Background: Myocardial failure and dysfunction is not uncommon during critical illness and following cardiac surgery. For optimal treatment, a better understanding of the effects of inotropic drugs is needed. In this thesis, two non-adrenergic mediated inotropes, milrinone and levosimendan were studied in different models of myocardial dysfunction. The study aims were to assess the following: the effects of milrinone on blood flow in coronary artery bypass grafts during CABG surgery; the effects of milrinone on left ventricular diastolic function during post-ischaemic myocardial dysfunction; whether milrinone or levosimendan are protective or injurious during acute myocardial ischaemia, and if levosimendan potentiates myocardial function when added to milrinone in an experimental model of post-ischaemic (stunned) myocardium. Material and Methods: In Study I, 44 patients undergoing coronary artery bypass surgery(CABG) were included as subjects. Milrinone or saline was administrated in a single dose during cardio-pulmonary bypass (CPB) and coronary graft flow measurements were recorded after 10 and 30 min following CPB. In Study II; 24 patients undergoing CABG had estimations of peak ventricular filling rates made before and after CPB with administration of milrinone or saline as a single dose during CPB, performed by assessment of the rate of change in diastolic cross-sectional left ventricular area. In Study III, energy-metabolic effects of milrinone and levosimendan were measured in an anaesthetized porcine model during 45 minutes of regional myocardial ischemia. Microdialysis sampling of metabolites of local ischemic metabolism allowed assessment of glycolytic activity and the degree of myocardial calcium overload. In Study IV, in a porcine model of postischaemic myocardial stunning, ventricular pressure-volume relationships were analyzed when milrinone or a combination of milrinone and levosimendan were given together. Results: In Study I, there was a clear increase in non-sequential saphenous vein graft blood flow with milrinone at 10 minutes (64.5 ± 37.4 compared to placebo 43.6 ± 25.7 ml/min (mean ± SD).). A decreasing but still measureable flow increase was seen for milrinone at 30 minutes. In Study II, an increase in early left ventricular filling rate (ventricular cross-sectional area rate of change,dA/dt) was seen in the milrinone treated group. Pre-bypass milrinone group dA/dt 22.0 ± 9.5 changed to post-bypass values dA/dt 27.8 ± 11.5 cm2/sec). Placebo group pre-bypass dA/dt was 21.0 ± 8.7 and post-bypass 17.1 ± 7.1 cm2/sec. A milrinone effect was demonstrated in an adjusted regression model (p = 0.001). In Study III, neither milrinone nor levosimendan led to a change in energy-metabolic activity during ischemia as reflected by interstitial glucose, pyruvate, lactate orglycerol. Neither drug exacerbated the relative myocardial calcium overload during ischemia. In Study IV, milrinone improved active relaxation (tau) in post-ischemic stunned myocardium, but did not markedly improve systolic function by preload recruitable stroke work. Levosimendan added to milrinone showed minimal effect on active relaxation but a positive effect on systolic function in combination with milrinone. Conclusions: We conclude that milrinone treatment leads to an increase in blood flow in newly implanted coronary saphenous vein grafts, and improves ventricular relaxation post-cardiopulmonary bypass. Neither milrinone nor levosimendan, in this porcine model, negatively influence myocardial energy metabolism or calcium overload during acute ischaemia. Addition of levosimendan to milrinone treatment during post-ischaemic ventricular dysfunction may provide additive inotropic effects on systolic function but probably not for active relaxation.

Mental stress ischemia (MSI) is associated with poor prognosis for coronary artery disease (CAD) and is amenable to treatment, yet no easily administered test exists to diagnose it. Given the known increase in systemic vascular tone in response to stress, we studied the ability of peripheral arterial tonometry (PAT), a noninvasive functional measure of arterial tone, to predict those vulnerable to MSI. Seventy-seven patients with chronic stable CAD were subjected to mental stress with concomitant assessment of myocardial perfusion and pulse wave amplitude. Nuclear perfusion imaging was used to document MSI, and PAT was used to measure pulse wave and microarterial tone. A ratio of PAT measurements during stress to those before stress was used to characterize vascular responses. Serum catecholamines and endothelin-1 (ET-1) were simultaneously measured. Subjects who experienced MSI had a lower average PAT ratio than those who did not (0.76 ¡À 0.04 vs. 0.91 ¡À 0.05, P = 0.03). A receiver operating characteristics curve for PAT ratio predicting MSI had an area under the curve of 0.613 (standard error, 0.065, one-sided P = 0.04). Maxima of sensitivity and specificity were observed at a threshold of 0.78 to define an abnormal PAT ratio. Cross-tabulation of groups above and below this threshold with groups of subjects with and without MSI showed a significant predictive relationship between PAT ratio and MSI (P = 0.03). Subjects at or below this threshold (¡Ü0.78) displayed a significant increase in norepinephrine levels during mental stress (235 pg/ml at baseline, 259 pg/ml during mental stress, P = 0.007). Subjects above this threshold (>0.78) displayed a significant decline in their ET-1 levels 24 hours after mental stress (1.15 pg/ml after mental stress, 0.93 pg/ml 24 hours later, P = 0.01), while those at or below threshold had a continued increase. PAT ratio is a complex functional measure of peripheral arterial tone that significantly predicts the occurrence of MSI. It may have clinical value as an easily administered screening test for MSI.

