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AIMS: Chronic obstructive pulmonary disease (COPD) is a frequent comorbidity in patients with heart failure (HF). We assessed the influence of COPD on circulating levels and prognostic value of three HF biomarkers: N-terminal pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity troponin T (hs-TnT), and soluble suppression of tumorigenesis-2 (sST2).METHODS: Individual data from patients with chronic HF, known COPD status, NT-proBNP and hs-TnT values (n = 8088) were analysed. A subgroup (n = 3414) had also sST2 values.RESULTS: Patients had a median age of 66 years (interquartile interval 57-74), 77% were men and 82% had HF with reduced ejection fraction. NT-proBNP, hs-TnT and sST2 were 1207 ng/l (487-2725), 17 ng/l (9-31) and 30 ng/ml (22-44), respectively. Patients with COPD (n = 1249, 15%) had higher NT-proBNP (P = 0.042) and hs-TnT (P CONCLUSIONS: Among patients with HF, those with COPD have higher NT-proBNP and hs-TnT, but not sST2. All these biomarkers yield prognostic significance regardless of the COPD status.

Objectives The goal of this study was to assess the predictive power of N-terminal pro–B-type natriuretic peptide (NT-proBNP) and the decision cutoffs in heart failure (HF) across body mas...

Background Higher body mass index (BMI) is associated with better outcome compared with normal weight in patients with HF and other chronic diseases. It remains uncertain whether the apparent protective role of obesity relates to the absence of comorbidities. Therefore, we investigated the effect of BMI on outcome in younger patients without co-morbidities as compared to older patients with co-morbidities in a large heart failure (HF) population. Methods In an individual patient data analysis from pooled cohorts, 5,819 patients with chronic HF and data available on BMI, co-morbidities and outcome were analysed. Patients were divided into four groups based on BMI (i.e. ≤ 18.5 kg/m2, 18.5–25.0 kg/m2; 25.0–30.0 kg/m2; 30.0 kg/m2). Primary endpoints included all-cause mortality and HF hospitalization-free survival. Results Mean age was 65 ± 12 years, with a majority of males (78%), ischaemic HF and HF with reduced ejection fraction. Frequency of all-cause mortality or HF hospitalization was significantly worse in the lowest two BMI groups as compared to the other two groups; however, this effect was only seen in patients older than 75 years or having at least one relevant co-morbidity, and not in younger patients with HF only. After including medications and N-terminal pro-B-type natriuretic peptide and high-sensitivity cardiac troponin concentrations into the model, the prognostic impact of BMI was largely absent even in the elderly group with co-morbidity. Conclusions The present study suggests that obesity is a marker of less advanced disease, but does not have an independent protective effect in patients with chronic HF. Graphic abstract Categories of BMI are only predictive of poor outcome in patients aged > 75 years or with at least one co-morbidity (bottom), but not in those aged

The use of serial measurement of cardiac troponin (cTn) is recommended by international guidelines for the diagnosis of myocardial infarction (MI) since 2000. This article focuses on factors influencing temporal changes in high-sensitive cTn (hs)-cTn and the impact of these factors on the diagnosis of non-ST-segment elevation MI (NSTEMI). The recommendations proposed by three different international guidelines published in 2020–2021 for the management of acute coronary syndromes (ACS) in patients presenting without persistent ST-segment elevation (NSTE) show some discrepancies. In particular, there is no agreement among these guidelines about cut-off or absolute change values to be used for the rule-in, especially regarding the use of sex-specific cut-off values. Furthermore, there are no sufficient evidences on the diagnostic accuracy and cost effectiveness related to cut-off values suggested for algorithms to be used by some hs-cTnI methods.

