STENOSI VALVOLARE AORTICA SEVERA E FUNZIONE MIOCARDICA: UTILITA' DIAGNOSTICA DELLA VALUTAZIONE SPECKLE TRACKING.

La stenosi valvolare aortica degenerativa rappresenta la più comune valvulopatia nativa nei paesi occidentali e la prima per cui vengano oggi poste indicazioni ad intervento. La progressione dalle forme di ostruzione lieve a severa è spesso graduale e si accompagna al lento instaurarsi di alterazioni fisiopatologiche a livello ventricolare sinistro dovute al sovraccarico pressorio, quali ipertrofia concentrica e progressiva fibrosi tissutale. Sono implicati in questo processo tanto trigger meccanici che fattori genetici. In particolare, la fibrosi sostitutiva contribuisce a determinare l’insorgere di disfunzione diastolica ed al progressivo scadimento dell’inotropismo e, complessivamente, è un correlato di malattia più avanzata. Attualmente, le indicazioni di classe I-A ad intervento di sostituzione valvolare sono poste all’insorgere di sintomi tipici, in presenza di stenosi valvolare di severa entità. Altrimenti, al manifestarsi di una riduzione della frazione di eiezione (FE<50%). Tuttavia, entrambi questi approcci possono essere inappropriati, poiché la comparsa di sintomi e la riduzione della frazione di eiezione si associano ad alterazioni della contrattilità e del tessuto miocardico a volte non reversibili dopo intervento. Molti dei parametri emodinamici di severità della valvulopatia hanno inoltre dimostrato di avere una spiccata flusso dipendenza ed una limitata correlazione tanto con il grado di ipertrofia miocardica che con la sintomatologia clinica dei pazienti. La frazione di eiezione è un indicatore poco sensibile delle alterazioni precoci della contrattilità e della funzione longitudinale. Quest’ultima, infatti, viene ad essere compromessa per prima nel processo di rimodellamento che interessa i pazienti con stenosi aortica, mentre si assiste ad un temporaneo compenso radiale dovuto all’ipertrofia parietale. Le moderne metodiche di imaging ecocardiografico consentono oggi una valutazione più accurata della meccanica cardiaca. In particolare, lo Speckle tracking imaging (STI) permette di stimare in maniera rapida, non invasiva e riproducibile, multi - direzionale ed angolo-indipendente, la deformazione miocardica e le alterazioni tissutali che caratterizzano questi pazienti sin dalle fasi precoci. In precedenti studi, gli indici di deformazione miocardica, in particolare il Global Longitudinal Strain (GLS), hanno dimostrato di possedere un rilevante potere diagnostico e prognostico, permettendo una migliore stratificazione dei pazienti. Inoltre, nuovi marcatori bioumorali, implicati nel processo fisiopatologico di sovraccarico pressorio e fibrosi tissutale alla base della stenosi aortica, come i microRNA (miRNA), possono avere un ruolo aggiuntivo nella stratificazione dei pazienti. Nel presente studio, 36 pazienti affetti da stenosi valvolare aortica severa sintomatica e frazione di eiezione preservata (FE >50%), sono stati sottoposti a valutazione clinica (visita, ECG, score di rischio cardiochirurgico), ecocardiografica (includente tissue Doppler imaging, TDI e speckle tracking imaging, STI) e laboratoristica (BNP, Tn-hs, miRNA 21). In particolare è stata effettuata una valutazione del global longitudinal strain (GLS) e del global longitudinal strain rate sistolico (GLSrS) e proto-diastolico (GLSrE). Sono state successivamente eseguite ripetute valutazioni della deformazione miocardica a livello del setto basale, al fine di ottenere valori segmentari di strain (SLs), strain rate sistolico (SrSs) e strain rate proto-diastolico (SrEs) longitudinali. 28 di questi soggetti sono stati sottoposti ad intervento di sostituzione valvolare aortica chirurgica e 15 a concomitante biopsia del setto interventricolare basale. Sui campioni di tessuto è stata effettuata una stima, dopo sezione e colorazione con Ematossilina/Eosina e Tricromica di Masson, della percentuale di fibrosi tissutale sostitutiva.E’stata inoltre effettuata un’analisi dei livelli di espressione di miRNA 21 plasmatico in 31 dei pazienti. Lo studio ecocardiografico ha rilevato, in una popolazione omogenea per frazione di eiezione e caratterizzata da ipertrofia di tipo concentrico, disfunzione diastolica e tendenziale aumento delle pressioni di riempimento, una netta compromissione della funzione longitudinale valutata tramite mitral annular plane sistolic excursion (MAPSE), TDI e GLS. Lo studio tissutale (15 pazienti) ha inoltre individuato una correlazione inversa tra GLS, strain rate settale sistolico (SrSs) e proto-diastolico (SrEs) e % di fibrosi tissutale, che è risultata un determinante indipendente di tutti gli indici di deformazione miocardica. Inoltre i parametri di deformazione miocardica e la fibrosi tissutale hanno dimostrato di possedere, a differenza degli altri indici di funzione sistolica, una capacità di discriminare accuratamente pazienti con classe funzionale avanzata e di correlare con i valori di peptide natriuretico cerebrale (BNP). I valori plasmatici di miRNA 21 hanno evidenziato una buona correlazione con quelli della massa ventricolare sinistra indicizzata (LVMi) ma non con la fibrosi o gli indici di severità emodinamica della valvulopatia. In conclusione, le alterazioni contrattili e tissutali nei pazienti con stenosi valvolare aortica severa sono già presenti in una fase di relativa stabilità della malattia ed in presenza di frazione di eiezione preservata. L’utilizzo di parametri bioumorali e metodiche strumentali più oggettive ed accurate per la valutazione della meccanica cardiaca, in particolare della deformazione miocardica, può consentire un migliore approccio terapeutico al trattamento dei pazienti con stenosi valvolare aortica, permettendo di individuare precocemente, e verosimilmente prevenire, alterazioni ultra-strutturali e deficit contrattili difficilmente reversibili anche dopo l’intervento

