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  • 1
    In: Heart Failure Reviews, Springer Science and Business Media LLC
    Abstract: Transthyretin cardiac amyloidosis (ATTR-CA) is a progressive disease characterized by the deposition of abnormal transthyretin protein fibrils in the heart, leading to cardiac dysfunction. Recent evidence suggests that sex differences may play a significant role in various steps of ATTR-CA, including clinical presentation, diagnostic challenges, disease progression, and treatment outcomes. ATTR-CA predominantly affects men, whereas women are older at presentation. Women generally present with a history of heart failure with preserved ejection fraction and/or carpal tunnel syndrome. When indexed, left ventricular (LV) wall thickness is equal, or even increased, than men. Women also have smaller LV cavities, more preserved ejection fractions, and apparently a slightly worse right ventricular and diastolic function. Given the under-representation on women in clinical trials, no data regarding sex influence on the treatment response are currently available. Finally, it seems there are no differences in overall prognosis, even if premenopausal women may have a certain level of myocardial protection. Genetic variations, environmental factors, and hormonal changes are considered as potential contributors to observed disparities. Understanding sex differences in ATTR-CA is vital for accurate diagnosis and management. By considering these differences, clinicians can improve diagnostic accuracy, tailor treatments, and optimize outcomes for both sexes with ATTR-CA.
    Type of Medium: Online Resource
    ISSN: 1573-7322
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
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  • 2
    In: European Heart Journal Supplements, Oxford University Press (OUP), Vol. 24, No. Supplement_K ( 2022-12-15)
    Abstract: Transthyretin (TTR) is a homotetrameric 55-KDa plasma protein that transports thyroxin and retinol complexed to retinol-binding protein (RBP). TTR misfolding and aggregation can lead to the extracellular deposition of amyloid (ATTR) representing one of the most frequent forms of amyloidosis in elderly. Aim of this study is to develop a native electrophoretic method to characterize circulating TTR in plasma samples of ATTR patients before and during treatment with tafamidis, a TTR stabilizer. Methods Plasma from ATTR patients (n=6), collected before (T0) and during tafamidis treatment, and plasma of healthy controls (n=6) were obtained from Fondazione Toscana G. Monasterio (Pisa, Italy). Plasma samples were separated on a native 4–20% Tris-Gly polyacrylamide gel. Western blot analysis was performed with anti-TTR (DAKO) or anti-RBP (Siemens Healthineer) antibodies. Proteins were detected by Clarity ECL substrate (BioRad). Results Circulating forms of TTR were qualitatively similar between ATTRwt patients at T0 and controls. In both groups, the most represented forms were: TTR dimers or trimers (∼37-50 kDa), TTR tetramers complexed with RBP protein in 1:1 ratio (∼80 kDa,) or 1:2 ratio (∼100 kDa), and high molecular weight (MW) aggregates ( & gt;150 kDa). Neither TTR monomers nor the tetramers were visible. RBP protein was detectable in association with TTR tetramers and some of the higher MW fractions (∼150 kDa, & gt;250 kDa). Following tafamidis treatment, all ATTRwt patients displayed a progressive increase of the intensity of the band corresponding to TTR-RBP complexes, in agreement with the drug stabilizing action on TTR tetramers. Interestingly dimers and trimers, detectable at T0, were progressively lost during tafamidis treatment. Conclusions The native electrophoretic allowed us to detect several circulating TTR fractions. Data suggest a similar pattern of circulating TTR both in patients and healthy control: TTR tetramer exists only complexed with RBP and in equilibrium with low and high MW forms. Furthermore, the method allowed to appreciate the stabilizing effect of tafamidis on circulating TTR tetramers complexed with RBP. The study of circulating TTR fractions can expand our knowledge on mechanisms triggering its destabilization even when not mutated.