Coronary artery disease (CAD) is known to impact on patients’ physical and mental health. The relationship between performance on treadmill exercise tolerance test (ETT) and health-related quality of life (HRQL)has never been specifically investigated in the setting of CAD. Consecutive patients undergoing an ETT with the Bruce protocol during a diagnostic workup for CAD (n = 1,631, age 55 ± 12 years) were evaluated. Exercise-related indices were recorded. Detailed information on cardiovascular risk factors and past medical history were obtained. HRQLwas assessed with the use of the validated 36-Item Short Form Survey (SF-36) questionnaire. Increasing age and the presence of cardiovascular risk factors and comorbidities correlated with lower scores on the physical and mental health component of SF-36(all P

Background and purpose Activation of hepatic thyroid hormone receptor β (THR-β) is associated with systemic lipid lowering, increased bile acid synthesis, and fat oxidation. In patients with non-alcoholic steatohepatitis (NASH), treatment with THR-β agonists decreased hepatic steatosis and circulating lipids, and induced resolution of NASH. We chose resmetirom (MGL-3196), a liver-directed, selective THR-β agonist, as a prototype to investigate the effects of THR-β activation in mice with diet-induced obesity (DIO) and biopsy-confirmed advanced NASH with fibrosis. Experimental approach C57Bl/6J mice were fed a diet high in fat, fructose, and cholesterol for 34 weeks, and only biopsy-confirmed DIO-NASH mice with fibrosis were included. Resmetirom was administered at a daily dose of 3 mg·kg-1 p.o., for 8 weeks. Systemic and hepatic metabolic parameters, histological non-alcoholic fatty liver disease (NAFLD) activity and fibrosis scores, and liver RNA expression profiles were determined to assess the effect of THR-β activation. Key results Treatment with resmetirom did not influence body weight but led to significant reduction in liver weight, hepatic steatosis, plasma alanine aminotransferase activity, liver and plasma cholesterol, and blood glucose. These metabolic effects translated into significant improvement in NAFLD activity score. Moreover, a lower content of α-smooth muscle actin and down-regulation of genes involved in fibrogenesis indicated a decrease in hepatic fibrosis. Conclusion and implications Our model robustly reflected clinical observations of body weight-independent improvements in systemic and hepatic metabolism including anti-steatotic activity.

A higher neprilysin activity has been suggested in women. In this retrospective analysis, we evaluated the association of sex and body mass index (BMI) with soluble neprilysin (sNEP) and recurrent admissions among 1021 consecutive HF outpatients. The primary and secondary endpoints were the number of HF hospitalizations and all-cause mortality, respectively. The association between sNEP with either endpoint was evaluated across sex and BMI categories (≥ 25 kg/m2 vs. 2). Bivariate count regression (Poisson) was used, and risk estimates were expressed as incidence rates ratio (IRR). During a median follow-up of 6.65 years (percentile 25%-percentile 75%:2.83–10.25), 702 (68.76%) patients died, and 406 (40%) had at least 1 HF hospitalization. Median values of sNEP and BMI were 0.64 ng/mL (0.39–1.22), and 26.9 kg/m2 (24.3–30.4), respectively. Left ventricle ejection fraction was p = 0.001) but not with mortality (p = 0.241). The predictive value of sNEP for HF hospitalizations varied non-linearly across sex and BMI categories (p-value for interaction = 0.003), with significant and positive effect only on women with BMI ≥ 25 kg/m2 (p = 0.039). For instance, compared to men, women with sNEP of 1.22 ng/mL (percentile 75%) showed a significantly increased risk (IRRs: 1.26; 95% CI: 1.05–1.53). The interaction analysis for mortality did not support a differential prognostic effect for sNEP (p = 0.072). In conclusion, higher sNEP levels in overweight women better predicted an increased risk of HF hospitalization.

