Johanna Kuusisto

Both hypertrophic cardiomyopathy (HCM) and hypertensive heart disease (HHD) are characterized by left ventricular hypertrophy. Distinguishing HCM from HHD is a common clinical problem, particularly in subjects with moderate left ventricular maximal wall thickness (LVMWT) < 18 mm. Previously, we showed that cardiac magnetic resonance (CMR)-derived septal convexity (SC) into the left ventricle is increased in subjects with HCM-causing mutations with and without LVH. Our objective now was to determine whether CMR-derived SC differentiates HCM from HHD. We measured the maximal distance between the LV septal endocardial border and a line connecting the proximal and distal septal mid-wall points in 4-chamber images, in subjects with hypertension and LVH (n = 29), in subjects with HCM (n = 49), and in healthy controls (n = 20). Here, we show significantly increased SC in subjects with HCM compared to subjects with HHD both in non-indexed and in BSA-indexed measurements. Cutoff SC values of 7.9 mm and 3.7 mm/m2 in all HCM patients and SC values of 7.9 mm and 3.8 mm/m2 in HCM patients with LVMWT < 18 mm differentiated between HCM and HHD with good sensitivity and excellent specificity: SC cutoff value of 7.9 mm had a sensitivity of 77% and a specificity of 90% in all HCM patients, and 67% and 90% in HCM patients with LVMWT < 18 mm, respectively. Our study shows that measuring CMR-derived septal convexity is straightforward and enhances diagnostic performance, providing a novel technique to distinguish between HCM caused by sarcomere mutations and hypertension-induced LVH.

Aims: To investigate the genetics, cardiac phenotype and cardiovascular outcomes of Finnish Fabry patients. Methods and results: Among the 109 patients with Fabry disease (FD) diagnosed in Finland by 2018, 97 (89%; 32 males and 65 females, mean ages 42 and 52 years) were followed for a mean of 12 years. Data on genetics, phenotypes, cardiac imaging and cardiovascular outcomes were collected from the Fabry Registry and medical records. The 26 families with FD harboured 22 different hemi−/heterozygous GLA variants, most commonly p.R227X, p.A143T or p.P409A. The Fabry phenotype in males was classic in 19 (59%), late-onset in 10 (31%) and intermediate in 3 (9%) patients. Among the females, 62 (95%) were symptomatic. Fabry cardiomyopathy (FC, maximal left ventricular wall thickness ≥13 mm, or an increased cardiac mass and decreased T1 time, or typical late gadolinium enhancement (LGE) in CMR) was present in 21 (66%) males manifesting since their 20s, and in 32 (49%) females since their 40s. LGE in CMR was detected in most subjects with cardiomyopathy, particularly in females. Among the 53 patients with FC, 16 (30%) developed atrial fibrillation, 17 (32%) stroke, 14 (26%) heart failure (HF) and 3 (6%) end-stage renal disease. Nine patients died during the follow-up at mean ages of 48 (males) and 75 years (females), three of whom died from HF and three from stroke. Eight of those who died had cardiomyopathy. Conclusions: In Finland, FD is caused by multiple GLA variants. Classic phenotype is more common. Contrasting previous studies, most women are symptomatic. Cardiomyopathy is very common also in women since their 40s and associates with atrial fibrillation, HF, stroke and death, emphasizing the malignant natural course of FC. Our findings highlight the need for even more diligent monitoring of cardiac manifestations also in females with FD by regular cardiac imaging with CMR.

