Pirfenidone as a novel cardiac protective treatment

Myocardial fibrosis is a common feature of several heart diseases. The progressive deposition of extracellular matrix due to a persistent injury to cardiomyocytes may trigger a vicious cycle that leads to persistent structural and functional alterations of the myocardium. Some drugs (like renin-angiotensin-aldosterone system inhibitors) have been shown to reduce extracellular matrix deposition, but no primarily anti-fibrotic medications are currently used to treat patients with heart failure (HF). Pirfenidone is an oral antifibrotic agent approved for the treatment of idiopathic pulmonary fibrosis. Although its exact mechanism of action is not fully understood, pirfenidone might reduce the expression of profibrotic factors such as transforming growth factor-β (TGF-β), and proinflammatory cytokines, like tumor necrosis factor-α (TNF-α), interleukin (IL)-4, and IL-13, which could modulate the inflammatory response and inhibit collagen synthesis in lung tissue. There is some evidence that pirfenidone has antifibrotic activity in various animal models of cardiac disease. Furthermore, the positive results of the PIROUETTE trial, evaluating pirfenidone in patients with HF with preserved ejection fraction, have been very recently announced. This review summarizes the data about pirfenidone as a potential cardioprotective treatment

Pirfenidone for Idiopathic Pulmonary Fibrosis and Beyond

Pirfenidone (PFD) slows the progression of idiopathic pulmonary fibrosis (IPF) by inhibiting the exaggerated fibrotic response and possibly through additional mechanisms, such as anti-inflammatory effects. PFD has also been evaluated in other fibrosing lung diseases. Myocardial fibrosis is a common feature of several heart diseases and the progressive deposition of extracellular matrix due to a persistent injury to cardiomyocytes may trigger a vicious cycle that leads to persistent structural and functional alterations of the myocardium. No primarily antifibrotic medications are used to treat patients with heart failure. There is some evidence that PFD has antifibrotic actions in various animal models of cardiac disease and a phase II trial on patients with heart failure and preserved ejection fraction has yielded positive results. This review summarises the evidence about the possible mechanisms of IPF and modulation by PFD, the main results about IPF or non-IPF interstitial pneumonias and also data about PFD as a potential protective cardiac drug

Pathophysiological Rationale and Clinical Evidence for Neurohormonal Modulation in Heart Failure with Preserved Ejection Fraction

Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome resulting from the interaction between cardiac diseases, comorbidities and ageing. HFpEF is characterised by the activation of neurohormonal axes, namely of the renin-angiotensin-aldosterone system and the sympathetic nervous system, although to a lesser extent compared with heart failure with reduced ejection fraction. This provides a rationale for neurohormonal modulation as a therapeutic approach for HFpEF. Nonetheless, randomised clinical trials have failed to demonstrate a prognostic benefit from neurohormonal modulation therapies in HFpEF, with the sole exception of patients with left ventricular ejection fraction in the lower range of normality, for whom the American guidelines suggest that such therapies may be considered. In this review, the pathophysiological rationale for neurohormonal modulation in HFpEF is summarised and the clinical evidence on pharmacological and nonpharmacological approaches backing current recommendations discussed

Role of Imaging in Cardiomyopathies

Imaging has a central role in the diagnosis, classification, and clinical management of cardiomyopathies. While echocardiography is the first-line technique, given its wide availability and safety, advanced imaging, including cardiovascular magnetic resonance (CMR), nuclear medicine and CT, is increasingly needed to refine the diagnosis or guide therapeutic decision-making. In selected cases, such as in transthyretin-related cardiac amyloidosis or in arrhythmogenic cardiomyopathy, the demonstration of histological features of the disease can be avoided when typical findings are observed at bone-tracer scintigraphy or CMR, respectively. Findings from imaging techniques should always be integrated with data from the clinical, electrocardiographic, biomarker, genetic and functional evaluation to pursue an individualised approach to patients with cardiomyopathy

Transtiretina circolante nell'amiloidosi cardiaca da transtiretina: caratterizzazione e correlati clinico-terapeutici