    Type of Medium: Online Resource
    ISSN: 1520-765X , 1554-2815
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
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  • 3
    In: European Heart Journal Supplements, Oxford University Press (OUP), Vol. 23, No. Supplement_G ( 2021-12-08)
    Abstract: Left ventricular (LV) remodelling after myocardial infarction (MI) is promoted by an intense fibrotic response, which could be targeted by an anti-fibrotic drug such as pirfenidone. Methods and results We explored the relationship between protein modulation by pirfenidone and post-MI remodelling, based on publicly available molecular information and transcriptomic data from a swine model of MI. We also compared the effects of pirfenidone and angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEi/ARB), mineralocorticoid receptor blockers (MRA) and beta-blockers. We identified six causative motives of post-MI remodelling (cardiomyocyte cell death, impaired myocyte contractility, extracellular matrix remodelling and fibrosis, hypertrophy, renin–angiotensin–aldosterone system activation, and inflammation), 4 pirfenidone targets and 21 bioflags (indirect effectors). When considering both targets and bioflags, pirfenidone showed a broad relationship encompassing all six motives. p38γ-MAPK12 blockade inhibits cardiomyocyte apoptosis, cardiomyocyte hypertrophy and inflammation. Furthermore, pirfenidone can modulate extracellular matrix remodelling and cardiac fibrosis by targeting the TGFβ1-SMAD2/3 pathway and other effector proteins such as matrix metalloproteases 2 and 14, PDGFA/B, and IGF1, which promote myocardial fibrosis, cardiomyocyte hypertrophy and impaired contractility. All the gold standard drugs were found to be important for specific clinical motives, but pirfenidone had a more widespread action on the molecular pathways active in the post-MI setting. Conclusions A bioinformatic approach allowed to identify several possible mechanisms of action of pirfenidone with beneficial effects in the post-MI LV remodelling, and suggests additional effects over guideline-recommended therapies. These findings support clinical studies evaluating the beneficial effects of pirfenidone in patients with MI.
    Type of Medium: Online Resource
    ISSN: 1520-765X , 1554-2815
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2021
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  • 4
    In: European Heart Journal Supplements, Oxford University Press (OUP), Vol. 23, No. Supplement_G ( 2021-12-08)
    Abstract: Hereditary amyloidosis are rare diseases characterized by extracellular deposition of insoluble fibril proteins in target organs disrupting their structure and function. The APOA1 gene encodes the precursor of apolipoprotein AI (ApoAI), whose mature form is the major component of high-density lipoproteins. There are some clusters of ApoAI amyloidosis (AApoAI) worldwide, including in the Lombardy and Veneto regions. Patients with AApoAI often present with chronic kidney disease, liver and spleen enlargement, with occasional involvement of the heart, peripheral nervous system, and other organs. Patterns of cardiac disease in AApoAI have never been systematically investigated. Methods and results We examined all patients with an established diagnosis of AApoAI referred to a dedicated outpatient clinic in Brescia from 2010 to 2020. The cardiac screening included a transthoracic echocardiogram with 2D speckle-tracking analysis. One-hundred and eighty-nine patients were evaluated [n = 102 (54%) men, median age 55 years (interquartile range 42–67)]. Renal disease was present in 39% and liver disease in 31%. Almost all patients were in sinus rhythm (96%). Median left ventricular ejection fraction (LVEF) was 60% (55–66), and just 2% of patients had LVEF & lt;50%. Diastolic function was preserved, with E/e′ ratio of 7 (6–10). Overall, patients did not display a prominent LV hypertrophy, with median interventricular septal thickness of 11 mm (9–12), a posterior wall thickness of 9 mm (8–11), and a LV mass index of 92 g/m2 (74–111). Global longitudinal strain [−19% (−21 to − 17)] , and the mass to strain ratio (MSR) [10.0 (6.8–12.1)] were within normal limits. Ten percent of patients displayed apical sparing, and 19% had a ‘granular sparkling’ appearance of the interventricular septum, which are both echocardiographic red flags of cardiac amyloidosis. Right ventricular (RV) function was preserved [median tricuspid annular plane systolic excursion of 23 mm (20–26)] , with a borderline RV free wall thickness [6 mm (5–8)]. A pericardial effusion was present in 11%. Moderate to severe mitral, aortic or tricuspid regurgitation or aortic stenosis were found in 11%, 4%, 6% and no patients, respectively. We found moderately strong correlations between age and several echocardiographic findings, namely: IVS (P  & lt; 0.001, r = 0.484), LVMI (P  & lt; 0.001, r = 0.459), E/e′ (P  & lt; 0.001, r = 0.501), and RV free wall thickness (P  & lt; 0.001, r = 0.459). Absolute GLS tended to decrease with age (P  & lt; 0.001, r = 0.380), and MSR to increase (P  & lt; 0.001, r = 0.357). Conclusions In the largest series of patients with AApoAI so far, minor signs of cardiac disease emerged from transthoracic echocardiography. Nonetheless, some red flags of cardiac amyloidosis were found in some patients. Furthermore, the correlations between age and echocardiographic findings suggested a progressive increase in wall thickness, a decline in systolic and diastolic function, and a greater uncoupling between LV mass and contractility over time.
