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Structural and functional alterations in the different etiologies of cardiac amyloidosis: analysis of echocardiographic and invasive hemodynamic parameters and their prognostic role
Full text linkBackground e scopo:
Tradizionalmente la cardiomiopatia amiloidotica (CA) è stata considerata una cardiomiopatia restrittiva, ma studi recenti hanno evidenziato il ruolo anche della disfuzione sistolica nella sua fisiopatologia. In questo contesto recente, raramente è stato indagato il profilo emodinamico invasivo.
Lo scopo dello studio è stato quello di caratterizzare il profilo emodinamico, strutturale e funzionale della CA nelle tre principali eziologie (amiloidosi da catene leggere (AL), amiloidosi transtiretino-relata (ATTR) mutata (ATTRm) e ‘wild-type’ (ATTRwt)), valutare le differenze del profilo ecocardiografico ed emodinamico nelle fasi diverse di malattia ed esplorare il ruolo prognostico delle principali variabili cliniche e strumentali nella CA.
Metodi e risultati:
Abbiamo analizzato retrospettivamente i dati di 224 pazienti con CA (AL, n=93; ATTRm, n=66; ATTRwt, n=65). Rispetto all'ATTRwt, i pazienti con AL presentano un minor interessamento morfologico cardiaco, ma dati emodinamici paragonabili, caratterizzati da elevate pressioni di riempimento biventricolari e riduzione della gittata sistolica. L’ATTRm, nonostante il profilo ecocardiografico analogo all’ATTRwt, mostra un quadro emodinamico migliore.
Gli indici di funzione diastolica e sistolica longitudinale del ventricolo sinistro (Vsn) sono alterati fin dagli stadi iniziali della malattia, mentre la frazione di eiezione (FEVsn) rimane preservata nella maggior parte dei pazienti, anche nelle fasi avanzate (FEVsn 50 [37-60]%; FEVsn <40% nel 28% dei pazienti NYHA III / IV). All'analisi multivariata, età, NYHA III/I, eziologia AL, frazione di contrazione miocardica (MCF), indice cardiaco (CI) e pressione atriale destra (RAP) sono indipendentemente associati a eventi clinici avversi.
Conclusioni
Questo studio conferma la complessa fisiopatologia della CA, in cui la disfunzione diastolica è accompagnata da una funzione sistolica longitudinale anormale sin dalle fasi iniziali della malattia. L'AL e l'ATTRwt, nonostante diversi gradi di alterazioni morfologiche, hanno un profilo emodinamico simile; l'ATTRm, invece, presenta un quadro emodinamico migliore. Tra i parametri strumentali, MCF, CI e RAP emergono come predittori significativi di eventi avversi.Background and aim
Traditionally, amyloidotic cardiomyopathy (CA) has been considered a restrictive cardiomyopathy, but recent studies have highlighted the greater complexity of its pathophysiology, in which even the systolic dysfunction plays an important role. In this recent context, the invasive hemodynamic profile has rarely been investigated.
Therefore, we sought to characterize the hemodynamic, structural and functional profiles of CA in the three main etiologies (light chain amyloidosis (AL), mutant transthyretin-related amyloidosis (ATTRm) and 'wild-type' ATTR (ATTRwt)), to evaluate their differences between various disease stages and to explore the prognostic role of the main clinical and instrumental variables in CA.
Methods and results
We retrospectively analyzed data of 224 patients with CA (AL, n=93; ATTRm, n=66; ATTRwt, n=65). Compared with ATTRwt, AL patients have a milder cardiac morphological involvement, but comparable hemodynamic data, characterized by increased biventricular filling pressures and reduced systolic stroke volume. ATTRm shows a better hemodynamic profile than ATTRwt, despite similar echocardiographic data.
