Małgorzata Szperl

Myocardial iron homeostasis in advanced chronic heart failure patients

BACKGROUND Although, correction of iron deficiency and/or anemia in heart failure (HF) with iron seems promising, little is known about myocardial iron load and homeostasis. Moreover iron supplementation indications are solely based on iron serum markers. The purpose was to assess myocardial iron (M-Iron), ferritin (M-FR), transferrin receptor (M-sTfR) in HF in relation to serum Iron markers. METHODS AND RESULTS Study group 33 patients, left/right ventricle (LV/RV) (LVEDV 245 ± 84 ml; LVESV 189 ± 85 ml; LVEF 22 ± 11%; RVD 32 ± 10 mm), NTproBNP (5464 ± 4825 pg/ml). Iron homeostasis assessment serum: iron, FR, transferrin/saturation (TSAT), sTfR; myocardial: M-Iron (Instrumental Neutron Activation Analysis, μg/g), M-FR, M-sTfR (ELISA - ng/mg protein) in the explanted failing hearts (FH), compared to non-failing hearts (NFH n=11). In FH as compared to NFH, M-Iron was reduced in RV (174 ± 45 vs 233 ± 97, respectively, p=0.07), LV (189 ± 58 vs 265 ± 119, p=0.04), without significant changes in M-FR/M-sTfR. Out of all serum iron markers only sTfR was negatively correlated with M-Iron in either ventricle (RV r=-0.44, p=0.03, LV r=-0.38, p=0.07). With regard to serum iron status, based on TSAT, patients were divided into two subgroups: reduced (TSAT<15%; n=11) and not-reduced serum iron (TSAT ≥ 15%; n=22). Both subgroups had similar grade of LV/RV dysfunction, NT-proBNP levels. M-FR was lower in TSAT<15% than in TSAT ≥ 15% (LV -31 ± 26 vs 46 ± 29; p=0.07) and (RV -24 ± 24 vs 43 ± 29; p=0.02), without differences in M-Iron and M-sTfR. CONCLUSIONS In HF, M-Iron levels were reduced. Serum iron markers did not reflect M-Iron levels, except for serum sTfR. In reduced serum iron group, decrease in myocardial storage protein M-FR was observed.

Influence of Renin-Angiotensin System Gene Polymorphisms on the Risk of ST-Segment-Elevation Myocardial Infarction and Association with Coronary Artery Disease Risk Factors

AbstractBackground: Recent advances in molecular biology have made it possible to identify numerous polymorphisms of the renin-angiotensin system, which play an important role in the etiology of cardiovascular disease. Objective: The aims of the study were (i) to assess the distribution of the angiotensin II type 1 receptor (AGTR1) gene 1166A/C polymorphism and two polymorphisms of the angiotensinogen (AGT) gene (Met235Thr and Thr174Met) in patients with ST-segment-elevation myocardial infarction (STEMI) who underwent coronary angiography, compared with healthy volunteers; (ii) to determine if there was any correlation between these polymorphisms and risk of STEMI; and (iii) to assess the association of the examined polymorphisms with such classic cardiovascular risk factors as hypertension, diabetes mellitus, obesity (based on a body mass index ≥25 kg/m2), smoking, dyslipidemia, and family history of cardiovascular disease. Methods: A total of 100 patients (mean age 57 ± 10 years [range 31–76 years]; 21% women) with diagnosed STEMI and a control group consisting of 95 healthy volunteers (mean age 38 ± 11 years [range 17–60 years]; 20% women) were investigated for the AGTR1 1166A/C polymorphism and two variants of AGT (Met235Thr and Thr174Met). All patients received standard therapy for STEMI. Results: There were significant differences in the distribution of genotypes and the AGT Met174 allele for AGT Thr174Met polymorphism between patients and healthy subjects (p<0.05). The AGTR1 1166A/C polymorphism genotype frequencies were significantly different in patients with hypertension compared with normotensive individuals. Specifically, the AGTR1 1166 AA genotype was twice as common in patients with hypertension as in those without (67% vs 33%), while the AC and CC genotypes were found predominantly in normotensive patients (p = 0.0016). The variant 1166C allele was much more common in patients without hypertension (67%) than in patients with hypertension (33%; p=0.0006). The variant AGT Thr235 allele was more common in patients without a family history of cardiovascular disease than in patients with this risk factor (p<0.05). The odds ratio (OR) for STEMI in patients with the heterozygous AGT 174 Thr/Met genotype was increased to 1.884 (95% confidence interval [CI] 1.03, 3.446; p<0.05), while the OR calculated for carriers of the AGT Met174 allele was 2.038 (95% CI 1.129, 3.68; p=0.0182). Significant genotypic associations of combinations of reninangiotensin system gene polymorphisms in STEMI were not observed. Conclusions: The most powerful predictive value for STEMI was represented by the Thr/Met genotype and the Met174 allele of the AGT Thr174Met gene polymorphism. In our study, in contrast to observations reported by other authors, the AA genotype of the AGTR1 1166A/C gene polymorphism — much more than other genotypes — was associated with hypertension.

