Modelling mitral valvular dynamics–current trend and future directions

Dysfunction of mitral valve causes morbidity and premature mortality and remains a leading medical problem worldwide. Computational modelling aims to understand the biomechanics of human mitral valve and could lead to the development of new treatment, prevention and diagnosis of mitral valve diseases. Compared with the aortic valve, the mitral valve has been much less studied owing to its highly complex structure and strong interaction with the blood flow and the ventricles. However, the interest in mitral valve modelling is growing, and the sophistication level is increasing with the advanced development of computational technology and imaging tools. This review summarises the state-of-the-art modelling of the mitral valve, including static and dynamics models, models with fluid-structure interaction, and models with the left ventricle interaction. Challenges and future directions are also discussed

Stem Cell Imaging: Tools to Improve Cell Delivery and Viability.

Stem cell therapy (SCT) has shown very promising preclinical results in a variety of regenerative medicine applications. Nevertheless, the complete utility of this technology remains unrealized. Imaging is a potent tool used in multiple stages of SCT and this review describes the role that imaging plays in cell harvest, cell purification, and cell implantation, as well as a discussion of how imaging can be used to assess outcome in SCT. We close with some perspective on potential growth in the field

Iron Deposition following Chronic Myocardial Infarction as a Substrate for Cardiac Electrical Anomalies: Initial Findings in a Canine Model

Purpose: Iron deposition has been shown to occur following myocardial infarction (MI). We investigated whether such focal iron deposition within chronic MI lead to electrical anomalies. Methods: Two groups of dogs (ex-vivo (n = 12) and in-vivo (n = 10)) were studied at 16 weeks post MI. Hearts of animals from ex-vivo group were explanted and sectioned into infarcted and non-infarcted segments. Impedance spectroscopy was used to derive electrical permittivity () and conductivity (). Mass spectrometry was used to classify and characterize tissue sections with (IRON+) and without (IRON-) iron. Animals from in-vivo group underwent cardiac magnetic resonance imaging (CMR) for estimation of scar volume (late-gadolinium enhancement, LGE) and iron deposition (T2*) relative to left-ventricular volume. 24-hour electrocardiogram recordings were obtained and used to examine Heart Rate (HR), QT interval (QT), QT corrected for HR (QTc) and QTc dispersion (QTcd). In a fraction of these animals (n = 5), ultra-high resolution electroanatomical mapping (EAM) was performed, co-registered with LGE and T2* CMR and were used to characterize the spatial locations of isolated late potentials (ILPs). Results: Compared to IRON- sections, IRON+ sections had higher, but no difference in. A linear relationship was found between iron content and (p1.5%)) with similar scar volumes (7.28%±1.02% (Iron (1.5%)), p = 0.51) but markedly different iron volumes (1.12%±0.64% (Iron (1.5%)), p = 0.02), QT and QTc were elevated and QTcd was decreased in the group with the higher iron volume during the day, night and 24-hour period (p<0.05). EAMs co-registered with CMR images showed a greater tendency for ILPs to emerge from scar regions with iron versus without iron. Conclusion: The electrical behavior of infarcted hearts with iron appears to be different from those without iron. Iron within infarcted zones may evolve as an arrhythmogenic substrate in the post MI period