Background: L’amiloidosi cardiaca da transtiretina (ATTR-CA) è una patologia sistemica caratterizzata dalla deposizione extracellulare di fibrille di amiloide di transtiretina (TTR), che può condurre progressivamente ad insufficienza cardiaca. Con il recente sviluppo di terapie disease-modifying, l'identificazione precoce dei pazienti con ATTR-CA in fase subclinica è diventata un'importante area di indagine. Ad oggi, tuttavia, non sono disponibili biomarcatori specifici per la ATTR-CA. Metodi e risultati: I livelli circolanti di TTR e retinol binding protein 4 (RBP4) sono stati valutati in 37 pazienti con ATTR-CA e 37 controlli abbinati per età, sesso, frazione d’eiezione e filtrato glomerulare. I pazienti con ATTR-CA e i controlli hanno mostrato simili livelli di TTR (19,9 vs. 21,8 mg/dL, p=0,623) e RBP4 (4,72 vs. 5,16 mg/dL, p=0,212). I valori di TTR e RBP4 erano strettamente correlati fra loro (ρ 0,652, p<0,001). È stata poi valutata la variazione longitudinale dei livelli di TTR e RPB4 al basale e al follow-up a 6 mesi in pazienti trattati con tafamidis (n=4) e in pazienti non trattati con terapie stabilizzanti il tetramero di TTR (n=7). La TTR è aumentata da a 16,9 a 27,2 mg/dL (p=0,068) nei pazienti trattati, mentre in quelli non trattati è rimasta invariata (22,3 vs. 22,4 mg/dL, p=0,866). I valori di RBP4 al basale e al follow-up a 6 mesi erano simili sia nei pazienti trattati con tafamidis (3,6 vs. 4,3 mg/dL; p=0,715) che in quelli non trattati (4,3 vs. 5,8 mg/dL; p=0,310). L’analisi elettroforetica delle forme circolanti di TTR ha dimostrato che il monomero e il tetramero di TTR non sembrano essere presenti in circolo. Sono presenti, invece, forme verosimilmente dimeriche, trimeriche, complessate con 1 o 2 RBP4, e forme di TTR ad alto peso molecolare. In corso di trattamento con tafamidis, il complesso TTR + 2 RBP4 sembra aumentare, mentre le forme dimeriche e trimeriche sembrano diminuire. Conclusioni: I livelli circolanti di TTR e RBP4 non differiscono significativamente fra pazienti con ATTR-CA e controlli. La riduzione della TTR osservata in seguito all’introduzione di terapia con tafamidis potrebbe rappresentare un marcatore precoce dell’efficacia dei farmaci stabilizzanti il tetramero. Le forme monomerica e tetramerica isolata di TTR, entrambe alla base dell’attuale paradigma interpretativo dell’amiloidogenesi, sono in realtà assenti nel circolo di pazienti e soggetti sani. La caratterizzazione delle forme circolanti di TTR potrebbe aiutare nella comprensione dei meccanismi fisiopatologici alla base della cascata amiloidogenica e nell’identificazione di marcatori diagnostici, prognostici o predittivi della risposta a terapie disease-modifying, nonché di nuovi bersagli terapeutici per la ATTR-CA

High-sensitivity troponins for outcome prediction in the general population: a systematic review and meta-analysis

Background: High-sensitivity (hs) assays allow to measure cardiac troponin T and I (cTnT/I) even in healthy individuals. The higher hs-cTn values, the higher the ongoing cardiomyocyte damage, and then reasonably the risk of developing symptomatic cardiac disease. Methods: We retrieved all studies evaluating the prognostic value of hs-cTnT or I in the general population. We calculated pooled hazard ratio (HR) values for all-cause and cardiovascular death, cardiovascular events and heart failure (HF) hospitalization. Results: We included 24 studies for a total of 203,202 subjects; 11 studies assessed hs-cTnT and 14 hs-cTnI. One standard deviation (SD) increase in baseline hs-cTn was associated with a 23% higher risk of all-cause death (HR 1.226, 95% CI 1.083-1.388, p&lt;0.001, I2=88.5%); all these studies measured hs-cTnI. In an exploratory analysis on 3 studies with 25,760 subjects, hs-cTn predicted cardiovascular death (HR 1.822, 95% CI 1.241-2.674, p=0.002, I2=87.2%). After synthesizing 9 studies with 58,565 subjects, hs-cTn predicted cardiovascular events (HR 1.328, 95% CI 1.167-1.513, p&lt;0.001, I2=93.8%). Both hs-cTnT (HR 1.627, 95% CI 1.145-2.311, p&lt;0.001) and hs-cTnI (HR 1.260, 95% CI 1.115-1.423, p&lt;0.001; p for interaction &lt;0.001). Furthermore, in 10 studies with 61,467 subjects, hs-cTn predicted HF hospitalization (HR 1.493, 95% CI 1.368-1.630, p&lt;0.001, I2=76.6%). Both hs-cTnT (HR 1.566, 95% CI 1.303-1.883, p&lt;0.001) and hs-cTnI (HR 1.467, 95% CI 1.321-1.628, p&lt;0.001) were associated with HF hospitalization (p for interaction &lt;0.001). Conclusions: hs-cTn values hold strong prognostic value in subjects from the general population, predicting the risk of all-cause and cardiovascular mortality, cardiovascular events, and HF hospitalization