Currently adopted diagnostic flow charts consider transthyretin and light-chain cardiac amyloidosis as mutually exclusive. Here, we report for the first time, to our knowledge, the demonstration of a biopsy-proven dual pathology in an 80-year-old man with sequential development of both wild-type transthyretin amyloidosis and light-chain cardiac amyloidosis cardiomyopathy over a 3-year timespan. (Level of Difficulty: Intermediate.), Graphical abstract

The aim of this study was to examine the impact of features of dysmetabolism on liver disease severity, evolution, and clinical outcomes in a real-life cohort of patients treated with direct acting antivirals for chronic hepatitis C virus (HCV) infection. To this end, we considered 7,007 patients treated between 2014 and 2018, 65.3% with advanced fibrosis, of whom 97.7% achieved viral eradication (NAVIGATORE-Lombardia registry). In a subset (n=748), liver stiffness measurement (LSM) was available at baseline and follow-up. Higher body mass index (BMI; odds ratio [OR] 1.06 per kg/m2, 1.03-1.09) and diabetes (OR 2.01 [1.65-2.46]) were independently associated with advanced fibrosis at baseline, whereas statin use was protective (OR 0.46 [0.35-0.60]; P&nbsp

Objective The use of combined hormonal contraceptives (CHCs) worsens glucose tolerance, but the risk for glucose metabolism disorders remains controversial. Design The study is a prospective longitudinal population-based cohort study. Methods The study was based on a cohort population that comprised 1879 women born in 1966. At age 46, the women answered a questionnaire on contraceptive use and underwent an oral glucose tolerance test. Glucose metabolism indices were evaluated in current CHC (n = 153), progestin-only contraceptive (POC, n = 842), and non-hormonal contraceptive users (n = 884). Results In the entire study population, current CHC use was significantly associated with prediabetes (OR: 2.0, 95% CI: 1.3–3.2) and type 2 diabetes (OR: 3.3, 95% CI: 1.1–9.7) compared to non-hormonal contraceptive use. After 5 years of use, the prediabetes risk increased 2.2-fold (95% CI: 1.3–3.7) and type 2 diabetes risk increased 4.5-fold (95% CI: 1.5–13.5). Compared with the current POC use, current CHC use was significantly associated with prediabetes (OR: 1.9, 95% CI: 1.2–3.0). Current POC use was not associated with any glucose metabolism disorders. The results prevailed after adjusting for BMI and socioeconomic status. Conclusions CHC use in perimenopausal women was associated with a significantly increased risk of glucose metabolism disorders. This association should be considered in women with increased metabolic risk.

Aims Immune checkpoint inhibitors (ICIs) are an emerging option for several advanced metastatic cancers, but have been associated with cardiotoxicity. The prognostic value of high-sensitivity troponin T (hs-TnT) measured before treatment start has never been investigated. Methods and results Thirty consecutive patients underwent measurement of hs-TnT before starting ICI therapy (pembrolizumab, 23%; nivolumab, 12%; atezolizumab, 6%; durvalumab, 5%). The primary endpoint was a composite of cardiovascular death, stroke or transient ischaemic attack, pulmonary embolism and new-onset heart failure. The secondary endpoint was progression of cardiac involvement according to the CARDIOTOX staging system. Patients (median age 68 years, 77% men, 13% with coronary artery disease, 90% current or former smokers, 67% overweight or obese, and 43% hypertensive) had a median hs-TnT of 12 ng/L (interquartile interval 8-23). At the 3-month timepoint, 7 patients (23%) had experienced the primary endpoint, and 13 (43%) the secondary endpoint. Area under the curve values were 0.909 for the primary, and 0.757 for the secondary endpoint. The best troponin-T cut-off was 14 ng/L for both the primary (100% sensitivity, 73% specificity) and secondary endpoint (sensitivity 75%, specificity 77%). Over a median follow-up duration of 2.6 months (2.0-3.6), survival free from the primary endpoint was shorter in patients with hs-TnT ≥14 ng/L (Log-rank: 10.3, p = 0.001), and all patients developing the primary endpoint had hs-TnT ≥14 ng/L at baseline. Conclusion In patients on ICIs, baseline hs-TnT predicts a composite cardiovascular endpoint and the progression of cardiac involvement at 3 months, with 14 ng/L as the best cut-off.