Variants of the lamin A/C (LMNA) gene in non-valvular atrial fibrillation patients: a possible pathogenic role of the Thr528Met mutation.

BACKGROUND AND OBJECTIVE Lamin A/C (LMNA) gene mutations cause dilated cardiomyopathy, often accompanied by conduction disturbances. Our aim was to search for LMNA mutations in individuals with atrial fibrillation. METHODS A cohort of Polish subjects (N = 103) with non-valvular atrial fibrillation with a high (48.5%) prevalence of conduction system disturbances was screened for LMNA variants by direct DNA sequencing. RESULTS We found a single non-synonymous variant (Thr528Met) in a 72-year-old patient with normal left ventricular function and episodes of advanced atrioventricular block. One of his two mutation-carrying daughters had episodes of type I second-degree atrioventricular block on a 24-hour Holter ECG and peak exercise arrhythmia. Interpretation of cardiac anomalies observed in the other daughter was complicated by thyroid insufficiency. A Thr528Met weak pathogenic effect was supported by transient transfections of C2C12 mouse myoblasts and computationally. Another interesting variant was Ile26Ile (c.78C>T), found in a New York Heart Association class III patient with a depressed left ventricular ejection fraction (30%), left bundle branch block, and a family history of heart disease. Ile26Ile was absent in 246 healthy individuals and was computationally predicted to interfere with splicing. CONCLUSION LMNA mutations are not a frequent cause of atrial fibrillation even when conduction disease is present. Unlike the majority of LMNA mutations clearly associated with a severe clinical phenotype and a poor prognosis, Thr528Met results in a more subtle pathogenic effect, while Ile26Ile should be considered as a variant of unknown significance.

Variants of the Lamin A/C (LMNA) Gene in Non-Valvular Atrial Fibrillation Patients

AbstractBackground and Objective: Lamin A/C (LMNA) gene mutations cause dilated cardiomyopathy, often accompanied by conduction disturbances. Our aim was to search for LMNA mutations in individuals with atrial fibrillation. Methods: A cohort of Polish subjects (N = 103) with non-valvular atrial fibrillation with a high (48.5%) prevalence of conduction system disturbances was screened for LMNA variants by direct DNA sequencing. Results: We found a single non-synonymous variant (Thr528Met) in a 72-year-old patient with normal left ventricular function and episodes of advanced atrioventricular block. One of his two mutation-carrying daughters had episodes of type I second-degree atrioventricular block on a 24-hour Holter ECG and peak exercise arrhythmia. Interpretation of cardiac anomalies observed in the other daughter was complicated by thyroid insufficiency. A Thr528Met weak pathogenic effect was supported by transient transfections of C2C12 mouse myoblasts and computationally. Another interesting variant was Ile26Ile (c.78C>T), found in a New York Heart Association class III patient with a depressed left ventricular ejection fraction (30%), left bundle branch block, and a family history of heart disease. Ile26Ile was absent in 246 healthy individuals and was computationally predicted to interfere with splicing. Conclusion:LMNA mutations are not a frequent cause of atrial fibrillation even when conduction disease is present. Unlike the majority of LMNA mutations clearly associated with a severe clinical phenotype and a poor prognosis, Thr528Met results in a more subtle pathogenic effect, while Ile26Ile should be considered as a variant of unknown significance.

Impact of genetic and clinical factors on dose requirements and quality of anticoagulation therapy in Polish patients receiving acenocoumarol: dosing calculation algorithm.