MRI of mouse heart failure

Heart failure (HF) is the inability of the heart to pump blood at a rate that satisfies the peripheral needs and is a final consequence of many pathologies. Left ventricular (LV) pressure overload and myocardial infarction are amongst the most important causes of HF. Common and important hallmarks of HF are myocardial hypertrophy, fibrosis, vascular adaptation and metabolic remodeling. The role of cardiac magnetic resonance (CMR) as a diagnostic tool for HF is rapidly increasing. The prognostic value of important measures of LV function such as ejection fraction, however, is limited. To improve diagnostic relevance and risk stratification additional MR imaging and spectroscopy techniques are therefore highly desired. For that, preclinical research in mouse models plays an important role. This goal of this thesis was to apply multiple, novel MR imaging methods and phosphorous 31PMR spectroscopy for the evaluation of mouse HF, with a focus on myocardial hypertrophy, fibrosis, perfusion and LV energy status. These techniques are part of an ever extending toolbox for mouse CMR that allows the researcher to perform a multi-parametric assessment of myocardial tissue status. Preferably, a time-efficient protocol is constructed from all these tools, which is tailored for a particular HF phenotype and yields the relevant, decisive features of the stage of development towards HF. After successful proof-of-concept studies in mice, these techniques could be translated for clinical use. Ultimately, these techniques might then contribute to improved diagnostic accuracy and a better characterization of the tissue status, new (surrogate) end-points to evaluate the success of therapies and interventions, and perhaps may even provide better prognostic markers for the disease course. The transverse aortic constriction (TAC) mouse model was used throughout this thesis as it is an important model of pressure overload induced hypertrophy and HF. Since the TAC model was first described, it has been extensively used to study various facets of pressure overload induced LV adaptation. In Chapter 2 we characterized cardiac function and morphology in a mild and severe TAC model. Mice underwent repeated measurements to evaluate the progression of cardiac parameters over time. The mild TAC mice developed a stage of compensated LV hypertrophy and mildly impaired LV function. No progressive deterioration of myocardial function was observed over time and LV maladaptation did not result in pulmonary remodeling and RV failure. LV function and morphology in severe TAC mice, on the other hand, progressively deteriorated over time resulting in overt decompensated hypertrophy, which was also indicated by profound pulmonary remodeling and impaired RV function. A repeatable method for quantitative, first-pass perfusion MRI of the mouse heart based on a dual-bolus approach was described in Chapter3. A non-saturated arterial input function was acquired from a low-dose containing Gd(DTPA)2- prebolus. The myocardial tissue response was measured from a separate high-dose full-bolus infusion. Perfusion (ml min-1 g-1) was quantified using a Fermi constrained deconvolution of the myocardial tissue response with the arterial input function. This calculation critically depends on linearity of the measured MR signal intensity with Gd(DTPA)2- concentration in the LV lumen during the prebolus and in the myocardial wall during the full-bolus. In separate experiments these assumptions were proven to be valid for our experimental conditions. Interestingly, this assumption was to the best of our knowledge never demonstrated in vivo, although Weber et al. confirmed the appropriateness of this assumption for quantitative first-pass perfusion measurements in the human heart using phantom experiments. The first-pass perfusion method was used in Chapter 4 to study myocardial perfusion in TAC mice, which was considerably decreased as compared to perfusion in control mice. Importantly, the relationship between perfusion and LV morphology and function was studied. Clear correlations were obtained between a decreased perfusion in TAC mice and the indices of LV function and morphology, e.g., LV ejection fraction, volumes as well as LV mass. Although group-averaged perfusion values in TAC mice did not change between measurements in the longitudinal study, these results revealed that with an ensuing hypertrophic growth and concomitantly declining LV function (Chapter 2) perfusion gradually diminishes. Current MRI techniques for the quantification of diffuse myocardial fibrosis suffer from severe limitations. In Chapter 5 ultra short echo time (UTE) MRI was used to study replacement and diffuse fibrosis in the ex vivo and in vivo mouse heart. Here, the MI mouse model was also used as it results in the formation of a spatially confined, collagenous scar providing an ideal model for proof-of-principle purposes. Subtraction of short- and long-TE images resulted in images highlighting tissue with short T2*, such as collagen. Indeed, a good correlation was obtained between the relative infarct volume as determined from histology and ex vivo UTE MRI. UTE MRI also resulted in signal differences between control and TAC hearts, which were related to the amount of collagen present in the hearts. Cardiovascular UTE MRI may thus provide a means for the assessment of diffuse fibrosis based on endogenous tissue contrast. Impaired myocardial energetics are thought to play an important role in HF. Chapter 6 describes 3D Image Selected In vivo Spectroscopy (ISIS) for single-voxel localized 31P-MRS of the in vivo mouse heart. From the resulting spectra the phosphocreatine-to-ATP (PCr/¿-ATP) ratio was quantified as a measure for myocardial energy status. When mice showed a markedly impaired LV systolic function and myocardial hypertrophy 7 weeks after TAC, PCr/ATP was approximately 25% lower 7 weeks as compared to control mice. Multiple studies have pointed to the possible predictive value of PCr/ATP, an important measure for myocardial energy status, for subsequent maladaptive ventricular remodeling. It is unclear though if PCr/ATP measured during the first stage of the remodeling process also predicts consecutive maladaptation. In Chapter 7 the hypothesis was therefore tested that PCr/ATP measured at the day of TAC or four days thereafter predicts subsequent remodeling. Such a relation could, however, not be established. Clear relations were obtained, on the other hand, between LV function and morphology four days after TAC and seven weeks, pointing to the importance of the severity of the initial pressure overload for maladaptive cardiac remodeling. In addition, these experiments showed an apparent decrease of PCr/ATP already at the day of TAC, whereas PCr/ATP four days after TAC was significantly decreased, pointing to the first signs of an impaired myocardial energy status