    Type of Medium: Online Resource
    ISSN: 1520-765X , 1554-2815
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2021
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  • 5
    In: European Heart Journal Supplements, Oxford University Press (OUP), Vol. 24, No. Supplement_K ( 2022-12-15)
    Abstract: Reduced left ventricular ejection fraction (LVEF) has been used as a key criterion for the management of mitral regurgitation (MR) in patients with heart failure (HF), including the decision about mitral valve repair. However, LVEF, not taking into account mitral regurgitant volume, may be an imprecise predictor of outcome in HF patients with MR. Conversely, the estimation of the forward volume through the LV outflow tract (LVOT) may be a better metric in this setting. In this regard, LVOT velocity time integral (LVOT-VTI), not relying on geometrical assumptions, has been shown to be more reproducible than the calculated stroke volume (i.e., LVOT-VTI * LVOT cross sectional area), at least in the acute setting. Objective To assess the prognostic significance of LVOT-VTI in a contemporary cohort of patients with chronic HF and significant MR. Methods Consecutive patients with chronic HF with reduced (≤40%) or mildly reduced (41-49%) LVEF and moderate-to-severe or severe MR, according to the latest European Society of Cardiology criteria, were selected and followed-up for the endpoint of cardiovascular death. Results 203 patients were enrolled in the study (74±11 years, 66% men, 47% ischemic etiology, HFrEF 86%, LVEF 31±9%, mean LVOT-VTI 21±6 cm). Most patients showed a NYHA class II (40%) or III (31%) and received beta-blockers (95%), ACE-inhibitors/ARBs or ARNI (77%), and mineralocorticoid receptor antagonists (82%). Seventy-seven patients (38%) had permanent atrial fibrillation and 46 (23%) a cardiac resynchronization therapy device. Over a median follow-up of 18 (7-33) months, 30 patients died, 24 of whom for a cardiovascular cause, and 10 underwent mitral valve repair/replacement. When stratified according to the optimal prognostic cut-off of LVOT-VTI, patients with a LVOT-VTI & lt;16 cm (n=36) showed the greater risk of cardiovascular death (Log Rank 18.2, p & lt;0.001, Figure). Similarly, patients with a LVEF & lt;33% (n=122) showed a higher risk of cardiovascular death (Log Rank 5.5, p=0.019). Nevertheless, at Cox regression analysis, a unit decrease in LVOT-VTI (hazard ratio, HR 0.87 [95%CI 0.79-0.95], p=0.002) but not in LVEF (p=0.729) was associated with a higher risk of cardiovascular death (Figure). Conclusion Left ventricular forward volume, noninvasively estimated through LVOT-VTI, but not LVEF, predicts the risk of cardiac death in patients with chronic HF and significant MR.