Background and Aims: To better understand nonalcoholic steatohepatitis (NASH) disease progression and to evaluate drug targets and compound activity, we undertook the development of an in vitro 3D model to mimic liver architecture and the NASH environment. Methods: We have developed an in vitro preclinical 3D NASH model by coculturing primary human hepatocytes, human stellate cells, liver endothelial cells and Kupffer cells embedded in a hydrogel of rat collagen on a 96-well plate. A NASH-like environment was induced by addition of medium containing free fatty acids and tumor necrosis factor-α. This model was then characterized by biochemical, imaging and transcriptomics analyses. Results: We succeeded in defining suitable culture conditions to maintain the 3D coculture for up to 10 days in vitro, with the lowest level of steatosis and reproducible low level of inflammation and fibrosis. NASH disease was induced with a custom medium mimicking NASH features. The cell model exhibited the key NASH disease phenotypes of hepatocyte injury, steatosis, inflammation, and fibrosis. Hepatocyte injury was highlighted by a decrease of CYP3A4 expression and activity, without loss of viability up to day 10. Moreover, the model was able to stimulate a stable inflammatory and early fibrotic environment, with expression and secretion of several cytokines. A global gene expression analysis confirmed the NASH induction. Conclusions: This is a new in vitro model of NASH disease consisting of four human primary cell-types that exhibits most features of the disease. The 10-day cell viability and cost effectiveness of the model make it suitable for medium throughput drug screening and provide attractive avenues to better understand disease physiology and to identify and characterize new drug targets.

Aims Cardiac magnetic resonance (CMR) is part of the diagnostic work-up for cardiac amyloidosis (CA). Deep learning (DL) is an application of artificial intelligence that may allow to automatically analyze CMR findings and establish the likelihood of CA. Methods and results 1.5 T CMR was performed in 187 subjects with suspected CA (n = 92, 49% with unexplained left ventricular—LV—hypertrophy; n = 95, 51% with blood dyscrasia and suspected light-chain amyloidosis). Patients were randomly assigned to the training (n = 121, 65%), validation (n = 28, 15%), and testing subgroups (n = 38, 20%). Short axis (SA), 2-chamber (2 C), 4-chamber (4 C) late gadolinium enhancement (LGE) images were evaluated by 3 networks (DL algorithms). The tags “amyloidosis present” or “absent” were attributed when the average probability of CA from the 3 networks was ≥50% or Conclusion A DL approach evaluating LGE acquisitions displayed a similar diagnostic performance for CA to a ML-based approach, which simulates CMR reading by experienced operators.

Background Cardiovascular magnetic resonance (CMR) is part of the diagnostic work-up for cardiac amyloidosis (CA). Deep learning (DL) is an application of artificial intelligence that may allow to automatically analyze CMR findings and establish the likelihood of CA. Methods 1.5 T CMR was performed in 206 subjects with suspected CA (n = 100, 49% with unexplained left ventricular (LV) hypertrophy; n = 106, 51% with blood dyscrasia and suspected light-chain amyloidosis). Patients were randomly assigned to the training (n = 134, 65%), validation (n = 30, 15%), and testing subgroups (n = 42, 20%). Short axis, 2-chamber, 4-chamber late gadolinium enhancement (LGE) images were evaluated by 3 networks (DL algorithms). The tags “amyloidosis present” or “absent” were attributed when the average probability of CA from the 3 networks was ≥ 50% or Results The DL strategy displayed good diagnostic accuracy (88%), with an area under the curve (AUC) of 0.982. The precision (positive predictive value), recall score (sensitivity), and F1 score (a measure of test accuracy) were 83%, 95%, and 89% respectively. A ML algorithm considering all CMR features had a similar diagnostic yield to DL strategy (AUC 0.952 vs. 0.982; p = 0.39). Conclusions A DL approach evaluating LGE acquisitions displayed a similar diagnostic performance for CA to a ML-based approach, which simulates CMR reading by experienced operators.

