and type 2 diabetes and 20 patients with heart failure but without a diagnosis of type 2 diabetes underwent manganese-enhanced magnetic resonance imaging. In study four, 20 people with type 1 diabetes mellitus (10 with low (≥50 pmol/L) and 10 with very low (<50 pmol/L) C-peptide concentrations) and 15 healthy volunteers underwent manganese-enhanced magnetic resonance imaging of the pancreas following an oral glucose load. Scan-rescan reproducibility was performed in 10 participants. In all the studies, cardiac and pancreatic manganese uptake (Ki) was measured using a two-compartment model, Patlak formulation. RESULTS: Intra-observer and inter-observer correlation was excellent in healthy volunteers for mean native T1 mapping (Lin’s correlation coefficient [LCC] 0.97 and 0.97 respectively) and myocardial manganese uptake (LCC: 0.99 and 0.96 respectively). Scan-rescan correlation for native T1 and myocardial manganese uptake was also excellent. Similarly, there was strong intra-observer agreement for native T1 and myocardial manganese uptake in patients with acute myocardial infarction (LCC: 0.97 and 0.97 respectively), hypertrophic (LCC: 0.98 and 0.97 respectively) and dilated cardiomyopathy (LCC: 0.99 and 0.95 respectively). In study two, we showed that myocardial manganese uptake was 23% and 22% lower in those with type 1 and 2 diabetes compared to healthy volunteers (Ki 6.43±0.77, 6.47±0.99 and 8.33±0.77 mL/100 g/min, respectively; P<0.001). There were no differences in left ventricular systolic and diastolic function (ejection fraction, global longitudinal strain, and peak early diastolic strain rate) between groups. In study three, we observed that myocardial manganese uptake was lower in patients with both heart failure and type 2 diabetes compared to patients with heart failure only (4.69±0.71 versus 5.48±0.88, p=0.03). There was no difference in left ventricular systolic function between the two groups. In study four, we demonstrated that mean pancreatic manganese uptake was 31±6 mL/100 g of tissue/min in healthy volunteers (median 32 [interquartile range 23-36] years, 6 women), falling to 23±4 and 13±5 mL/100 g of tissue/min (p≤0.002 for both) in people with type1 diabetes mellitus (52 [44-61] years, 6 women) and low or very low plasma Cpeptide concentrations respectively. Furthermore, pancreatic manganese uptake correlated strongly with plasma C-peptide concentrations in people with type1 diabetes mellitus (r=0.73, p<0.001). CONCLUSIONS: We have demonstrated excellent intra-observer and inter-observer repeatability and scanrescan reproducibility for manganese-enhanced T1 mapping and kinetic modelling. Therefore, it has potential for future clinical applications. We have shown significant dysregulation of myocardial calcium handling in patients with either type 1 or type 2 diabetes mellitus in the absence of any apparent cardiac disease. Hence, abnormal calcium uptake may be an early pathologic feature of the diabetic heart, reduced to a similar extent in both type 1 and type 2 diabetes mellitus. In patients with heart failure, we observed a greater reduction in myocardial calcium uptake in patients with both heart failure and type 2 diabetes mellitus versus patients with heart failure without type 2 diabetes. This suggests that type 2 diabetes mellitus has a profound effect on myocardial calcium handling in patients with heart failure. Finally, we showed that manganese19 enhanced magnetic resonance imaging provides a reproducible non-invasive imaging technique to assess functional beta-cell mass in people with type 1 diabetes mellitus. Overall, we have demonstrated that dysregulated myocardial calcium handling plays an important role in the pathophysiology of diabetic cardiomyopathy and beta-cell dysfunction in type 1 diabetes. Furthermore, manganese-enhanced magnetic resonance imaging is a promising novel imaging technique for the diagnosis and risk stratification of a variety of cardiometabolic disorders. It has the potential to be used as a non-invasive biomarker to monitor disease progression and tracking response to novel therapies."],"dc:identifier.uri":["https://hdl.handle.net/1842/41735","http://dx.doi.org/10.7488/era/4458"],"dc:language.iso":["en"],"dc:publisher":["The University of Edinburgh"],"dc:subject":["diabetes","manganese-enhanced magnetic resonance imaging","heart muscle abnormalities","manganese contrast agent","calcium movement"],"dc:title":["Manganese-enhanced magnetic resonance imaging in cardiometabolic disorders"],"dc:type":["Thesis or Dissertation"],"dc:type.qualificationlevel":["Doctoral"],"dc:type.qualificationname":["PhD Doctor of Philosophy"]},"updated_at":"2026-07-24T02:14:20Z"}