Advances in computational modelling for personalised medicine after myocardial infarction

Myocardial infarction (MI) is a leading cause of premature morbidity and mortality worldwide. Determining which patients will experience heart failure and sudden cardiac death after an acute MI is notoriously difficult for clinicians. The extent of heart damage after an acute MI is informed by cardiac imaging, typically using echocardiography or sometimes, cardiac magnetic resonance (CMR). These scans provide complex data sets that are only partially exploited by clinicians in daily practice, implying potential for improved risk assessment. Computational modelling of left ventricular (LV) function can bridge the gap towards personalised medicine using cardiac imaging in patients with post-MI. Several novel biomechanical parameters have theoretical prognostic value and may be useful to reflect the biomechanical effects of novel preventive therapy for adverse remodelling post-MI. These parameters include myocardial contractility (regional and global), stiffness and stress. Further, the parameters can be delineated spatially to correspond with infarct pathology and the remote zone. While these parameters hold promise, there are challenges for translating MI modelling into clinical practice, including model uncertainty, validation and verification, as well as time-efficient processing. More research is needed to (1) simplify imaging with CMR in patients with post-MI, while preserving diagnostic accuracy and patient tolerance (2) to assess and validate novel biomechanical parameters against established prognostic biomarkers, such as LV ejection fraction and infarct size. Accessible software packages with minimal user interaction are also needed. Translating benefits to patients will be achieved through a multidisciplinary approach including clinicians, mathematicians, statisticians and industry partners

Impact of heart rate on myocardial salvage in timely reperfused patients with STSegment elevation myocardial infarction. new insights from cardiovascular magnetic resonance

BACKGROUND: Previous studies evaluating the progression of the necrotic wave in relation to heart rate were carried out only in animal models of ST-elevated myocardial infarction (STEMI). Aim of the study was to investigate changes of myocardial salvage in relation to different heart rates at hospital admission in timely reperfused patients with STEMI by using cardiovascular magnetic resonance (CMR). METHODS: One hundred-eighty-seven patients with STEMI successfully and timely treated with primary coronary angioplasty underwent CMR five days after hospital admission. According to the heart rate at presentation, patients were subcategorized into 5 quintiles: &lt;55 bpm (group I, n = 44), 55-64 bpm (group II, n = 35), 65-74 bpm (group III, n = 35), 75-84 bpm (group IV, n = 37), ≥85 bpm (group V, n = 36). Area at risk, infarct size, microvascular obstruction (MVO) and myocardium salvaged index (MSI) were assessed by CMR using standard sequences. RESULTS: Lower heart rates at presentation were associated with a bigger amount of myocardial salvage after reperfusion. MSI progressively decreased as the heart rates increased (0.54 group I, 0.46 group II, 0.38 group III, 0.34 group IV, 0.32 group V, p&lt;0.001). Stepwise multivariable analysis showed heart rate, peak troponin and the presence of MVO were independent predictor of myocardial salvage. No changes related to heart rate were observed in relation to area at risk and infarct size. CONCLUSIONS: High heart rates registered before performing coronary angioplasty in timely reperfused patients with STEMI are associated with a reduction in salvaged myocardium. In particular, salvaged myocardium significantly reduced when heart rate at presentation is ≥85 bpm

Inhibition of Autophagy Signaling via 3-methyladenine Rescued Nicotine-Mediated Cardiac Pathological Effects and Heart Dysfunctions.