Background Despite the recent emergence of new oral anticoagulants, vitamin K antagonists remain the primary therapy in patients with atrial fibrillation and the only therapy licensed for use in patients with artificial heart valves. Objective The aim of this study was (a) to assess the impact of clinical and genetic factors on acenocoumarol (AC) dose requirements and the percentage of time in therapeutic range (%TTR) and (b) to develop pharmacogenetic-guided AC dose calculation algorithm. Materials and methods We included 235 outpatients of the Institute of Cardiology (Warsaw), mean age 69.3, 46.9% women, receiving AC for artificial heart valves and/or atrial fibrillation. A multiple linear-regression analysis was performed using log-transformed effective AC dose as the dependent variable, and combining CYP2C9 and VKORC1 genotyping with other clinical factors as independent predictors. Results We identified factors that influenced the AC dose: CYP2C9 polymorphisms (P=0.004), VKORC1 polymorphisms (P<0.0001), age (P<0.0001), creatinine clearance lower than 40 ml/min (P=0.035), body mass (P=0.02), and dietary vitamin K intake (P=0.026). Clinical and genetic factors explained 49.0% of AC dose variability. We developed a dosing calculation algorithm that is, to the best of our knowledge, the first one to assess the effect of such clinical factors as creatinine clearance and dietary vitamin K intake on the AC dose. The clinical usefulness of the algorithm was assessed on separate validation group (n=50) with 70% accuracy. Dietary vitamin K intake higher than 200 mcg/day improved international normalized ratio control (%TTR 73.3±17 vs. 67.7±18, respectively, P=0.04). Conclusion Inclusion of a variety of genetic and clinical factors in the dosing calculation algorithm allows for precise AC dose estimation in most patients and thus improves the efficacy and safety of the therapy.

Titin Truncating Variants in Dilated Cardiomyopathy – Prevalence and Genotype-Phenotype Correlations

TTN gene truncating variants are common in dilated cardiomyopathy (DCM), although data on their clinical significance is still limited. We sought to examine the frequency of truncating variants in TTN in patients with DCM, including familial DCM (FDCM), and to look for genotype-phenotype correlations. Clinical cardiovascular data, family histories and blood samples were collected from 72 DCM probands, mean age of 34 years, 45.8% FDCM. DNA samples were examined by next generation sequencing (NGS) with a focus on the TTN gene. Truncating mutations were followed up by segregation study among family members. We identified 16 TTN truncating variants (TTN trunc) in 17 probands (23.6% of all cases, 30.3% of FDCM, 17.9% of sporadic DCM). During mean 63 months from diagnosis, there was no difference in adverse cardiac events between probands with and without TTN truncating mutations. Among relatives 29 mutation carriers were identified, nine were definitely affected (31%), eight probably affected (27.6%) one possibly affected (3.4%) and eleven were not affected (37.9%). When relatives with all affected statuses were combined, disease penetrance was still incomplete (62.1%) even after exclusion of unaffected relatives under 40 (82%) and was higher in males versus females. In all mutation carriers, during follow-up, 17.4% had major adverse cardiac events, and prognosis was significantly worse in men than in women. In conclusion, TTN truncating variants were observed in nearly one fourth of young DCM patient population, in vast majority without conduction system disease. Incomplete penetrance suggests possible influence of other genetic and/or environmental factors on the course of cardiotitinopathy. Counseling should take into account sex and incomplete penetrance.

Pheochromocytoma presenting as takotsubo-like cardiomyopathy following delivery

OBJECTIVE Diagnosis of pheochromocytoma during pregnancy can be difficult, and the tumor carries an unfavorable prognosis if not diagnosed and treated in a timely manner. METHODS To present a case of Takotsubo-like cardiomyopathy characterized by transient left ventricular apical ballooning due to pheochromocytoma following delivery. RESULTS A few hours after Caesarean section, a 32-year-old Caucasian female presented with pulmonary edema followed by cardiac arrest with echocardiographic and ventriculographic evidence of reversible acute myocardial failure characteristic of Takotsubo-like cardiomyopathy. A previously unrecognized adrenal pheochromocytoma was found during her clinical work-up. Left ventricle (LV) function normalized after surgical removal of the tumor, which was carried out after implementing an alpha-adrenoreceptor blockade. Hemorrhagic necrosis of the pheochromocytoma was seen on histopathologic analysis; this may have triggered the sequence of events leading to the development of Takotsubo-like cardiomyopathy and hemodynamic collapse. CONCLUSION To the best of our knowledge, this is the first reported case of Takotsubo-like cardiomyopathy related to pheochromocytoma following delivery. This emphasizes the increased cardiovascular risk if pheochromocytoma is not diagnosed and treated in a timely manner, especially during pregnancy.