SAMMANFATTNING Hjärt-kärlsjukdom är det största folkhälsoproblemet för både män och kvinnor i Sverige. I hjärtkärlsjukdom inkluderas kranskärlsjukdom (koronarsjukdom), plötslig hjärtdöd, hjärtsvikt, claudicatio intermittens, stroke och övriga hjärtkärlmanifestationer (Schenk-Gustafsson, 2011). Hjärtinfarkt är den vanligaste dödsorsaken för kvinnor över femtiofem år och män över fyrtiofem år i Sverige (Schenck-Gustafsson, 2011). Mortaliteten i hjärt-kärlsjukdomar sjunker i Sverige och kvinnors medelöverlevnad är fortfarande högre än männens, men denna skillnad har minskat då hjärtsjukvården har förbättrats. Kvinnors medelöverlevnad har sjunkit från 84 till 81 år det senaste decenniet medan männens medelöverlevnad har ökat från 75 till 78 år. Antalet hjärtinfarkter hos svenska kvinnor kan komma att öka på grund av livsstilsfaktorer såsom rökning och psykosociala faktorer. Det pågår en diskussion bland forskare om kvinnor får sämre vård än män och om kvinnor upplever symtom annorlunda än män vid kranskärlssjukdom. Studier har visat att kvinnor har längre fördröjning än män för att söka hjälp vid insjuknandet i kranskärlssjukdom. Syftet var att belysa kvinnors upplevelse av symtom och hur de hanterar dessa symtom i samband med insjuknandet i akut kranskärlssjukdom. För att få svar på syftet valdes litteraturöversikt som metod. Arton artiklar identifierades och inkluderades i denna litteraturöversikt. Sju av artiklarna hade kvalitativ ansats och elva artiklar hade kvantitativ ansats. Slutsatsen var att kvinnor upplevde prodromala symtom månader/år innan kranskärlsdiagnosen ställdes och det var ovanligt att kvinnor sökte sjukvård för dessa symtom. Bröstsmärta var det vanligaste symtomet hos kvinnor vid insjuknande i kranskärlssjukdom men ospecifika symtom förekom också. Kvinnor upplevde illamående i högre grad än män i detta sammanhang. Kvinnor hanterade symtom på kranskärlssjukdom genom att kontakta anhöriga eller med självmedicinering innan de kontaktade sjukvården, vilket bidrog till fördröjning av vården. Kunskapsnivå, känslomässiga och psykosociala faktorer inverkade på hur kvinnor hanterade symtom på kranskärlssjukdom. Sjukvården och kvinnor behövde ökad kunskap och förståelse angående hur kvinnor upplevde symtom på kranskärlssjukdom och hur kvinnor hanterade dessa symtom.

Background: Heart disease remains the leading cause of morbidity and mortality worldwide. Typical symptoms of heart disease are lacking in nearly one-third of patients with acute myocardial infarction (AMI). Simplified ECG assessment via lead I by various handheld and smartphone-based electrocardiogram (ECG) devices may be used for rapid screening without the traditional delays, privacy concerns, or costs of 12-lead ECG recording in patients who are asymptomatic or have atypical symptoms. The purpose of this DNP project was to compare ECG data from lead I to the standard 12-lead ECG to determine its potential efficacy as an early screening tool for AMI. Methods: This project compared ECGs in 84 patients with cardiac diagnoses, 66 (78.6%) had acute myocardial infarction with abnormal 12-lead ECGs and 18 (22.6 %) were without AMI or abnormal findings on the standard 12-lead ECG. ST-segment and T-wave amplitude and characteristics were compared between infarction territories. Results: Lead I in those with abnormal ECGs had a mean ST-segment deviation from baseline of 1.0 ± 0.7 mm, which was significantly different than those with normal ECGs (mean 0.1 ± 0.3 mm)(p = .000). The mean T-wave amplitude in patients with abnormal ECGs was 0.7 ± 1.3 mm, which was a significant reduction compared to those with normal ECGs group of 2.2 ± 1.5 mm (p = .000). Conclusion: ST-segment deviations and reduction in T-wave amplitude are significant indicators of acute myocardial infarction in lead I ECG, the same vector used in handheld single-lead ECG devices.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 6 uppsatser.