Aims Accurate and reproducible diagnostic techniques are essential to detect left-sided cardiac thrombi (either in the left ventricle [LV] or in the left atrial appendage [LAA]) and to guide the onset and duration of antithrombotic treatment while minimizing the risk for thromboembolic and hemorrhagic events. Methods and results We conducted a systematic review and meta-analysis aiming to compare the diagnostic performance of transthoracic echocardiography (TTE) vs. cardiac magnetic resonance (CMR) for the detection of LV thrombi, and transesophageal echocardiography (TEE) vs. computed tomography (CT) for the detection of LAA thrombi. Six studies were included in the first meta-analysis. Pooled sensitivity and specificity values were 62% (95% confidence interval [CI], 37-81%) and 97% (95% CI, 94-99%). The shape of the hierarchical summary receiver operating characteristic (HSROC) curve and the area under the curve (AUC) of 0.96 suggested a high accuracy. Ten studies were included in the meta-analysis of the diagnostic accuracy of CT vs. TEE. The pooled values of sensitivity and specificity were 97% (95% CI, 77-100%) and 94% (95% CI, 87-98%). The pooled DOR was 500 (95% CI, 52-4810), and the pooled LR+ and LR- values were 17% (95% CI, 7-40%) and 3% (95% CI, 0-28%). The shape of the HSROC curve and the 0.99 AUC suggested a high accuracy of CT vs. TEE. Conclusion TTE is a valid alternative to DE-CMR for the identification of LV thrombi, and CT has a good accuracy compared to TEE for the detection of LAA thrombosis.

As a gut-restricted, nonabsorbed therapy, polymeric bile acid sequestrants (BAS) play an important role in managing hyperlipidemia and hyperglycemia. Similarly, nonabsorbable sequestrants of dietary phosphate have been used for the management of hyperphosphatemia in end-stage renal disease. To evaluate the potential utility of such polymer sequestrants to treat type 2 diabetes (T2D) and its associated renal and cardiovascular complications, we synthesized a novel polymeric sequestrant, SAR442357, possessing optimized bile acid (BA) and phosphate sequestration characteristics. Long-term treatment of T2D obese cZucker fatty/Spontaneously hypertensive heart failure F1 hybrid (ZSF1) with SAR442357 resulted in enhanced sequestration of BAs and phosphate in the gut, improved glycemic control, lowering of serum cholesterol, and attenuation of diabetic kidney disease (DKD) progression. In comparison, colesevelam, a BAS with poor phosphate binding properties, did not prevent DKD progression, whereas losartan, an angiotensin II receptor blocker that is widely used to treat DKD, showed no effect on hyperglycemia. Analysis of hepatic gene expression levels of the animals treated with SAR442357 revealed upregulation of genes responsible for the biosynthesis of cholesterol and BAs, providing clear evidence of target engagement and mode of action of the new sequestrant. Additional hepatic gene expression pathway changes were indicative of an interruption of the enterohepatic BA cycle. Histopathological analysis of ZSF1 rat kidneys treated with SAR442357 further supported its nephroprotective properties. Collectively, these findings reveal the pharmacological benefit of simultaneous sequestration of BAs and phosphate in treating T2D and its associated comorbidities and cardiovascular complications. SIGNIFICANCE STATEMENT: A new nonabsorbed polymeric sequestrant with optimum phosphate and bile salt sequestration properties was developed as a treatment option for DKD. The new polymeric sequestrant offered combined pharmacological benefits including glucose regulation, lipid lowering, and attenuation of DKD progression in a single therapeutic agent.