Rationale: Cigarette smoking is a well-established risk factor for myocardial infarction and sudden cardiac death. The deleterious effects are mainly due to nicotine, but the mechanisms involved and theranostics remain unclear. Thus, we tested the hypothesis that nicotine exposure increases the heart sensitivity to ischemia/reperfusion injury and dysfunction, which can be rescued by autophagy inhibitor. Methods: Nicotine or saline was administered to adult rats via subcutaneous osmotic minipumps in the absence or presence of an autophagy inhibitor, 3-methyladenine (3-MA). After 30 days of nicotine treatment, the rats underwent the cardiac ischemia/reperfusion (I/R) procedure and echocardiography analysis, and the heart tissues were isolated for molecular biological studies. Results: Nicotine exposure increased I/R-induced cardiac injury and cardiac dysfunction as compared to the control. The levels of autophagy-related proteins including LC3 II, P62, Beclin1, and Atg5 were upregulated in the reperfused hearts isolated from nicotine-treated group. In addition, nicotine enhanced cardiac and plasma ROS production, and increased the phosphorylation of GSK3β (ser9) in the left ventricle tissues. Treatment with 3-MA abolished nicotine-mediated increase in the levels of autophagy-related proteins and phosphorylation of GSK3β, but had no effect on ROS production. Of importance, 3-MA ameliorated the augmented I/R-induced cardiac injury and dysfunction in the nicotine-treated group as compared to the control. Conclusion: Our results demonstrate that nicotine exposure enhances autophagy signaling pathway, resulting in development of ischemic-sensitive phenotype of heart. It suggests a potentially novel therapeutic strategy of autophagy inhibition for the treatment of ischemic heart disease

Molecular imaging of tissue repair after myocardial infarction : preclinical evaluation of novel 68Ga-labeled PET tracers

