Spectrum of transthyretin gene mutations and clinical characteristics of Polish patients with cardiac transthyretin amyloidosis

Background: Transthyretin amyloidosis (ATTR) is a rare, life-threatening systemic disorder. We present first findings on the cardiac hereditary ATTR in Poland.Methods: Sixty-eight consecutive patients with suspected or known cardiac amyloidosis were evaluated, including blood tests, standard 12-lead electrocardiography (ECG) and transthoracic echocardiography. ATTR was confirmed histologically or non-invasively using 99mTc-DPD scintigraphy. Transthyretin (TTR) gene sequencing was performed.Results: In 2017–2019, 10 unrelated male patients were diagnosed with hereditary ATTR. All patients had very uncommon TTR gene mutations: 7 patients had p.Phe53Leu mutation, 2 patients had p.Glu109Lys mutation and 1 patient had p.Ala101Val mutation. The age of onset ranged from 49 to 67 years (mean [SD] age, 58.7 [6.4] years). On ECG, most patients (70%) had pseudoinfarct pattern and/or low QRS voltage. The maximal wall thickness (MWT) on echocardiography varied considerably among the patients from moderate (16 mm) to massively increased (30 mm). Most patients (90%) had decreased left ventricular ejection fraction (mean [SD], 43 [11] %). On follow-up, we observed progressive heart failure in almost all cases. The first patient with p.Phe53Leu mutation died of heart failure, the second died suddenly, the third successfully underwent combined heart and liver transplant with 15 months survival from the surgery. The patient with p.Ala101Val mutation died of stroke.Conclusions: According to available data, this is the first time that the types of TTR mutations and the clinical characteristics of Polish patients with cardiac hereditary ATTR have been described. Previous literature data about Polish background in families with p.Phe53Leu mutation and the present results, suggest that this TTR mutation might be endemic in the Polish population

Amyloidoza łańcuchów lekkich immunoglobulin z punktu widzenia kardiologa

Light-chain amyloidosis (amyloidosis AL) is diagnosed in approx. 70% of patients with cardiac amyloidosis. This type of amyloidosis has the worst prognosis, especially if the diagnosis is made in advanced stages. The majority of patients are referred to a cardiologist, but unfortunately only every fifth of them has the proper diagnosis. Therefore, strategies promoting early diagnosis are important. One of them is the measurement of serum free light chains concentration in every patient with heart failure with preserved ejection fraction. The acknowledgement of free light chains (FLCs) cardiotoxicity rendered the picture of AL amyloidosis from infiltrative cardiomyopathy into a toxic one. Best improvement in regard to heart failure is achieved upon hematological treatment resulting in decrease of FLCs concentration. Therefore, cardiological treatment is rather a supportive therapy. The role of cardiologist is the rapid diagnosis of the disease and referral of the patient to the hematologist. The standard heart failure treatment encompassing use of beta-blockers and angiotensin converting enzyme inhibitors aggravates orthostatic hypotension and congestion. Instead, up-to-date hematological treatment improves the prognosis of AL amyloidosis markedly, as long as early diagnosis is made.Amyloidozę łańcuchów lekkich (amyloidozę AL) rozpoznaje się u około 70% pacjentów z amyloidozą serca. Ta postać choroby wiąże się z najgorszym rokowaniem, szczególnie jeśli wykrywa się ją na zaawansowanym etapie. Kardiolog jest najczęściej odwiedzanym specjalistą przez pacjentów z amyloidozą AL. Niestety tylko u co piątego pacjenta jest stawiana właściwa diagnoza. Dlatego ważne jest, aby promować działania umożliwiające wczesne stwierdzenie choroby. Należy do nich oznaczanie wolnych łańcuchów lekkich (FLC) w surowicy u pacjentów z niewydolnością sercaz zachowaną frakcją wyrzutową. Wykazanie kardiotoksycznej roli FLC zmieniło postrzeganie amyloidozy AL jako choroby polegającej wyłącznie na pozakomórkowym gromadzeniu się nieprawidłowych złogów białkowych. Największą poprawę funkcji serca uzyskuje się, obniżając stężenie FLC w surowicy poprzez leczenie cytoredukcyjne. Leczenie kardiologiczne ma znaczenie uzupełniające. Rola kardiologa sprowadza się do jak najszybszego rozpoznania choroby i przekazania pacjenta do hematologa. Standardowa farmakoterapia niewydolności serca, obejmująca beta-adrenolityki i inhibitory konwertazy angiotensyny, u pacjentów z amyloidozą wywołuje nasilenie hipotensji ortostatycznej i objawów zastoinowych. Natomiast dzięki nowoczesnemu leczeniu cytoredukcyjnemu i antyamyloidowemu istotnie poprawiły się wyniki leczenia, pod warunkiem wczesnego rozpoznania amyloidozy AL