LV diastolic and longitudinal systolic function indices (S wave at Tissue Doppler Imaging and longitudinal strain) are abnormal from the initial stage of the disease, while LV ejection fraction remains preserved in most patients, even in the advanced stages (FE 50 [37-60] %; FE < 40% in 28% of NYHA III/IV patients). At multivariable analysis, age, NYHA III/IV, AL etiology, myocardial contraction fraction (MCF), cardiac index (CI) and right atrial pressure (RAP) at catheterization are independently associated with adverse clinical events.
Conclusions
This study confirms the complex pathophysiology of CA, in which the diastolic dysfunction is accompanied by abnormal longitudinal systolic function from the initial disease stages. AL and ATTRwt, despite different degrees of morphological alterations, have a similar hemodynamic profile; ATTRm, instead, has more favorable hemodynamic parameters. Among the instrumental parameters, MCF, CI and RAP emerged as significant predictors of adverse events
Compression of left main coronary artery in patients with pulmonary arterial hypertension asymptomatic for angina
No full textLa dilatazione dell’Arteria Polmonare (AP) è frequente in pazienti con ipertensione arteriosa polmonare (IAP) e può favorire l’insorgenza di complicanze meccaniche, come la stenosi del Tronco Comune della coronaria sinistra (TCCS). Una stenosi ab estrinseco del TCCS nei pazienti con IAP può determinare aritmie fatali e morte improvvisa. Sebbene siano disponibili alcuni dati in letteratura sui pazienti che presentano angina, poco è noto negli asintomatici. L’obiettivo principale di questo studio è di definire la prevalenza della stenosi critica ab estrinseco del TCCS nei pazienti con IAP asintomatici. Tra gli obiettivi secondari abbiamo voluto definire il cutoff del diametro dell’AP che determina un incremento del rischio di compressione del TCCS, i fattori che correlano con la dilatazione dell’AP e con la sua crescita nel tempo, la correlazione tra la mortalità totale e il diametro dell’AP o la sua crescita nel tempo e la correlazione tra l’endpoint composito di morte improvvisa e/o compressione del TCCS e il diametro dell’AP o la sua crescita nel tempo. È stata svolta un’analisi retrospettiva di tutti i pazienti con IAP riferiti al Centro di ipertensione polmonare di Bologna. Sono stati inclusi nello studio 958 pazienti con IAP, di cui 180 con sintomi e 778 asintomatici. La compressione è stata confermata in 65 pazienti e di questi, 50 avevano avuto sintomi (28% dei pazienti sintomatici) e 15 erano asintomatici (1.9% dei pazienti asintomatici). Il miglior predittore di stenosi critica del TCCS all’angiografia coronarica in pazienti con IAP è risultato un diametro dell’AP ≥ 40 nei pazienti sintomatici e ≥ 42 mm nei pazienti asintomatici. La crescita annuale del diametro dell’AP è risultata essere predittrice di morte per ogni causa in pazienti con IAP. Il diametro dell’AP e la crescita annua del diametro dell’AP sono risultati correlati all’endpoint composito di morte improvvisa e/o compressione del TCCS.A dilation of the pulmonary artery (PA) is frequent in patients with pulmonary arterial hypertension (PAH) and can lead to mechanical complications, such as the compression of the left main coronary artery (LMCA). A compression of the LMCA in PAH patients can induce fatal arrhythmias and sudden death. Even though there is some available data concerning patients symptomatic for angina, little is known in asymptomatic patients. The main goal of this study is to define the prevalence of ab estrinseco LMCA compression in asymptomatic PAH patients. As secondary endpoints we tried to define a cutoff of the PA diameter beyond which the risk of compression is increased, the factors that correlate with the diameter of the PA and its growth over time, the correlation between total mortality and the diameter of the PA and its growth over time and the correlation between the composite endpoint of sudden death and/or compression of the LMCA and the