Management of heart failure with preserved ejection fraction: from neurohormonal antagonists to empagliflozin

: Heart failure with preserved ejection fraction (HFpEF) is a highly prevalent syndrome with multifaceted pathophysiology. All approaches to neurohormonal modulation were shown not to improve survival in HFpEF, despite their well-established efficacy in heart failure with reduced ejection fraction (HFrEF). This might be attributed to suboptimal study design, inadequate diagnostic criteria, or statistical power, but is also likely to reflect a lack of consideration for its clinical heterogeneity. The attention then shifted to the phenotypic heterogeneity of HFpEF, with the ultimate goal of developing therapies tailored to individual patient phenotypes. Recently, the sodium-glucose co-transporter-2 inhibitor (SGLT2i) empagliflozin has been found to reduce the combined risk of cardiovascular death or hospitalization for HF in patients with HFpEF, a result driven by a reduction in HF hospitalizations. This paper recapitulates the journey from the failure of trials on neurohormonal antagonists to the attempts of personalized approaches and the new perspectives of SGLT2i therapy for HFpEF

Shared and unique characteristics of metabolic syndrome in psychotic disorders: a review

IntroductionPeople with psychosis spectrum disorders (PSD) face an elevated risk of metabolic syndrome (MetS), which may reduce their life expectancy by nearly 20%. Pinpointing the shared and specific characteristics and clinical implications of MetS in PSD is crucial for designing interventions to reduce this risk, but an up-to-date review on MetS across the psychosis spectrum is lacking.MethodsThis narrative review fills this gap by examining the clinical literature on characteristics and implications of MetS in both distinct PSD and transdiagnostically, i.e., across traditional categorical diagnoses, with a focus on psychiatric and cardio-metabolic management.ResultsWe discuss common and specific characteristics of MetS in PSD, as well as factors contributing to MetS development in PSD patients, including unhealthy lifestyle factors, genetic predisposition, pro-inflammatory state, drugs consumption, antipsychotic medication, and psychotic symptoms. We highlight the importance of early identification and management of cardio-metabolic risk in PSD patients, as well as the existing gaps in the literature, for instance in the screening for MetS in younger PSD patients. We compare hypotheses-generating clinical associations and characteristics of MetS in different PSD, concluding by reviewing the existing recommendations and challenges in screening, monitoring, and managing MetS in PSD.ConclusionEarly identification and management of MetS are crucial to mitigate the long-term cardio-metabolic toll in PSD patients. Interventions should focus on healthy lifestyle and appropriate pharmacological and behavioral interventions. Further translational and clinical research is needed to develop targeted interventions and personalized treatment approaches for this vulnerable population, aiming at improving physical health and overall well-being

Indications of beta-adrenoceptor blockers in takotsubo syndrome and theoretical reasons to prefer agents with vasodilating activity

Takotsubo syndrome (TTS) is estimated to account for 1-3% of all patients presenting with suspected ST-segment elevation myocardial infarction. A sudden surge in sympathetic nervous system is considered the cause of TTS. Nonetheless, no specific recommendations have been provided regarding β-blocking therapy. Apart from specific contra-indications (severe LV dysfunction, hypotension, bradycardia and corrected QT interval&nbsp;&gt;500&nbsp;ms), treatment with a β-blocker seems reasonable until full recovery of LV ejection fraction, though evidence is limited to a few animal studies, case reports or observational studies. In this review, we will reappraise the rationale for β-blocker therapy in TTS and speculate on the pathophysiologic basis for preferring non-selective agents with vasodilating activity over β1-selective drugs

Sex differences in transthyretin cardiac amyloidosis

: 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