Congestive heart failure (HF) develops soon after acute myocardial infarction (AMI) in almost 25% of initial survivors. Modern cardiac imaging methods are useful for HF diagnostics and, possibly, the detection of underlying molecular mechanisms involved in myocardial repair. CD44, a cell-surface glycoprotein, is involved in various cellular functions, including cell proliferation, adhesion, migration and lymphocyte activation. Integrins are transmembrane proteins involved in various signaling pathways related to inflammation, angiogenesis and fibrosis. Expression of proteolytic matrix metalloproteinases 2 and 9 (MMP-2/9) also associates with extracellular matrix remodeling. The purpose of this thesis was to evaluate novel Gallium-68 labeled imaging agents targeting αvβ3 integrin, MMP-2/9, or CD44, for positron emission tomography (PET) imaging of post-MI repair in a surgical rat model. The MMP- 2/9 targeting tracer watarkias also evaluated for imaging of atherosclerotic lesions in a hypercholesterolemic mouse model. In vivo PET imaging, ex vivo biodistribution, ex vivo autoradiography, and immunohistochemistry were utilized to assess tracer stability, uptake in various tissues, as well as uptake correlation with various cellular level processes. Of the studied tracers, αvβ3 integrin targeting tracer showed the most optimal characteristics for imaging of myocardial healing processes. Tracer uptake in the damaged myocardium was clearly visible in vivo, and blood clearance as well as tracer stability were sufficient. The CD44 targeting tracer showed initial potential warranting further development, as the tracer uptake was associated with myocardial inflammation. MMP-2/9 targeted imaging showed significant limitations due to tracer instability and slow clearance. In conclusion, imaging of αvβ3 integrin expression is a potential tool for the purpose of evaluating myocardial repair after MI.Sydänkudoksen infarktinjälkeisen paranemisen molekyylikuvantaminen : uusien 68Ga-leimattujen merkkiaineiden prekliininen arviointi Sydämen vajaatoiminta kehittyy pian akuutin sydäninfarktin jälkeen lähes 25 prosentille eloonjääneistä. Nykyaikaiset sydämen kuvantamismenetelmät ovat hyödyllisiä diagnostiikassa ja mahdollisesti sydänlihaksen muovautumiseen liittyvien molekyylimekanismien havaitsemisessa. Solupinnan glykoproteiini CD44 osallistuu erilaisiin soluvälitteisiin toimintoihin, kuten proliferaatioon, adheesioon, migraatioon ja lymfosyyttien aktivaatioon. Integriinit ovat transmembraaniproteiineja, jotka osallistuvat erilaisiin signalointireitteihin liittyen tulehdukseen, angiogeneesiin ja fibroosiin. Proteolyyttisten matriksin metalloproteinaasi 2:n ja 9:n (MMP-2/9) ilmentyminen liittyy niin ikään solunulkoisen matriksin uudelleenmuovautumiseen. Tämän väitöskirjan tarkoituksena on arvioida uusia Gallium-68-leimattuja koettimia positroniemissiotomografiaa (PET) varten. Tutkitut koettimet kohdistuvat joko αvβ3-integriiniin, MMP-2/9:ään tai CD44:ään. Tutkimus toteutettiin infarktinjälkeisen sydämen vajaatoiminnan kirurgisessa rottamallissa. MMP-2/9-koetinta arvioitiin myös ateroskleroottisten muutosten kuvantamiseen hyperkolesterolemisessa hiirimallissa. αvβ3-integriiniin kohdentuvan merkkiaineen kertymä näkyi selkeästi in vivo, ja veren puhdistuma sekä merkkiaineen stabiilisuus olivat riittävät. CD44 kuvantamiskohteena osoitti alkuvaiheen potentiaalia, joka mahdollistaa jatkokehityksen, sillä merkkiaineen kertymä assosioitui infarktinjälkeiseen tulehdusreaktioon. MMP-2/9- kohdennetulle kuvantamiselle puolestaan ilmeni merkittäviä rajoituksia merkkiaineiden epävakauden ja hitaan veripuhdistuman vuoksi Yhteenvetona voidaan todeta, että αvβ3-integriinifragmentin kuvantaminen on potentiaalinen työkalu sydänlihaksen paranemisprosessien arvioimiseksi akuutin sydäninfarktin jälkeen

Temporal dynamics and pathophysiology of the edematous response after acute myocardial infarction: a translational journey

Post-myocardial infarction tissue composition is highly dynamic and can be characterized by cardiac magnetic resonance, which has been used to assess surrogate outcomes and efficacy endpoints in many experimental and clinical studies. However, there is a paucity of studies tracking the temporal dynamics of these processes and analyzing their pathophysiology in a comprehensive manner. The experimental and clinical work contained in this dissertation shows that the degree and extent of post-myocardial infarction tissue composition changes (mainly edema; but also necrosis, hemorrhage and microvascular obstruction) as assessed by cardiac magnetic resonance are variable according to the time from infarction, duration of ischemia, cardioprotective strategies, and the interplay between them. These dynamic changes should be taken into consideration when performing image acquisition. Comparative studies should be performed at similar timings to avoid the bias of these dynamic changes. Thus, and in contrast to the accepted view, it is shown for the first time that myocardial edema in the week after ischemia/reperfusion is a bimodal phenomenon, both in pigs and humans. The initial wave of edema, appearing abruptly upon reperfusion and which is significantly attenuated at 24 hours, is due to the reperfusion process itself. The deferred wave of edema, appearing progressively days after ischemia/reperfusion and reaching a plateau between days 4 to 7, is mainly caused by the tissue healing processes. These findings highlight the need for standardizing experimental and clinical protocols for post-myocardial infarction tissue characterization aiming to quantify edema, myocardial area at risk, infarct size, myocardial salvage, intramyocardial hemorrhage and microvascular obstruction. The timeframe between day 4 and 7 post-infarction seems a good compromise solution according to translational data here presented. However, further studies and expert consensus are needed to stablish more precise recommendations