diameter of the PA and its growth over time. We performed a retrospective analysis of all the patients with PAH that were referred to our centre. Overall, 958 patients were included in the analysis; 180 of them were symptomatic and 778 were not. The compression of the LMCA was confirmed in 65 patients of whom 50 were symptomatic (28%) and 15 were asymptomatic (15%). The best predictor the LMCA compression was a diameter of the PA ≥ 40 mm in symptomatic patients and ≥ 42 mm in asymptomatic patients. The annual growth rate of the PA was found to be a predictor of death for any cause. The diameter of the PA and its annual growth rate were related to the composite endpoint of sudden death and/or compression of the LMCA
Therapeutic strategy in patients with pulmonary arterial hypertension at intermediate-risk
Full text linkLe attuali linee guida stratificano il rischio dei pazienti con ipertensione arteriosa polmonare (IAP) in basso, intermedio e alto (rispettivamente con mortalità a 1 anno 10%). La maggior parte dei pazienti è però classificata nella categoria intermedia. Per stratificare ulteriormente questi pazienti, abbiamo valutato il ruolo prognostico dello stroke volume index (SVI) misurato al cateterismo cardiaco destro (CCDx) in 725 pazienti naïve da terapia con IAP idiopatica/ereditaria, associata a malattie del tessuto connettivo o cardiopatie congenite. I pazienti sono stati valutati al basale e 3-4 mesi dopo l'inizio della terapia (1° F-UP) con CCDx, livelli plasmatici di peptide natriuretico cerebrale (BNP), test dei 6 minuti (T6M) e classe funzionale OMS. Abbiamo applicato una tabella di rischio semplificata utilizzando i criteri: classe funzionale OMS, T6M, pressione atriale destra o livelli plasmatici di BNP e indice cardiaco (IC) o saturazione di ossigeno venoso misto (SvO2). Le classi di rischio sono state definite come: basso= almeno 3 criteri a basso rischio e nessun criterio ad alto rischio; alto= almeno 2 criteri ad alto rischio inclusi IC o SvO2; intermedio= tutti gli altri casi. Lo SVI, mediante la regressione di Cox, stratifica la prognosi dei pazienti a rischio intermedio al 1° F-UP [p=0.008] ma non al basale [p=0.085]. Considerandone l’ottimale cut-off predittivo (38 ml/m2) i pazienti a rischio intermedio sono ulteriormente classificabili in intermedio-basso e intermedio-alto. Considerando l'effetto dei 3 principali farmaci che agiscono sulla via della prostaciclina in aggiunta alla duplice terapia di combinazione con inibitori della fosfodiesterasi-5 e antagonisti dell'endotelina, i pazienti trattati con epoprostenolo e.v. hanno ottenuto un maggiore miglioramento rispetto ai pazienti trattati con selexipag; col treprostinil s.c. vi è stata una risposta intermedia. Abbiamo quindi proposto un algoritmo di terapia con selexipag in pazienti a rischio intermedio-basso e con prostanoidi parenterali in pazienti a rischio intermedio-alto.Current guidelines stratify the risk of patients with pulmonary arterial hypertension (PAH) in low, intermediate and high-risk categories (respectively 1-year mortality 10%). Most patients anyway are classified in the intermediate risk category. In order to further stratify this group of patients we evaluate the prognostic role of stroke volume index (SVI) measured during right heart catheterization (RHC) in 725 treatment naïve patients with idiopathic/heritable PAH and PAH associated with connective tissue disease and congenital heart disease. All patients were assessed at baseline and 3-4 months after starting PAH-specific therapy (1st F-UP) with RHC, brain natriuretic peptide (BNP) plasma levels, 6-min walking distance (6MWD) and WHO functional class. We applied a simplified risk assessment strategy using the following criteria: WHO functional class, 6MWD, right atrial pressure or BNP plasma levels and cardiac index (CI) or mixed venous oxygen saturation (SvO2). Risk strata were defined as: Low risk= at least 3 low risk and no high-risk criteria; High risk= at least 2 high risk criteria including CI