To investigate a comprehensive panel of biomarkers and risk of aortic stenosis (AS) in a prospective population-based study. Anthropometric, metabolic, and inflammatory biomarkers were measured in the Metabolic Syndrome in the Men Study of 10,144 Finnish men without AS at baseline. Cases of AS were identified from the medical records. Cox regression analysis was used to identify variables predicting AS over a follow-up time of 10.8 years. Principal component (PC) analysis was applied to the biomarkers that predicted AS. Cox regression analysis was used to investigate the resulting PCs as AS predictors. AS was diagnosed in 116 men (1.1%), with a median age of 62 years. In Cox regression analyses, fasting, 30 min, and 120 min plasma insulin, and proinsulin, with hazard ratios (HR) ranging from 1.38 (1.12-1.69, p = 2.1E-3) to 1.44 (1.23-1.68, p = 4.0E-6), Matsuda index [HR 0.68 (0.56-0.82, p = 6.9E-5)], and serum C-peptide [HR 1.47 (1.22-1.77, p = 5.0E-5)] were associated with incident AS, in addition to age, systolic blood pressure, BMI, waist circumference, waist/hip ratio, height, body fat mass, fat-free mass, and hs-CRP, and remained significant after adjustments, or if diabetic subjects were excluded. PC 1, consisting of fasting plasma insulin, C-peptide, Matsuda index, waist/hip ratio, and urine albumin excretion, and PC 2, consisting of age, body fat mass, and systolic blood pressure, were significantly associated with AS [HRs 1.37(1.09-1.73) and 1.77 (1.45-2.17), respectively]. Biomarkers reflecting insulin resistance are risk factors for AS, a novel finding indicating that insulin resistance is important in the pathogenesis of AS.

Introduction Central obesity (CO), characterized by an increased waist circumference increases the risk of cardiovascular disease (CVD) and morbidity, yet the underlying mechanisms are not fully understood. CO is often associated with general obesity, hypertension, and abnormal glucose tolerance, confounding the independent contribution of CO to CVD. Aim We investigated the relationship of CO (without associated disorders) with left ventricular (LV) characteristics and intrathoracic adipose tissue (IAT) by cardiac magnetic resonance. Methods LV characteristics, epicardial (EAT), and mediastinal adipose tissue (MAT) were measured from 29 normoglycemic, normotensive males with CO but without general obesity (waist circumference >100 cm, body mass index (BMI) 2) and 18 non-obese male controls. Results LV maximal wall thickness (LVMWT) and IAT but not LV mass or volumes were increased in CO subjects compared to controls (LVMWT, 12.3±1.2 vs. 10.7±1.5 mm, p < 0.001; EAT, 5.5±3.0 vs. 2.2±2.0 cm², p = 0.001; MAT, 31.0±12.8 vs. 15.4±10.7 cm², p < 0.001). The LVMWT was ≥12 mm in 69% of subjects with CO and 22% of controls (p = 0.002). In CO suspects, EAT correlated inversely with LV end-diastolic volume index (r = − 0.403, p = 0.037) and LV stroke volume (SV) (r = − 0.425, p = 0.027). MAT correlated inversely with SV (r = − 0.427, p=0.026) and positively with LVMWT (r = 0.399, p = 0.035). Among CO subjects, the waist-to-hip ratio (WHR) was an independent predictor of LVMWT (B = 22.4, β = 0.617, p < 0.001). The optimal cut-off with Youden’s index for LV hypertrophy was identified at WHR 0.98 (sensitivity 85%, specificity 89%). Conclusions CO independent of BMI is associated with LV hypertrophy and intrathoracic adipose tissue contributing to cardiovascular burden.

Objective: To present phenotypic characteristics and biomarkers of a family with the rare mutation Thr410Ala of the α-galactosidase A gene (T410A/GLA) causing Fabry disease (FD). Methods and results: In a woman in her 60s with hypertrophic cardiomyopathy, T410A/GLA was found in screening for variants in 59 cardiomyopathy-related genes. Her son in his 40s, two granddaughters and two great grandsons carried T410A/GLA. The son had a history of hypertension and paroxysmal AF but no microalbuminuria or classic symptoms or signs of FD. Baseline α-galactosidase A enzyme (α-Gal A) activity varied from 0% to 26.5%. Cardiac MRI showed mild Fabry cardiomyopathy (FC). During 11 years of enzyme replacement therapy (ERT), FC progressed and he suffered sudden cardiac death in his 50s. The great grandsons with T410A/GLA had no active α-Gal A, high lyso-Gb₃ levels and normal cardiac imaging. They suffered from neuropathic pain and gastrointestinal symptoms and were started with ERT at the age under 10. Granddaughters with T410A/GLA had α-Gal A activities of 8–18 and 10% of normal. The older granddaughter in her 30s was diagnosed with incipient FC. Plasma lyso-Gb₃ analogues were elevated, markedly in the elder male with FC and moderately in the elder granddaughter. In young males with classic phenotype, plasma lyso-Gb₃ analogues were only slightly elevated. Conclusions: The T410A/GLA mutation caused late-onset FD with progressive cardiomyopathy in elder male, and classic FD in young males of the same family. Varying levels of α-Gal A and lyso-Gb₃ analogues reflected variable phenotype of FD in the family.