Impact of empagliflozin on subclinical left ventricular dysfunctions and on the mechanisms involved in myocardial disease progression in type 2 diabetes: rationale and design of the EMPA-HEART trial.

BACKGROUND: Asymptomatic left ventricular (LV) dysfunction is highly prevalent in type 2 diabetes patients. Unlike the other hypoglycemic drugs, SGLT2 inhibitors have shown potential benefits for reducing cardiovascular death and risk factors, aside from lowering plasma glucose levels. With this study we aim at determining whether the treatment with empagliflozin is associated with an improvement in LV functions in diabetic patients with asymptomatic LV dysfunction against Sitagliptin, which is presumably neutral on myocardial function. To determine changes in LV systolic and diastolic functions we will use speckle-tracking echocardiography, a novel sensitive, non-invasive, bedside method allowing the calculation of LV global longitudinal strain (GLS), an index of myocardial deformability, as well as 3D echocardiography, which allows a better evaluation of LV volumes and mass. METHODS: The EMPA-HEART trial will be a phase III, open label, active-controlled, parallel groups, single centre, exploratory study conducted in Pisa, Italy. A cohort of 75 diabetic patients with normal LV systolic (2D-Echo EF > 50%) and renal (eGFR sec MDRD > 60 ml/min/1.73 mq) functions and no evidence of valvular and/or ischemic heart disease will be randomized to either Empagliflozin 10 mg/die or Sitagliptin 100 mg/die. The primary outcome is to detect a change in GLS from baseline to 1 and 6 months after treatment initiation. The secondary outcomes include changes from baseline to 6 months in 3-D Echocardiography EF, left atrial volume and E/E', VO2max as measured at cardiopulmonary test, cardiac autonomic function tests (R-R interval during Valsalva manoeuvre, deep-breathing, lying-to-standing), and the determination of a set of plasma biomarkers aimed at studying volume, inflammation, oxidative stress, matrix remodelling, myocyte strain and injury. DISCUSSION: SGLT2 inhibitors might affect myocardial functions through mechanisms acting both directly and indirectly on the myocardium. The set of instrumental and biohumoral tests of our study might actually detect the presence and entity of empagliflozin beneficial effects on the myocardium and shed light on the mechanisms involved. Further, this study might eventually provide information to design a clinical strategy, based on echocardiography and/or biomarkers, to select the patients who might benefit more from this intervention. Trial registration EUDRACT Code 2016-0022250-10