Diagnosis and treatment of transthyretin amyloidosis cardiomyopathy: A position statement of the Polish Cardiac Society

Considering the rare incidence of transthyretin amyloidosis cardiomyopathy (ATTR-CM) in Poland, patients encounter difficulties at the stages of diagnosis and treatment. For successful diagnosis, it is vital to raise the suspicion of ATTR-CM, that is, to identify typical clinical scenarios such as heart failure with preserved ejection fraction or the red flags of amyloidosis. In most cases, it is possible to establish the diagnosis on the basis of noninvasive tests. This article presents the recommended diagnostic algorithms including laboratory workup, imaging tests (in particular, isotope scanning), and genetic tests. Since ATTR-CM should be differentiated from light chain amyloidosis, we also discuss aspects related to hematological manifestations and invasive diagnosis. We describe neurological signs and symptoms in patients with amyloidosis and present therapeutic options, including the causative treatment of ATTR-CM with the only currently approved drug, tafamidis. We also discuss drugs that are being assessed in ongoing clinical trials. We outline differences in the symptomatic treatment of heart failure in ATTR-CM and recommendations for nonpharmacological treatment and monitoring of the disease. Finally, we underline the need for providing access to the causative treatment with tafamidis as part of a drug program, as in other rare diseases, so that patients with ATTR-CM can be treated according to the European Society of Cardiology guidelines on heart failure and cardiomyopathy

Clinical features, etiology, and survival in patients with restrictive cardiomyopathy: A single-center experience

Background: Numerous prognostic factors have been proposed for cardiac amyloidosis (CA). The knowledge about other subtypes of restrictive cardiomyopathy (RCM) is scant.Aims: This study aimed to elucidate the etiology and prognostic factors of RCM as well as assess cardiac biomarkers: high-sensitive troponin T (hs-TnT), growth differentiation factor-15 (GDF-15), N-terminal pro-B-type natriuretic peptide (NT-proBNP), and soluble suppression of tumorigenicity 2, as mortality predictors in RCM.Methods: We enrolled 36 RCM patients in our tertiary cardiac department. All patients were screened for CA. Genetic testing was performed in 17 patients without CA.Results: Pathogenic or likely pathogenic gene variants were found in 86% of patients, including 5 novel variants. Twenty patients died, and 4 had a heart transplantation during the study. Median overall survival was 29 months (8–55). The univariate Cox models analysis indicated that systolic and diastolic blood pressure, GDF-15, hs-TnT, NT-proBNP, left ventricular stroke volume, the ratio of the transmitral early peak velocity (E) estimated by pulsed wave Doppler over the early mitral annulus velocity (e’), tricuspid annulus plane systolic excursion, early tricuspid valve annular systolic velocity, the presence of pulmonary hypertension, and pericardial effusion influenced survival (P <0.05). A worse prognosis was observed in patients with GDF-15 >1316 pg/ml, hs-TnT >42 ng/l, NT-proBNP >3383 pg/ml, and pericardial effusion >3.5 mm (Kaplan-Meier analysis, log-rank test, P <0.001).Conclusions: Genetic testing should be considered in every RCM patient where light-chain amyloidosis has been excluded. Survival remains poor regardless of etiology. Increased concentrations of GDF-15, hs-TNT, NT-proBNP, and pericardial effusion are associated with worse prognosis. Further studies are warranted

Perfusion cardiovascular magnetic resonance as the first-line technique in patients with stable chest pain