Background/Introduction: Fabry disease (FD) is a lysosomal storage disorder caused by mutations in the α- galactosidase A gene (GLA) leading to lack of an active GLA enzyme and accumulation of glycosphingolipids in different organs, including heart. Because of X-linked inheritance, the phenotype is usually more severe in males than in females. Purpose: There are very few national studies on FD. Our aim was to investigate the genetics, phenotype, treatment and prognosis of Finnish Fabry patients by gender. Methods: Finnish Fabry Registry includes 98 patients, approximately 90% of all Finnish patients with FD, diagnosed from 1972 to 2018. Cardiovascular, neurological and renal events, and cardiac imaging data were recorded from medical charts until 2020. Cardiac ultrasound and MRI (CMR) were performed in 86% and 77% of females and 88% and 78% of males, respectively. Results: Altogether, 24 different pathogenic GLA mutations were found in 66 females and 32 males from 27 Finnish families. FD, or the causative mutation, was diagnosed at an average age of 41 years in females, and at 29 years in males. During the mean 17 years of follow-up, either ERT or migalastat was started for 58% of females and 88% of males. At the end of the follow-up, Fabry cardiomyopathy (FCM; maximal left ventricular wall thickness (LVMWT) 13 mm or more in cardiac imagining) had been diagnosed in 47% of females and 66% of males at the mean age of 55 years and 41 years, respectively. Atrial fibrillation (AF) was diagnosed in 21% of females and 9% of males. Heart failure (HF) due to FCM was diagnosed in 20% of females and in 12% of males at the mean age of 62 and 54 years, respectively. A bradycardia pacemaker was required for 9 females and for 2 males and one female and one male had also implantable cardioverter defibrillator. Over 20% of both female and male FD patients suffered a stroke during the follow-up. End-stage kidney disease was not found in females, but 9% of males received a renal transplantation. During the follow-up 5 females and 3 males died. The mean age at death was 77 years in females, and 48 years in males. All deceased males and 40% of females had been treated with ERT from an average age of 40 and 66 years, respectively. All deceased subjects had FCM. All females and one male died of FD. Two females died of a stroke and three of HF. All deceased males had severe classical FD phenotype. One male suffering from severe HF died of a stroke. One male with an ICD and renal transplant, died of malignancy. The third male withdrew from follow-up and died of gastrointestinal bleeding. Conclusions: In Finnish patients with FD, cardiomyopathy, related arrhythmias and heart failure were common in both genders. All eight deceased subjects had Fabry cardiomyopathy, and the immediate cause of death was most often heart failure or stroke. Funding Acknowledgement: Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Finnish Heart Research Foundationand Sanofi Genzyme

Objective Transthyretin amyloid cardiomyopathy (ATTR-CM) is a rare, progressive and fatal condition caused by deposition of transthyretin amyloid fibrils in the heart. This study aims to identify all patients diagnosed with ATTR-CM in Sweden, estimate the prevalence of ATTR-CM, describe patient characteristics and mortality, assess the importance of early symptoms (red flags) for identification of ATTR-CM, and compare with patients with heart failure (HF). Methods This retrospective study combined multiple national health registers covering all specialist visits and prescriptions for the entire population of Sweden. Between January 2008 and December 2018, patients with ATTR-CM were identified retrospectively based on a combination of diagnosis codes and compared with matched, all-cause non-ATTR HF patients. Results Overall, a total of 994 patients diagnosed with ATTR-CM were identified, with an average age at diagnosis of 73 years, and 30% of whom were female. The prevalence of diagnosed ATTR-CM cases in 2018 was 5.0 per 100 000. The median survival from diagnosis was 37.6 months (CI 33.8 to 43.8), with a lower median survival in women (27.9 months, CI 23.3 to 33.8) compared with men (43.5 months, CI 37.6 to 49.6). Patients with ATTR-CM demonstrated reduced survival compared with patients with HF (pConclusions This study provides the first nationwide estimates of ATTR-CM prevalence and risk factors. The results reinforce the severity of the disease and the importance of earlier diagnosis, especially for female patients, in order to allow effective treatment and prevention of disease progression.