    Type of Medium: Online Resource
    ISSN: 1520-765X , 1554-2815
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
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  • 6
    In: European Heart Journal Supplements, Oxford University Press (OUP), Vol. 24, No. Supplement_K ( 2022-12-15)
    Abstract: The echocardiographic evaluation of cardiac output relies on the product of the flow across the left ventricular outflow tract (LVOT), estimated through its velocity time integral (LVOT-VTI), and its cross-sectional area, estimated through the formula πr2. Considering the geometrical assumption behind such formula, LVOT-VTI may be a more reproducible surrogate of systolic function and showed prognostic value in the critical care setting. However, the role of this measure in patients with chronic heart failure (HF) remains unexplored. Objective To assess the clinical and prognostic significance of LVOT-VTI in a contemporary cohort of patients with chronic HF. Methods Outpatients with chronic HF with either reduced (≤40%) or mildly reduced (41-49%) LV ejection fraction (LVEF) were prospectively enrolled to undergo a clinical, echocardiographic, and biohumoral assessment, and were followed-up for the endpoint of cardiac death. Results Finally, 971 patients were enrolled (71±12 years, 72% men, 50% ischemic etiology, LVEF 35±9%, 74% HFrEF). Most patients showed a NYHA class I-II (74%) and were treated with ACE-inhibitors/ARBs or ARNI (81%), beta-blockers (95%), and mineralocorticoid receptor antagonists (71%). Patients were distinguished in three subgroups according to LVOT-VTI tertiles, i.e., ≤19 (n=324), 20-24 (n=324), or & gt;24 (n=323). Compared with the other two subgroups, patients with LVOT-VTI ≤19 showed worse NYHA class, lower LVEF and tricuspid annular plane systolic excursion (TAPSE), and higher E/e’, left atrial volume index (LAVi), estimated systolic pulmonary arterial pressure, and NT-proBNP concentration (all p & lt;0.001). No differences were observed as for patients’ age, HF etiology, and therapies (all p & gt;0.05). Over a median follow-up of 22 (9-34) months, 68 (7%) patients met the primary endpoint. LVOT-VTI significantly stratified the risk of cardiac death, observing 44 (13%), 15 (5%), and 9 (3%) events across the subgroups with values ≤19, 20-24, or & gt;24 (log-rank 25.9, p & lt;0.001). At multivariable regression analysis, LVOT-VTI ≤19 (HR 2.32 [95% 1.20-4.49], p=0.002), but not LVEF & lt;30% (p=0.614) was an independent predictor of cardiac death in a model adjusted for age, sex, ischemic etiology, renal function, hemoglobin, E/e’, LAVi, TAPSE, and NT-proBNP. Of note, this finding was consistent both in the HFrEF and HFmrEF subsets (p for interaction =0.899). Conclusion LVOT-VTI is associated with disease severity and is a strong predictor of all-cause death in patients with chronic HF.
    Type of Medium: Online Resource
    ISSN: 1520-765X , 1554-2815
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
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  • 7
    In: European Journal of Preventive Cardiology, Oxford University Press (OUP), Vol. 29, No. 11 ( 2022-08-22), p. 1510-1518
    Abstract: Gamma-glutamyltransferase (GGT) has been recognized as a cardiovascular risk factor, and its highest molecular weight fraction [big GGT (b-GGT)] is found in vulnerable atherosclerotic plaques. We explored the relationship between b-GGT, computed tomography findings, and long-term outcomes in the general population. Methods and results Between May 2010 and October 2011, subjects aged 45–75 years living in a Tuscan city and without known cardiac disease were screened. The primary endpoint was a composite of cardiovascular death or acute coronary syndrome requiring urgent coronary revascularization. Gamma-glutamyltransferase fractions were available in 898 subjects [median age 65 years (25th–75th percentile 55–70), 46% men]. Median plasma GGT was 20 IU (15–29), and b-GGT was 2.28 (1.28–4.17). Coronary artery calcium (CAC) score values were 0 (0–60), and the volume of pro-atherogenic epicardial fat was 155 mL (114–204). In a model including age, sex, low-density lipoprotein (LDL) cholesterol, current or previous smoking status, hypertension, diabetes, obesity, b-GGT independently predicted epicardial fat volume (EFV) (r = 0.162, P & lt; 0.001), but not CAC (P = 0.198). Over a 10.3-year follow-up (9.6–10.8), 27 subjects (3%) experienced the primary endpoint. We evaluated couples of variables including b-GGT and a cardiovascular risk factor, CAC or EFV. Big GGT yielded independent prognostic significance from age, LDL cholesterol, current or previous smoking status, hypertension, diabetes, obesity, but not CAC or EFV. Conversely, GGT predicted the primary endpoint even independently from CAC and EFV. Conclusion Big GGT seemed at least as predictive as the commonly available GGT assay; therefore, the need for b-GGT rather than GGT measurement should be carefully examined.
