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Patient stratification and treatment effects in diseases with disturbed cardiac function
Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
2020 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Background: Cardiovascular disease characteristics are often measured using a combination of different measurement modalities. By combining information from these modalities using statistical modelling we can gain additional knowledge about these diseases. 

Patients with hereditary transthyretin amyloidosis (ATTRv amyloidosis) often present with heart rate disturbances and ventricular hypertrophy. Although ATTRv amyloidosis can lead to a thick ventricular myocardium and heart failure this can also be due to other pathologies e.g. hypertrophic cardiomyopathy (HCM), which may lead to misdiagnosis. Children with hereditary long QT syndrome (LQTS) carry the risk of lethal cardiac events linked to increased sympathetic activity. If the regulatory pattern, measured by heart rate variability (HRV), could differentiate between LQTS genotypes and healthy children during childhood, it may then establish a role for HRV in evaluating such patients. Statins is the most common pharmaceutical treatment for atherosclerosis. However, the effect of statins on coronary calcification has shown mixed results between studies.

Aim: The overall aim of this thesis was to use statistically rigorous methodology to explore stratification of subgroups of patients and estimate treatment effects in diseases with cardiac involvement. The specific aims were: to evaluate discriminating features between ATTRv amyloidosis and HCM patients in different clinical examinations of their hearts; to evaluate the longitudinal growth pattern in HRV in children with LQTS; and, to estimate the short- and long-term treatment effects of statin treatment on coronary calcification in patients with coronary arteriosclerosis. 

Methods: In Study I we used classification and regression trees in order to create a clinical interpretable decision tree in order to differentiate between 35 ATTRv amyloidosis patients and 37 HCM patients based on features derived from echocardiography and ECG. In Study II a retrospective sample of 38 ATTRv amyloidosis patients, 41 HCM patients and 62 healthy controls were analyzed using k-means clustering and Random forest models in order to investigate similarities and differences in echocardiographic features and HRV. In Study III we calculated gender and treatment dependent age trends for spectral HRV features from longitudinal measurements from 70 children with LQTS (58 LQT1, 12 LQT2) and 65 healthy controls, using generalized additive mixed effects models. In Study IV data from two large clinical trials, in total 1585 patients with mild cardiac symptoms, was used to estimate the short- and long-term treatment effects of statin treatment on coronary calcification.

Results: In study I we found that a decision tree using both ECG and echocardiographic measurements provided the best separation between HCM and ATTRv amyloidosis. In study II we found that HRV could be used for discriminating between these diseases and that abnormalities in HRV are related on ATTRv fibril type but uncommon in HCM. In study III we found that the age trend in HRV in LQTS-patients showed no clear differences between controls and patients different LQTS genotypes. In study IV we found that high dose statin treatment resulted in a dose dependent increase in calcium score at both short- and long-term follow up. At the long-term follow up, we found no evidence to suggest that the increased calcium score had resulted in increased cardiac events.

Conclusions: The results from our studies could be used for differentiating HCM and ATTRv amyloidosis patients. The heterogeneity within these patient groups could further be characterized using features from echocardiography and HRV. Our data do not support evidence for a different age trend in HRV parameters in children with LQTS compared to controls of similar age. We also found that statin treatment increased calcium score on both short-and long-term follow up. Taken together the results and methods from this thesis may be used for future support in clinical decisions regarding patient stratification and knowledge of treatment effects.

Place, publisher, year, edition, pages
Umeå: Umeå universitet , 2020. , p. 82
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 2089
Keywords [en]
Biostatistics, Heart rate variability, Cardiac amyloidosis, hypertrophic cardiomyopathy, cluster analysis, Echocardiography, Long QT syndrome, Pediatric, Statins, Coronary artery calcium, Computer tomography, Machine learning, Predictive modeling
National Category
Medical Engineering
Identifiers
URN: urn:nbn:se:umu:diva-173971ISBN: 978-91-7855-311-2 (electronic)ISBN: 978-91-7855-310-5 (print)OAI: oai:DiVA.org:umu-173971DiVA, id: diva2:1457313
Public defence
2020-09-04, Sal 933, Unod B9, 9tr. Norrlands Universitetssjukhus, Norrlands Universitetssjukhus, Daniel Naezéns väg, 907 37 Umeå, Umeå, 13:00 (Swedish)
Opponent
Supervisors
Available from: 2020-08-17 Created: 2020-08-11 Last updated: 2020-08-12Bibliographically approved
List of papers
1. Can echocardiography and ECG discriminate hereditary transthyretin V30M amyloidosis from hypertrophic cardiomyopathy?
Open this publication in new window or tab >>Can echocardiography and ECG discriminate hereditary transthyretin V30M amyloidosis from hypertrophic cardiomyopathy?
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2015 (English)In: Amyloid: Journal of Protein Folding Disorders, ISSN 1350-6129, E-ISSN 1744-2818, Vol. 22, no 3, p. 163-170Article in journal (Refereed) Published
Abstract [en]