Speckle-Tracking Imaging, Principles and Clinical Applications: A Review for Clinical Cardiologists

Evaluation of myocardial mechanics, although complex, has now entered the clinical arena, thanks to the introduction of bedside imaging techniques, such as speckle-tracking echocardiography

Cardiovascular toxicity from therapies for light chain amyloidosis

: Amyloid light-chain (AL) amyloidosis is a hematological disorder characterized by abnormal proliferation of a plasma cell clone producing monoclonal free light chains that misfold and aggregate into insoluble fibrils in various tissues. Cardiac involvement is a common feature leading to restrictive cardiomyopathy and poor prognosis. Current first-line treatments aim at achieving hematological response by targeting the plasma cell clones, and these have been adapted from multiple myeloma therapy. Patients with AL amyloidosis often exhibit multiorgan involvement, making them susceptible to cancer therapy-related cardiovascular toxicity. Managing AL amyloidosis is a complex issue that requires enhanced knowledge of the cardio-oncological implications of hematological treatments. Future research should focus on implementing and validating primary and secondary prevention strategies and understanding the biochemical basis of oncological therapy-related damage to mitigate cardiovascular toxicity

Cardiovascular toxicity from therapies for light chain amyloidosis

Amyloid light-chain (AL) amyloidosis is a hematological disorder characterized by abnormal proliferation of a plasma cell clone producing monoclonal free light chains that misfold and aggregate into insoluble fibrils in various tissues. Cardiac involvement is a common feature leading to restrictive cardiomyopathy and poor prognosis. Current first-line treatments aim at achieving hematological response by targeting the plasma cell clones, and these have been adapted from multiple myeloma therapy. Patients with AL amyloidosis often exhibit multiorgan involvement, making them susceptible to cancer therapy-related cardiovascular toxicity. Managing AL amyloidosis is a complex issue that requires enhanced knowledge of the cardio-oncological implications of hematological treatments. Future research should focus on implementing and validating primary and secondary prevention strategies and understanding the biochemical basis of oncological therapy-related damage to mitigate cardiovascular toxicity

Growth Differentiation Factor 15 in Severe Aortic Valve Stenosis: Relationship with Left Ventricular Remodeling and Frailty

Background: Frailty is an important outcome predictor in patients with aortic stenosis who are candidates for transcatheter or surgical aortic valve replacement (AVR). Growth/differentiation factor 15 (GDF15) is a cytokine playing a role in the pathophysiology of ventricular remodeling. We assessed its potential role as an independent soluble biomarker of frailty in these patients. Methods: We studied 62 patients (age, mean 79 years, 95% confidence interval (CI) 77-81; 54.8% female) with severe aortic valve stenosis and candidates for AVR. We systematically assessed pre-intervention GDF15 levels for their relationship with frailty (Katz score) and echocardiographic parameters of left ventricular dysfunction/remodeling. Fifteen hypertensive patients with left ventricular (LV) hypertrophy served as controls. Results: Patients with aortic valve stenosis featured higher GDF15 levels than controls (1773, 95% CI 1574-1971 pg/mL vs. 775, 95% CI 600-950 pg/mL, respectively, p &lt; 0.0001). Subjects in the upper GDF15 tertile were older (p = 0.004), with a more advanced NYHA functional class (p = 0.04) and a higher prevalence of impaired renal function (p = 0.004). Such patients also showed a higher frailty score (p = 0.04) and higher indices of LV dysfunction, including reduced global longitudinal strain (p = 0.01) and a higher left ventricular mass (p = 0.001). GDF15 was significantly related to the Katz score, and predicted (OR 1.05; 95% CI 0.9-1.1; p = 0.03) a low (&lt;5) Katz score, independent of the relationship with LV mass, age, renal function or indices of LV dysfunction. Conclusions: GDF15 is increased in patients with severe aortic stenosis and appears to be a soluble correlate of patients' frailty, independent of indices of left ventricular dysfunction

Incremental value of 3D echocardiography and two-dimensional speckle tracking in the early detection of cardiotoxicity linked to chemotherapy and trastuzumab in patients with HER-2 positive breast cancer