Usefulness of Somatostatin Receptor Scintigraphy (99mTc-[HYNIC, Tyr3]-Octreotide) and 123I-Metaiodobenzylguanidine Scintigraphy in Patients with SDHx Gene-Related Pheochromocytomas and Paragangliomas Detected by Computed Tomography

Aims: The aim of this study was to assess the usefulness of somatostatin receptor scintigraphy (SRS) using 99mTc-[HYNIC, Tyr3]-octreotide (TOC) and 123I-metaiodobenzylguanidine (mIBG) in patients with SDHx-related syndromes in which paragangliomas were detected by computed tomography and to establish an optimal imaging diagnostic algorithm in SDHx mutation carriers. Methods: All carriers with clinical and radiological findings suggesting paragangliomas were screened by SRS and 123I-mIBG. Lesions were classified by body regions, i.e. head and neck, chest, abdomen with pelvis and adrenal gland as well as metastasis. Results: We evaluated 46 SDHx gene mutation carriers (32 index cases and 14 relatives; 28 SDHD, 16 SDHB and 2 SDHC). In this group, 102 benign tumors were found in 39 studied patients, and malignant disease was diagnosed in 7 patients. In benign tumors, the sensitivity of SRS was estimated at 77% and of 123I-mIBG at 22.0%. The SRS and mIBG sensitivity was found to be clearly region dependent (p < 0.001). The highest SRS sensitivity was found in head and neck paragangliomas (HNP; 91.4%) and the lowest was found in abdominal paragangliomas and pheochromocytomas (40 and 42.9%, respectively). The highest 123I-mIBG sensitivity was found in pheochromocytomas (sensitivity of 100%) and the lowest in HNP (sensitivity of 3.7%). In metastatic disease, SRS was superior to mIBG (sensitivity of 95.2 vs. 23.8%, respectively). Conclusion: SRS and 123I-mIBG single photon emission computed tomography (SPECT) sensitivity in SDHx patients is highly body region dependent. In malignant tumors, SRS is superior to 123I-mIBG SPECT.

GROWTH RATE OF PARAGANGLIOMAS RELATED TO GERMLINE MUTATIONS OF THE SDHX GENES

OBJECTIVE The purpose was to determine the growth rate of succinate dehydrogenase subunit (SDHx) gene-related paragangliomas based on computed tomography (CT) measurements. METHODS Twenty-seven patients with SDHx mutations who underwent subsequent CT examinations were enrolled in the study. Tumors were classified as head and neck (HNP), thoracic, or abdominal/pelvic paragangliomas (PGLs). The percentage volume increase and volume doubling time were estimated. RESULTS We analyzed 56 PGLs (21 with SDHD, 6 with SDHB mutations) in 27 patients (16 men, 11 women; mean age 37.7 years). The estimated median of the follow-up was 23 months. Twenty-two (39.3%) PGLs were located in the abdomen, 8 (14.3%) in the thorax, and 26 (46.4%) in the head and neck region. The median volume growth rate was estimated at 10.4% per year (interquartile range [IQR]: -1.3; 36.3). The volume doubling time was estimated as 7.01 (2.24;+∞) years. By tumor site, the estimated medians of the annual volume growth rates were 13.6% (IQR:0.8 -30.4) for HNP, -6.06% (IQR: -1.79;47.32) for thoracic PGLs, and 10.5% (IQR: -2.2;44.6) for abdominal PGLs. The volume doubling time was 5.44 years (2.61; 87.0) for HNP, 11.8 years (1.79;+∞) for thoracic PGLs, and 6.94 years (1,88;+∞) for abdominal PGLs. There was no significant difference in the volume growth rate according to tumor location or initial size (P>.7 and P = .07, respectively) or gene mutation type (SDHB vs. SDHD, P>.8). CONCLUSION PGLs related to SDHx mutations are slowly growing tumors. There were no correlations between tumor location, growth rate or initial size over a 23-month follow-up period. ABBREVIATIONS CT = computed tomography HNP = head and neck paraganglioma IQR = interquartile range PGL = paraganglioma PPGL = pheochromocytoma and paraganglioma SDH = succinate dehydrogenase.

Coexistence of Andersen–Tawil Syndrome with Polymorphisms in hERG1 Gene (K897T) and SCN5A Gene (H558R) in One Family

Andersen–Tawil Syndrome (ATS) is a channelopathy caused by mutations in KCNJ2 gene. It is characterized by symptoms of ventricular arrhythmias, periodic paralysis or muscle weakness, and dysmorphic features. ATS can present with the triad of symptoms, any combination or none of them. Risk factors for dangerous arrhythmias are unknown. The study assessed the impact of K897T polymorphism in hERG1 gene and H558R polymorphism in SCN5A gene coexisting with R218Q mutation in KCNJ2 in one family on clinical manifestation.