Novel diagnostic and prognostic tools in infiltrative cardiomyopathy
Eldhagen, Per
2024-05-17
09.00
Torsten Gordh, Eugeniavägen 27, Norrbacka (S2:02), Karolinska University Hospital, Solna
Inst för medicin, Solna / Dept of Medicine, Solna
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.