or SvO2; Intermediate risk= definitions of low or high risk not fulfilled. SVI, according to Cox regression analysis, can stratify the prognosis of intermediate-risk patients at 1st F-UP [p=0.008] but not at baseline [p=0.085]. According to the best predictive cut-off value (38 ml/m2) intermediate risk patients were further stratified in intermediate-low and intermediate-high. Considering the effect of the 3 main drugs acting on the prostacyclin pathway on top of the dual combination therapy with phosphodiesterase-5 inhibitors and endothelin receptor antagonists patients treated with i.v. Epoprostenol obtained a higher improvement than the patients treated with Selexipag while the patients treated with s.c. Treprostinil presented an intermediate response. According to these results we propose a therapeutic approach with Selexipag in intermediate-low risk patients and with parenteral prostanoids in intermediate-high risk patients
Cardiac amyloidosis: hemodynamic profile and prognostic implications
No full textBackground: Cardiac amyloidosis (CA) is a hypertrophic phenotype cardiomyopathy characterized by a clinical presentation predominantly defined by heart failure. This study evaluates the invasive hemodynamic characteristics and their prognostic implications in consecutive patients diagnosed with CA (in its three main etiologies: light chain amyloidosis AL, transthyretin variant amyloidosis ATTRv, and transthyretin wild-type amyloidosis ATTRwt) who underwent RHC at IRCCS S. Orsola Hospital in Bologna between 1992 and December 2023.
Results: A total of 274 patients were enrolled (121 [44.2%] AL, 66 [24.1%] ATTRv, and 87 [31.7%] ATTRwt). At baseline, the hemodynamic profile was characterized by elevated biventricular filling pressures and pulmonary hypertension, with a median mean pulmonary artery pressure (mPAP) of 24 mmHg [IQR: 18–30], predominantly post-capillary or combined pre- and post-capillary. The stroke volume index (SVi) was reduced, with a median of 30 mL/m² [IQR: 24–37], and the cardiac index (CI) was at the lower limit of normality, with a median of 2.4 L/min/m² [IQR: 1.9–2.8]. Patients with advanced NYHA class at presentation (III/IV) presented a more severe echocardiographic and hemodynamic profile. Invasive hemodynamic parameters showed a good correlation with echocardiographic measurements. During a median follow-up of 30 months, 159 deaths were recorded. Classic cut-offs for RAP, PCWP, mPAP, and SVi emerged as predictors of mortality in Kaplan-Meier curves. In multivariate Cox regression analysis, independent predictors of overall mortality included age at diagnosis, AL etiology, advanced NYHA functional class at presentation (III/IV), estimated glomerular filtration rate (eGFR), RAP, and SVi.
Conclusions: The hemodynamic profile of patients with cardiac amyloidosis is characterized by concomitant systolic and diastolic dysfunction, elevated biventricular filling pressures, and reduced SVi. Both RAP and SVi are independently associated with mortality in this population
Correlations between cardiac magnetic resonance and histologic findings in Anderson Fabry disease
Full text linkABSTRACT
Background
Cardiac magnetic resonance (CMR) has been shown as promising diagnostic tool in Anderson-Fabry disease (AFD) cardiomyopathy due to its ability to detect fat deposits through lower native T1 values. However no histological validation has been provided to date.
Objectives
To correlate CMR and histologic findings in different cardiac stages of AFD focusing on T1 mapping. Methods Fifteen AFD patients (49 years [IQR 39-63], 60% females) undergoing CMR (cines, native T1 and T2 mapping, LGE and post-contrast T1 imaging) and endomyocardial biopsy (EMB, n=11) or septal myectomy (n=4), were retrospectively evaluated. Tissue specimens were analyzed with light/electron microscopy and vacuolization amount calculated as percentages of vacuolated myocytes and vacuolated myocyte area (%VMA) through a quantitative histomorphometric color-based analysis.