Perfusion imaging with cardiovascular magnetic resonance is a noninvasive test free of ionizing radiation recommended by the latest European Society of Cardiology guidelines as one of the functional tests for coronary artery disease (CAD) detection. It has been demonstrated in numerous studies that perfusion imaging with cardiovascular magnetic resonance is highly accurate, provide strong prognostic data, and reduce the number of unnecessary invasive angiographies in patients with stable chest pain. Implementation of this method as the first‑line technique in patients with stable chest pain provides an important refinement of the current concept for the assessment of CAD and in a unique way extends the diagnostic workup beyond simply ruling in or out myocardial ischemia

CMR in Pericardial Diseases - an Update

Purpose of Review: To review the latest developments and the current role of the cardiac magnetic resonance (CMR) in pericardial diseases and their complications. Recent Findings: Cardiac Magnetic Resonance (CMR) has the ability to incorporate anatomy, physiology, and “virtual histology” strategies to achieve the most accurate diagnosis for even the most demanding, pericardial diseases. Summary: Acute, chronic, recurrent, and constrictive pericarditis as well as pericarditis related complications, pericardial masses and congenital pericardial defects are commonly encountered in clinical practice with relatively significant morbidity and mortality. Owing to the challenging diagnosis, CMR imaging is often employed in confirming the diagnosis and elucidating the underling pathophysiology. In this review we outline the common CMR techniques and their expected diagnostic outcomes

Znaczenie sST2 i galektyny-3 jako nowych biomarkerów w kardiomiopatii przerostowej