Abstract not availabl

Valve disease in cardiac amyloidosis: an echocardiographic score

Cardiac amyloidosis (CA) may affect all cardiac structures, including the valves. From 423 patients undergoing a diagnostic workup for CA we selected 2 samples of 20 patients with amyloid transthyretin (ATTR-) or light-chain (AL-) CA, and age- and sex-matched controls. We chose 31 echocardiographic items related to the mitral, aortic and tricuspid valves, giving a value of 1 to each abnormal item. Patients with ATTR-CA displayed more often a shortened/hidden and restricted posterior mitral valve leaflet (PMVL), thickened mitral chordae tendineae and aortic stenosis than those with AL-CA, and less frequent PMVL calcification than matched controls. Score values were 15.8 (13.6-17.4) in ATTR-CA, 11.0 (9.3-14.9) in AL-CA, 12.8 (11.1-14.4) in ATTR-CA controls, and 11.0 (9.1-13.0) in AL-CA controls (p = 0.004 for ATTR- vs. AL-CA, 0.009 for ATTR-CA vs. their controls, and 0.461 for AL-CA vs. controls). Area under the curve values to diagnose ATTR-CA were 0.782 in patients with ATTR-CA or matched controls, and 0.773 in patients with LV hypertrophy. Patients with ATTR-CA have a prominent impairment of mitral valve structure and function, and higher score values. The valve score may help identify patients with ATTR-CA among patients with CA or unexplained hypertrophy

Micro‑RNA‑21 (biomarker) and global longitudinal strain (functional marker) in detection of myocardial fibrotic burden in severe aortic valve stenosis: a pilot study

Aims: Myocardial fibrosis (MF) is a deleterious consequence of aortic valve stenosis (AVS). Global longitudinal strain (GLS) is a novel left ventricular (LV) functional parameter potentially useful to non-invasively estimate MF. MicroRNAs (miRNAs) are non-coding small ribonucleic acids (RNA) modulating genes function, mainly through RNA degradation. miRNA-21 is a biomarker associated with MF in pressure overload. The aim of the present study was to find an integrated algorithm for detection of MF using a combined approach with both bio- and functional markers. Methods: Thirty-six patients (75.2±8 y.o.; 63% Female) with severe AVS and preserved LV ejection fraction (EF), candidate to surgical aortic valve replacement (sAVR) were enrolled. Clinical, bio-humoral evaluation (including plasmatic miRNA-21 collected using specific tubes, PAXgene, for stabilization of peripheral RNA) and a complete echocardiographic study, including GLS and septal strain, were performed before sAVR. Twenty-eight of those patients underwent sAVR and, in 23 of them, an inter-ventricular septum biopsy was performed. Tissues were fixed in formalin and embedded in paraffin. Sections were stained with Hematoxylin and Eosin for histological evaluation and with histochemical Masson trichrome for collagen fibers. The different components were calculated and expressed as micrometers2. To evaluate tissue miRNA components, sections2-μm thick were cut using a microtome blade for each slide. Regression analysis was performed to test association between dependent variable and various predictors included in the model. Results: Despite a preserved EF (66±11%), patients presented altered myocardial deformation parameters (GLS -14,02±3.8%; septal longitudinal strain, SSL -9.63±2.9%; septal longitudinal strain rate, SL-Sr -0.58±0.17 1/s; Septal Longitudinal early-diastolic strain rate, SL-SrE 0.62±0.32 1/s). The extent of MF showed an inverse association with both GLS and septal longitudinal deformation indices (GLS: R2=0.30; p=0.02; SSL: R2=0.36; p=0.01; SL-Sr: R2=0.39; p&lt;0.001; SL-SrE: R2=0.35; p=0.001). miRNA-21 was mainly expressed in fibrous tissue (p&lt;0.0001). A significant association between MF and plasmatic miRNA-21, alone and weighted for measures of structural (LVMi R2=0.50; p=0.0005) and functional (SSL R2=0.35; p=0.006) remodeling, was found. Conclusions: In AVS, MF is associated with alterations of regional and global strain. Plasmatic miRNA-21 is directly related to MF and associated with LV structural and functional impairment. © 2016 The Author(s)