Summary: Systematic insight into cellular dysfunctions can improve understanding of disease etiology, risk assessment and patient stratification. We present a multiparametric high-content imaging platform enabling quantification of low-density lipoprotein (LDL) uptake and lipid storage in cytoplasmic droplets of primary leukocyte subpopulations. We validated this platform with samples from 65 individuals with variable blood LDL-cholesterol (LDL-c) levels, including familial hypercholesterolemia (FH) and non-FH subjects. We integrated lipid storage data into a novel readout, lipid mobilization, measuring the efficiency with which cells deplete lipid reservoirs. Lipid mobilization correlated positively with LDL uptake and negatively with hypercholesterolemia and age, improving differentiation of individuals with normal and elevated LDL-c. Moreover, combination of cell-based readouts with a polygenic risk score for LDL-c explained hypercholesterolemia better than the genetic risk score alone. This platform provides functional insights into cellular lipid trafficking from a few ml’s of blood and is applicable to dissect metabolic disorders, such as hypercholesterolemia. Motivation: We have limited information on how cellular lipid uptake and processing differ between individuals and influence the development of metabolic diseases, such as hypercholesterolemia. Available assays are labor intensive, require skilled personnel and are difficult to scale to higher throughput, making it challenging to obtain systematic functional cell-based data from individuals. To overcome this problem, we established a scalable automated analysis pipeline enabling reliable quantification of multiple cellular readouts, including lipid uptake, storage and mobilization, from different white blood cell populations. This approach provides new personalized insights into the cellular basis of hypercholesterolemia and obesity. Graphical

Aims There are only a few studies on novel biomarkers for incident heart failure (HF). We investigated the association of multiple circulating biomarkers with incident HF in a large prospective population‐based study. Methods and results Conventional risk factors and inflammatory biomarkers were measured, and systemic metabolic measures determined by a high‐throughput serum nuclear magnetic resonance platform in a population‐based Metabolic Syndrome in Men study including 10 106 Finnish men without HF at baseline. During an 8.8 year follow‐up, 172 (1.7%) participants developed HF. Adiponectin, high‐sensitivity C‐reactive protein (hs‐CRP), glycoprotein acetyls, alanine, phenylalanine, glycerol, and pyruvate were associated with incident HF in unadjusted Cox regression analyses, in addition to age, systolic blood pressure, body mass index (BMI), waist circumference, fasting plasma glucose and insulin, haemoglobin A1c (HbA1c), and urinary albumin excretion rate (UAER). After adjustment for age, BMI, diabetes, and statin medication, only adiponectin [hazard ratio (HR) 1.18 (1.10–1.26, P = 4.1E‐08)], pyruvate [HR 1.38 (1.28–1.50, P = 8.2E‐05)], and UAER [HR 1.15 (1.11—1.18, P = 7.8E‐06)] remained statistically significant. In principal component analysis of biomarkers associated with HF in univariate Cox regression analysis, we identified six components, explaining 61.7% of total variance. Four principal components, one with significant loadings on waist, BMI, fasting plasma insulin, interleukin 1 receptor antagonist, and hs‐CRP; another on pyruvate, glycoprotein acetyls, alanine, glycerol and HbA1c; third on age and glomerular filtration rate; and fourth on systolic blood pressure, UAER, and adiponectin, significantly associated with incident HF. Conclusions Several novel metabolic and inflammatory biomarkers were associated with incident HF, suggesting early activation of respective pathways in the pathogenesis of HF.