Background: Estimation of sudden cardiac death (SCD) risk is an integral part of clinical management of patients with hypertrophic cardiomyopathy (HCM). Identification of novel biomarkers of this disease can provide additional criteria for SCD risk stratification. Soluble suppression of tumourigenicity (sST2) and galectin-3 (Gal-3) are useful biomarkers for prognosis of heart failure (HF). Both of them appear to mediate cardiac fibrosis — an important pathogenetic process in HCM. Data about sST2 and Gal-3 usefulness in patients with HCM are limited. Aim: The aim of this study was to evaluate sST2 and Gal-3 as potential novel biomarkers for better risk stratification in hypertrophic cardiomyopathy. Methods: Serum sST2 and serum Gal-3 levels were measured in 57 patients with HCM and in 18 healthy controls. The patients with HCM underwent routine evaluation including medical history, physical examination, blood tests (including N-terminal pro-B-type natriuretic peptide [NT-proBNP] and high-sensitivity cardiac troponin T [hs-cTnT] measurements), 12-lead electrocardiography (ECG), 48-h Holter monitoring and two-dimensional (2D) echocardiography with the assessment of the maximal left ventricular wall thickness, left atrial diameter, maximal left ventricular outflow tract gradient, and left ventricular ejection fraction. Risk of SCD at five years according to HCM SCD-risk calculator was evaluated. The control group underwent ECG, 2D echocardiography, and NT-proBNP measurements to exclude asymptomatic heart disease. Results: Concentrations of sST2 and Gal-3 were significantly higher in patients with HCM than in controls (14.9 ± 5.8 ng/mL vs. 11.7 ± 3.3 ng/mL, p = 0.03 and 8.4 ng/mL [6.8–10.0] vs. 6.2 ng/mL [5.8–7.7], p = 0.005, respectively). Levels of sST2 and Gal-3 were considerably different in the New York Heart Association (NYHA) groups (p = 0.008, p = 0.009, respectively). Patients who presented non-sustained ventricular tachycardia (nsVT) on 48-h Holter monitoring had higher levels of sST2 (19.1 ng/mL [12.2–24.2] vs. 13.2 ng/mL [10.0–17.1], p = 0.02). There were no significant relationships between sST2 and Gal-3 levels and HCM SCD-risk, history of syncope presence, family history of SCD, and echocardio­graphic parameters. Conclusions: Gal-3 levels and sST2 levels were higher in patients with HCM than in the control group. There were significant differences in Gal-3 levels between NYHA classes, but no correlations between Gal-3 levels and other parameters were found. Apart from differences in sST2 levels between NYHA classes, we demonstrated higher levels of sST2 in patients with nsVT. These findings suggest that sST2 may be useful as an additional biomarker for better risk stratification in hypertrophic cardiomyopathy.  Wstęp: Oszacowanie ryzyka nagłego zgonu (SCD) jest kluczową częścią oceny klinicznej pacjentów z kardiomiopatią przerostową (HCM). Identyfikacja nowych biomarkerów tej choroby może wnieść wiele cennych informacji, a być może dostarczy także dodatkowe kryteria stratyfikacji ryzyka SCD u osób z HCM. Białko sST2 i galektyna-3 (Gal-3) są przydatnymi biomarkerami prognostycznymi w niewydolności serca. Wydaje się, że oba te biomarkery mają związek z włóknieniem miokardium — często obserwowanym i niekorzystnym procesem patogenetycznym w HCM. Dotychczas przydatność kliniczna sST2 i Gal-3 u pacjentów z HCM nie była szerzej badana. Cel: Celem pracy jest ocena przydatności klinicznej wybranych biochemicznych markerów włóknienia: sST2 i Gal-3 w HCM. Metody: Stężenia sST2 i Gal-3 zmierzono w surowicy 57 pacjentów z HCM oraz 18 zdrowych ochotników. U każdego chorego z HCM przeprowadzono badania podmiotowe i przedmiotowe, badania laboratoryjne z pomiarem stężeń N-końcowego propeptydu natriuretycznego typu B (NT-proBNP) i troponiny T oznaczonej za pomocą testu o wysokiej czułości (hs-cTnT), EKG, 48-godzinne badanie Holter EKG pod kątem złożonej arytmii komorowej (nsVT), badanie echokardiograficzne z oce­ną: maksymalnej grubości ściany lewej komory, wymiaru lewego przedsionka, gradientu w drodze odpływu lewej komory oraz frakcji wyrzutowej lewej komory. Ryzyko SCD w ciągu 5 lat zostało wyliczone na podstawie kalkulatora HCM SCD-risk. W grupie kontrolnej złożonej ze zdrowych ochotników wykonano EKG, echokardiografię oraz oznaczono NT-proBNP w celu wykluczenia asymptomatycznej choroby serca. Wyniki: Stężenia sST2 i Gal-3 były istotnie wyższe w grupie pacjentów z HCM w porównaniu z grupą kontrolą (14,9 ± 5,8 ng/ml vs. 11,7 ± 3,3 ng/ml; p = 0,03 i 8,4 ng/ml [6,8–10,0] vs. 6,2 ng/ml [5,8–7,7]; p = 0,005, odpowiednio). Stężenia sST2 i Gal-3 różniły się między grupami pacjentów w różnych klasach niewydolności serca wg New York Heart Association (NYHA) (p = 0,008; p = 0,009, odpowiednio) i wzrastały wraz z nasileniem objawów niewydolności serca. Pacjenci, u których zarejestrowano nsVT w 48-godzinnym badaniu Holter EKG, charakteryzowali się istotnie wyższym stężeniem sST2 (19,1 ng/ml [12,2–24,2] vs. 13,2 ng/ml [10,0–17,1]; p = 0,02). Nie zaobserwowano związku między stężeniami badanych biomarkerów a ryzykiem SCD obliczonym wg kalkulatora HCM SCD-risk, omdleniami, wywiadem SCD w rodzinie oraz parametrami echokardiograficznymi. Wnioski: Stężenia sST2 i Gal-3 były wyższe u pacjentów z HCM w porównaniu z grupą kontrolną. Stwierdzono także związek między stężeniami sST2 i Gal-3 a zaawansowaniem niewydolności serca u pacjentów z HCM. Nie zaobserwowano żadnych innych zależności pomiędzy stężeniami Gal-3 a klinicznymi cechami pacjentów z HCM. W przypadku sST2 stwierdzono związek między tym biomarkerem a występowaniem złożonej arytmii komorowej, niezależnie od nasilenia objawów niewy­dolności serca. sST2 może mieć potencjał jako dodatkowy biomarker stratyfikacji ryzyka SCD w HCM