    Type of Medium: Online Resource
    ISSN: 2047-4873 , 2047-4881
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
    detail.hit.zdb_id: 2646239-4
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  • 8
    In: European Journal of Preventive Cardiology, Oxford University Press (OUP), Vol. 29, No. 17 ( 2022-12-07), p. 2163-2172
    Abstract: Since the introduction of anthracyclines into clinical practice in the 1960s, chemotherapy has always been associated with cardiotoxicity. Patients on cardiotoxic drugs can develop a wide range of cardiovascular diseases, including left ventricular (LV) systolic dysfunction and heart failure (HF), arrhythmias, hypertension, and coronary artery disease (CAD). The rising number of cancer patients, population ageing, and the frequent overlap of cardiovascular and oncological diseases have highlighted the importance of close collaboration between cardiologists and oncologists. As a result, in 1995, cardiologists at the IEO (European Institute of Oncology) coined the term cardioncology, a new discipline focused on the dynamics of cardiovascular disease in cancer patients. Given the complex scenario characterized by a constant dialogue between the oncological condition and cardiovascular comorbidity, it is essential for the clinician to get the knowledge to properly fulfill the needs of the oncological patient under cardiotoxic treatment. Through the answer to 10 questions, we aim to describe the complex issue of cardiotoxicity by addressing the main critical points and current evidence related to the assessment, management, treatment, and surveillance of cancer patients under chemotherapy.
    Type of Medium: Online Resource
    ISSN: 2047-4873 , 2047-4881
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
    detail.hit.zdb_id: 2646239-4
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  • 9
    In: Heart Failure Reviews, Springer Science and Business Media LLC, Vol. 27, No. 4 ( 2022-07), p. 1091-1104
    Abstract: Cancer and cardiovascular diseases, including heart failure (HF), are the main causes of death in Western countries. Several anticancer drugs and radiotherapy have adverse effects on the cardiovascular system, promoting left ventricular dysfunction and ultimately HF. Nonetheless, the relationship between cancer and HF is likely not unidirectional. Indeed, cancer and HF share common risk factors, and both have a bidirectional relationship with systemic inflammation, metabolic disturbances, and neurohormonal and immune activation. Few studies have assessed the impact of untreated cancer on the heart. The presence of an active cancer has been associated with elevated cardiac biomarkers, an initial impairment of left ventricular structure and function, autonomic dysfunction, and reduced exercise tolerance. In turn, these conditions might increase the risk of cardiac damage from chemotherapy and radiotherapy. HF drugs such as beta-blockers or inhibitors of the renin–angiotensin–aldosterone system might exert a protective effect on the heart even before the start of cancer therapies. In this review, we recapitulate the evidence of cardiac involvement in cancer patients naïve from chemotherapy and radiotherapy and no history of cardiac disease. We also focus on the perspectives for an early diagnosis and treatment to prevent the progression to cardiac dysfunction and clinical HF, and the potential benefits of cardioactive drugs on cancer progression.
    Type of Medium: Online Resource
    ISSN: 1382-4147 , 1573-7322
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
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  • 10
    In: Journal of the American College of Cardiology, Elsevier BV, Vol. 79, No. 13 ( 2022-04), p. 1288-1303
    Type of Medium: Online Resource
    ISSN: 0735-1097
    RVK:
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2022
    detail.hit.zdb_id: 1468327-1
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