Diss. (sammanfattning) Göteborg : Göteborgs universitet, 2009. / Härtill 4 uppsatser.

A loss of sarcolemmal dystrophin was observed by immuno-fluorescence studies in rabbit hearts subjected to in situ myocardial ischemia and by immuno-blotting of the Triton soluble membrane fraction of isolated rabbit cardiomyocytes subjected to in vitro ischemia. This ischemic loss of dystrophin was a specific event in that no ischemic loss of sarcolemmal α-sarcoglycan, γ-sarcoglycan, αDG, or βDG was observed. The maintenance of sarcolemmal βDG (43 Kd) during ischemia was interesting in that dystrophin binds to the C-terminus of βDG. However, during late in vitro ischemia, a 30 Kd band was observed that was immuno-reactive for βDG. Additionally, this 30 Kd-βDG band was observed in rabbit myocardium subjected to autolysis. Finally, the 30 Kd-βDG was observed in the purified sarcolemmal fraction of rabbit cardiomyocytes subjected to a prolonged period of in vitro ischemia, confirming the sarcolemmal localization of this band. The potential patho-physiologic significance of this band was indicated by the appearance of this band at 120-180 min of in vitro ischemia, directly correlating with the onset of irreversible injury, as manifested by osmotic fragility. Additionally the appearance of this band was significantly reduced by the endogenous cardioprotective mechanism, in vitro ischemic preconditioning, which delays the onset of osmotic fragility. In addition to dystrophin, βDG binds caveolin-3 and Grb-2 at its C-terminus. The presence of Grb-2 and caveolin-3 in the membrane fractions of oxygenated and ischemic cardiomyocytes was determined by Western blotting. An increase in the level of membrane Grb-2 and caveolin-3 was observed following ischemic preconditioning as compared to control cells. The formation of this 30 Kd-βDG degradation product is potentially related to the transition from the reversible to the irreversible phase of myocardial ischemic cell injury and a decrease in 30 Kd-βDG might mediate the cardioprotection provided by ischemic preconditioning.

Indiana University-Purdue University Indianapolis (IUPUI) / Recent clinical outcome studies demonstrate that Sodium glucose cotransporter 2 inhibitors (SGLT2i) significantly reduce major adverse cardiovascular events and heart failure outcomes in subjects with type 2 diabetes mellitus. At present, several hypotheses have been proposed to explain the observed cardiovascular benefit of SGLT2i, however, the mechanisms responsible remain to be elucidated. This investigation tested the hypothesis that SGLT2i improves cardiac function and efficiency during acute, regional ischemia/reperfusion injury via preferential shifts in myocardial substrate selection and/or inhibition of cardiac sodium/hydrogen exchanger-1 (NHE-1). Our initial investigation evaluated the effects of 24 hour pretreatment of the SGLT2i canagliflozin on cardiac contractile function, substrate utilization, and efficiency before and during regional myocardial ischemia/reperfusion injury in healthy swine. At the onset of ischemia, canagliflozin increased left ventricular end diastolic and systolic volumes which returned to baseline with reperfusion. This increased end diastolic volume was directly associated with increased stroke volume and stroke work relative to controls during ischemia. Canagliflozin also increased cardiac work efficiency during ischemia relative to control swine. No differences in myocardial substrate uptake of glucose, lactate, fatty acids or ketones were detected between groups. In separate experiments using a longer 60 min coronary occlusion, canagliflozin significantly diminished myocardial infarct size. Subsequent studies investigated the effect of an acute administration (15-30 min pre-treatment) of canagliflozin and the NHE-1i cariporide on cardiac contractile function efficiency in response to myocardial ischemia/reperfusion injury. Similar to our initial studies, canagliflozin increased diastolic filling, stroke work and improved cardiac work efficiency relative to untreated control hearts during the ischemic period. In contrast, cariporide did not alter ventricular filling volume, cardiac output or work efficiency at any time point. Additional examination of AP-1 cells transfected with wild-type NHE-1 showed dose-dependent inhibition of NHE-1 activity by cariporide, while canagliflozin had minimal effect on overall activity. This investigation demonstrates that SGLT2i improves cardiac function and efficiency during acute, regional ischemia in healthy swine. However, the present data fail to support the hypothesis that these SGLT2i-mediated improvements involve either preferential alterations in myocardial substrate utilization or the inhibition of NHE-1 activity.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第21677号 / 医博第4483号 / 新制||医||1036(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 中山 健夫, 教授 木村 剛, 教授 湊谷 謙司 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Diss. (sammanfattning) Stockholm : Karol. inst., 2005. / Härtill 4 uppsatser.