Results
In patients without increased indexed left ventricular mass (LVMi) at CMR (67%), T1 fell as %VMA increased (r= -0.883; p<0.001), whereas no clear relationship was evident once increased LVMi occurred (r= -0.501; p=0.389). At least 45% of vacuolized myocytes and 10% of VMA were needed for low T1 to occur. %VMA positively correlate with maximal wall thickness (MWT, r=0.860, p<0.0001) and LVMi (r= 0.762; p<0.001). Increased MWT and LVMi were present with at least 45% and 80% of vacuolated myocytes, respectively, and 18% and 22% of VMA.
Conclusions
This study demonstrated an inverse correlation between native T1 and the vacuolization amount in patients without increased LVMi at CMR, providing a histological validation of low native T1 in AFD. Importantly, a significant vacuolization burden was needed before low T1 and left ventricle hypertrophy occurred
Analisi dei fattori prognostici e della risposta al trattamento nei pazienti con ipertensione arteriosa polmonare
No full textDevelopment and validation of an echocardiography score for diagnosis of cardiac masses
Full text linkBackground
Echocardiography is the cornerstone in the evaluation of cardiac masses and provides accurate characterization. Despite, its accuracy in diagnosis of cardiac masses (CM) remains challenging and, up to date, no validated diagnostic algorithm is validated.
Purpose
The aim of our study was to evaluate the diagnostic accuracy of echocardiography, to identify the echocardiographic predictors of malignancy and to develop and then validate a multiparametric echocardiographic score that could be used to estimate the likelihood of the histological nature of a CM.
Materials and methods
The final sample consisted of 273 consecutive patients who had a 2D-echocardiographic evaluation and a histologic diagnosis. Logistic regression was performed to evaluate the ability of echocardiographic findings to discriminate benign versus malignant masses, then a scoring system was developed and validated in a separate test cohort.
Results
Of the 322 patients initially included in the Bologna Cardiac Masses Registry, 13 with a poor acoustic window, 27 with no histological examination patients and 9 extra-cardiac masses were excluded. In the remaining 273 patients, classical 2-D echocardiogram identified 249 masses with a diagnostic accuracy of 88%. A weighted score [Diagnostic Echocardiographic Mass (DEM) Score] ranging from 0 to 9 was obtained from 6 variables: infiltration, polylobate mass, moderate-severe pericardial effusion. The AUC for the score was 0.965 (95% CI [0.938-0.993]). In a logistic regression analysis using the DEM score as a predictor, the likelihood of malignant CM increased more than 4 times for a 1-unit increase in the score (OR=4.468; 95% CI 2.733-7.304). A score < 3 denoted a high probability of a benign diagnosis, and a score ≥ 5 points corresponded to a higher risk of malignancy.
Conclusion
2D-Echocardiography provides a high diagnostic accuracy in identifying cardiac masses and our multiparametric echocardiographic score could be useful to predict the histological nature of cardiac masses
Triple combination therapy in pulmonary arterial hypertension
Full text linkPulmonary arterial hypertension is a severe disease characterized by increasing in pulmonary vascular resistance leading to right ventricular failure and death. Currently available drugs for treatment of PAH act on three different pathways responsible of the pathogenesis of this disease: the endothelin pathway, the nitric oxide pathway and the prostacyclin pathway.
The purpose of our study was to reassess our experience on the use of drugs that interact on the pathobiological line of prostacyclin so we retrospectively included all patients, referred to our center from February 1995 to December 2021, who received therapy with i.v. Epoprostenol, s.c. Treprostinil or oral Selexipag.
Firstly, we observed that patients treated with Epoprostenol were significantly more compromised at baseline when compared to the two other groups and evaluating the effects of the three different drugs, it emerged that patients treated with Epoprostenol had significantly greater improvements in respect to those treated with Treprostinil and Selexipag.