Objective: Hereditary transthyretin (ATTR) amyloidosis with increased left ventricular wall thickness could easily be misdiagnosed by echocardiography as hypertrophic cardiomyopathy (HCM). Our aim was to create a diagnostic tool based on echocardiography and ECG that could optimise identification of ATTR amyloidosis. Methods: Data were analysed from 33 patients with biopsy proven ATTR amyloidosis and 30 patients with diagnosed HCM. Conventional features from ECG were acquired as well as two dimensional and Doppler echocardiography, speckle tracking derived strain and tissue characterisation analysis. Classification trees were used to select the most important variables for differentiation between ATTR amyloidosis and HCM. Results: The best classification was obtained using both ECG and echocardiographic features, where a QRS voltage >30 mm was diagnostic for HCM, whereas in patients with QRS voltage <30 mm, an interventricular septal/posterior wall thickness ratio (IVSt/PWt) >1.6 was consistent with HCM and a ratio <1.6 supported the diagnosis of ATTR amyloidosis. This classification presented both high sensitivity (0.939) and specificity (0.833). Conclusion: Our study proposes an easily interpretable classification method for the differentiation between HCM and increased left ventricular myocardial thickness due to ATTR amyloidosis. Our combined echocardiographic and ECG model could increase the ability to identify ATTR cardiac amyloidosis in clinical practice.

Keywords
cardiac amyloidosis, classification tree, echocardiography, electrocardiography, hypertrophic rdiomyopathy, hypertrophy
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:umu:diva-109962 (URN)10.3109/13506129.2015.1037831 (DOI)000361295200004 ()26104852 (PubMedID)2-s2.0-84940032324 (Scopus ID)
Available from: 2015-10-09 Created: 2015-10-09 Last updated: 2023-03-24Bibliographically approved
2. Multimodal analysis of the pattern of disturbances in heart rate variability and echocardiographic features in patients with hereditary transthyretin amyloidosis and hypertrophic cardiomyopathy
Open this publication in new window or tab >>Multimodal analysis of the pattern of disturbances in heart rate variability and echocardiographic features in patients with hereditary transthyretin amyloidosis and hypertrophic cardiomyopathy
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(English)Manuscript (preprint) (Other academic)
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:umu:diva-173966 (URN)
Available from: 2020-08-11 Created: 2020-08-11 Last updated: 2020-08-25
3. A study of heart rate variability in long QT syndrome children and adolescents: HRV in children with LQTS
Open this publication in new window or tab >>A study of heart rate variability in long QT syndrome children and adolescents: HRV in children with LQTS
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(English)Manuscript (preprint) (Other academic)
National Category
Pediatrics
Identifiers
urn:nbn:se:umu:diva-173968 (URN)
Available from: 2020-08-11 Created: 2020-08-11 Last updated: 2022-10-03
4. High dose and long-term statin therapy accelerate coronary artery calcification
Open this publication in new window or tab >>High dose and long-term statin therapy accelerate coronary artery calcification
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2015 (English)In: International Journal of Cardiology, ISSN 0167-5273, E-ISSN 1874-1754, Vol. 184, p. 581-586Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: In randomized clinical trials statins and placebo treated patients showed the same degree of coronary artery calcium (CAC) progression. We reanalyzed data from two clinical trials to further investigate the time and dose dependent effects of statins on CAC. Additionally, we investigated whether CAC progression was associated with incident cardiovascular events.

METHODS AND RESULTS: Data were pooled from two clinical trials: St. Francis Heart Study (SFHS) (419 and 432 patients treated with placebo and 20mg atorvastatin daily, respectively) and EBEAT Study (164 and 179 patients respectively treated with 10mg and 80mg atorvastatin daily). CAC scores were assessed at baseline, 2years and 4-6years in SFHS; in EBEAT they were measured at baseline and 12months. After a short-term follow-up (12 to 24months) placebo and low dose atorvastatin showed a similar CAC increase, although 80mg/daily atorvastatin increased CAC an additional 12-14% over placebo (p<0.001). In the long-term, atorvastatin caused a greater progression of CAC compared to placebo (additional 1.1%, p=0.04). In SFHS 42 cardiovascular events occurred after the second CT scan. The baseline and progression of CAC were greater in patients with events. However, only baseline CAC and family history of premature cardiovascular disease but not CAC progression were independent predictors of events.

CONCLUSIONS: Despite a greater CAC increase with high dose and long-term statin therapy, events did not occur more frequently in statin treated patients. This suggests that CAC growth under treatment with statins represents plaque repair rather than continuing plaque expansion.

Keywords
Statins,  Coronary artery calcium,  Computed tomography
National Category
Cardiac and Cardiovascular Systems
Identifiers
urn:nbn:se:umu:diva-101972 (URN)10.1016/j.ijcard.2015.02.072 (DOI)000353763800140 ()25769003 (PubMedID)2-s2.0-84929360502 (Scopus ID)
Available from: 2015-04-17 Created: 2015-04-17 Last updated: 2023-03-24Bibliographically approved

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