Novel diagnostic and prognostic tools in infiltrative cardiomyopathy

Background: Heart failure is a severe medical condition, increasingly common in the aging population, causing both vast morbidity and mortality. Amongst different etiologies of heart failure, infiltrative cardiomyopathies are relatively rare but associate with worse prognosis. The two most common infiltrative cardiomyopathies, cardiac amyloidosis (CA) and cardiac sarcoidosis (CS) are underdiagnosed. Treatments addressing their specific pathophysiologic mechanisms may be considered in both conditions. Increased awareness of these diseases, better tools to establish an early diagnosis and improved understanding of prognostication is of value to optimize treatment and potentially improve outcomes in both CA and CS. Previous studies indicate that lumbar spinal stenosis (LSS) associate with transthyretin (ATTR) amyloidosis and that LSS might be a possible early sign of disease, preceding CA. In sarcoidosis, variants of the HLA-DRB1 gene associate with different phenotypes, but the association with cardiac involvement is less studied.

The aims of this thesis are to 1) Investigate the prevalence, type, and grade of amyloid deposits in ligamentum flavum in LSS, explore signs of systemic amyloidosis and determine the prevalence of manifest CA, at time of surgery and at six years follow up. 2) Characterize Swedish CS patients, assess if variants of the HLA-DRB1 gene associate with cardiac involvement and explore baseline characteristics in association with severe outcomes.

Methods and Results: Study I. 250 consecutive patients that underwent surgery for LSS at Stockholm Spine Center were included. Connective tissue removed at surgery was analyzed for the presence, grade, and type of amyloid deposits. 37% were found to have ATTR amyloid deposits in ligament tissue. Subjects with higher grades of ATTR deposits were evaluated with cardiac investigations. Several findings indicate systemic disease but none of the patients had significant cardiac involvement, at time of surgery. Study II. Retrospective data on 87 patients diagnosed with CS at Karolinska University Hospital and Sahlgrenska University Hospital were collected from the electronic medical records, including HLA-DRB1 allele genotyping. The majority (59%) presented with cardiac symptoms as first sign of sarcoidosis (de novo CS). CS as first manifestation associated with worse cardiac function than those previously diagnosed with sarcoidosis in other organs. We did not observe significant differences in HLA-DRB1 allele frequencies in patients with CS compared to sarcoidosis in general, but trends towards significant differences in subgroups were observed. Study III. Data on the combined endpoint of death, heart transplantation (HTx) or sustained ventricular arrhythmias (VT/VF) were extracted from the electronic medical records. De novo CS and initial presentation of VT/VF associated with worse outcomes. 42 different possible predictors were assessed using a machine learning algorithm to decide their relative importance in the prediction of the combined endpoint. De novo CS and right ventricular (RV) dysfunction displayed the highest relative importance in predicting outcomes in this model. Study IV. Prospective follow-up study with multimodality cardiac imaging of 21 patients, with high grades of amyloid deposits in ligament tissue, six years after surgery for LSS. 16% (3/19) were diagnosed with age-related transthyretin (ATTRwt) CA. 48% (10/21) had been diagnosed with other tenosynovial disorders that associate with ATTR amyloidosis. Changes in cardiac function and signs of interstitial pathology in the overall cohort were assessed with echocardiography and cardiac magnetic resonance imaging.

Conclusion: ATTR amyloid deposits are common in ligament tissue in LSS. Several findings support the hypothesis that LSS is a possible systemic manifestation of ATTRwt and longitudinal cardiac follow up after surgery is a promising diagnostic pathway to find early cases of ATTRwt-CA. Around half of the CS patients presented with de novo CS and this presentation associated with more severe cardiac dysfunction and increased risk of death, cardiac transplantation, and VT/VF. Increased awareness of CS as a primary manifestation may improve detection and enable earlier treatment. In a machine learning model, cardiac symptoms as first presentation together with RV dysfunction displayed the highest relative importance in predicting worse outcomes. In CS, HLA-DRB1 allele frequencies did not differ from the sarcoidosis population in general.

List of scientific papers

I. Eldhagen P, Berg S, Lund LH, Sörensson P, Suhr OB, Westermark P. Transthyretin amyloid deposits in lumbar spinal stenosis and assessment of signs of systemic amyloidosis. J Intern Med. 2021 Jun ;289(6):895-905.
https://doi.org/10.1111/joim.13222

II. Eldhagen P, Bobbio E, Darlington P, Grunewald J, Eklund A, Polte CL, Bergh N, Bollano E, Sörensson P, Kullberg S. Phenotypic and HLA-DRB1 allele characterization of Swedish cardiac sarcoidosis patients. Int J Cardiol. 2022 Jul 15;359:108-112.
https://doi.org/10.1016/j.ijcard.2022.04.006

III. Bobbio E, Eldhagen P, Polte CL, Hjalmarsson C, Karason K, Rawshani A, Darlington P, Kullberg S, Sörensson P, Bergh N, Bollano E. Clinical Outcomes and Predictors of Long-Term Survival in Patients With and Without Previously Known Extracardiac Sarcoidosis Using Machine Learning: A Swedish Multicenter Study. J Am Heart Assoc. 2023 Aug ;12(15):e029481.
https://doi.org/10.1161/JAHA.123.029481

IV. Eldhagen P, Tzortzakakis A, Lund LH, Söderström L, Berg S, Westermark P, Sörensson P. Prevalence of cardiac amyloidosis and other signs of systemic amyloidosis six years after lumbar spinal stenosis surgery, in patients with transthyretin amyloid deposits in ligamentum flavum. [Manuscript]