In the second part of our analysis we assessed the effects of these drugs when used as third line strategy in order to limit many confounding factors that could influence demographic, clinical and hemodynamic characteristics of patient populations. The differences emerged in exercise capacity and baseline hemodynamics reflect the fact that in our clinical practice, we add Epoprostenol as third line therapy in more compromised patients, Treprostinil in intermediate situations and Selexipag in less impaired conditions. Comparing the effects of treatments between baseline and first follow-up we noticed smaller benefits with Selexipag when compared with intravenous and subcutaneous strategies but it’s important to weight baseline patient’s differences. Our analysis confirmed clinical and functional benefits for the use of both prostacyclin analogues and prostacyclin receptor agonists in terms of improved functional class, six-minute walking distance and cardiopulmonary hemodynamics
The role of invasive hemodynamic evaluation and pump optimization in the management of patients supported with left ventricular assist devices (LVAD)
Full text linkDespite improved outcomes, LVAD patients still present with frequent rehospitalizations, including those for heart failure (HF). The aim of this study was to investigate the changes in hemodynamic parameters after LVAD implant and the role of hemodynamic optimization obtained by the invasive ramp test (RT) in improving survival and reducing HF admissions. We enrolled patients implanted with centrifugal pumps between 2013 and 2024 who underwent post-implant right catheterization (RHC) during the index hospitalization. Optimal hemodynamics were defined as a right atrial pressure 2.2 l/min/m2. The endpoint was survival free from HF admission according to the hemodynamic profile at 24 months. 63 patients were included in the study. After the implant there was a significant improvement in pulmonary pressure and a reduction in the indices of right ventricular function without changes in central venous pressure. 41% of the patients already had an optimal hemodynamic profile, while 14% achieved it after RT. At 24 months, survival free from HF admission was significantly reduced in patients with non-optimized profiles (81 vs. 58 %, OR 3.2 [1.2-8.2], p = 0.01). This difference was not significant when the effect of the ramp test was not considered (p=0.07). In patients with LVAD, survival free from HF admissions was significantly higher in those with optimized hemodynamics, and RT provided the opportunity to further improve hemodynamic profiles. The non-optimized profile was an independent predictor of mortality and hospitalization for HF
Characterization and natural history of different phenotypes in hereditary transthyretin amyloidosis: 40-year experience at a single Italian referral center
Full text link- Aims: Hereditary Transthyretin Amyloidosis (ATTRv) is one of the leading etiologies of systemic amyloidosis with more than 135 mutations described and a broad spectrum of clinical manifestations. We aimed to provide a systematic description of a population of individuals carrying pathogenic mutations of transthyretin (TTR) gene and to investigate the major clinical events during follow up.
- Methods: Observational, retrospective, cohort study including consecutive patients with mutations of TTR gene, admitted to a tertiary referral center in Bologna, Italy, between 1984 and 2022.
- Results: Three hundred twenty-five patients were included: 106 asymptomatic carriers, 49 cardiac phenotype, 49 neurological phenotype and 121 mixed phenotype. Twenty-three different mutations were found, with Ile68Leu (41.8%), Val30Met (19%), and Glu89Gln (10%) being the most common. After a median follow-up of 51 months data from 290 subjects were analyzed; among them 111 (38.3%) died and 123 (42.4%) had a major clinical event (death or hospitalization for heart failure). Nine (11.5%) of the 78 asymptomatic carriers showed signs and symptoms of the disease. Carriers had a prognosis comparable to healthy population, while no significant differences were seen among the three phenotypes adjusted by age. Age at diagnosis, NYHA functional class, left ventricular ejection fraction, mPND score and disease-modifying therapy were independently associated with survival.
- Conclusions: This study offers a wide and comprehensive overview of ATTRv from the point of view of a tertiary referral center in Italy. Three main phenotypes can be identified (cardiac, neurological and mixed) with specific clinical and instrumental features. Family screening programs are essential to identify paucisymptomatic affected patients or unaffected carriers of the mutation, to be followed through the years. Lastly, disease-modifying therapy represents an evolving cornerstone of the management of ATTRv, with a great impact on mortality
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