This is the peer reviewed version of the following article: Aimo, A., Januzzi, J.L., Vergaro, G., Richards, A.M., Lam, C.S.P., Latini, R. ... Emdin, M. (2020). Circulating levels and prognostic value of soluble ST2 in heart failure are less influenced by age than N-terminal pro-B-type natriuretic peptide and high-sensitivity troponin T, European Journal of Heart Failure, which has been published in final form at https://doi.org/10.1002/ejhf.1701. . This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. Aims - N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP), high‐sensitivity troponin T (hs‐TnT) and soluble suppression of tumorigenesis‐2 (sST2) predict outcome in chronic heart failure (HF). We assessed the influence of age on circulating levels and prognostic significance of these biomarkers. Methods and results - Individual data from 5301 patients with chronic HF and NT‐proBNP, hs‐TnT, and sST2 data were evaluated. Patients were stratified according to age: Conclusions - Soluble ST2 is less influenced by age than NT‐proBNP or hs‐TnT; all these biomarkers predict outcome regardless of age. The use of age‐ and outcome‐specific cut‐offs of NT‐proBNP, hs‐TnT and sST2 allows more accurate risk stratification than NT‐proBNP alone or the combination of NT‐proBNP and hs‐TnT.

Cardiac involvement in systemic amyloidosis, due either to immunoglobulin light-chain or transthyretin amyloidosis, influences clinical presentation and is a strong predictor of unfavourable outcome. Until recently considered as a rare, incurable disease, cardiac amyloidosis, is still mis/underdiagnosed, although treatments effective in improving patient survival are now available for both subtypes, including chemotherapy regimens for immunoglobulin light-chain amyloidosis and tetramer stabiliser for transthyretin amyloidosis. Achieving a timely diagnosis allows initiating life-saving therapies and requires the early recognition of clinical, laboratory and imaging signs of cardiac involvement, some of them may be apparent well before the disease becomes clinically manifest. Given the systemic nature of amyloidosis, a close interaction among experts in multiple specialties is also required, including cardiologists, nephrologists, haematologists, neurologists, radiologists, nuclear medicine specialists and internists. As an increased awareness about disease presentation is required to ameliorate diagnostic performance, we aim to provide the clinician with a guide to the screening and early diagnosis of cardiac amyloidosis, and to review the clinical, biohumoral and instrumental ‘red flags’ that should raise the suspicion of cardiac amyloidosis.

Background Preventing the evolution of subclinical cardiac disease into overt heart failure is of paramount importance. Imaging techniques, particularly transthoracic echocardiography (TTE), are well suited to identify abnormalities in cardiac structure and function that precede the development of heart failure. Methods This meta-analysis provides a comprehensive evaluation of 32 studies from 11 individual cohorts, which assessed cardiac indices from TTE (63%), cardiovascular magnetic resonance (CMR; 34%) or cardiac computed tomography (CCT; 16%). Eligible studies focused on measures of left ventricular geometry and function and were highly heterogeneous. Results Among the variables that could be assessed through a meta-analytic approach, left ventricular systolic dysfunction, defined as left ventricular ejection fraction (LVEF) lower than 50%, and left ventricular dilation were associated with a five-fold [hazard ratio (HR) 4.76, 95% confidence interval (95% CI) 1.85-12.26] and three-fold (HR 3.14, 95% CI 1.37 -7.19) increased risk of heart failure development, respectively. Any degree of diastolic dysfunction conveyed an independent, albeit weaker, association with heart failure (HR 1.48, 95% CI 1.11-1.96), although there was only a trend for left ventricular hypertrophy in predicting incident heart failure (hazard ratio 2.85, 95% CI 0.82-9.85). Conclusion LVEF less than 50%, left ventricular dilation and diastolic dysfunction are independent predictors of incident heart failure among asymptomatic individuals, while left ventricular hypertrophy seems less predictive. These findings may serve as a framework for implementing imaging-based screening strategies in patients at risk of heart failure and inform future studies testing preventive or therapeutic approaches aiming at thwarting or halting the progression from asymptomatic (preclinical) to overt heart failure.

Myocardial infarction with nonobstructed coronary arteries (MINOCA) can be triggered by intense emotions. We report 5 cases of emotional stress–related death where forensic examination attributed myocardial infarction to a coronary spasm, with the ultimate cause of death being arrhythmias in 4 cases and cardiac rupture in the fifth. (Level of Difficulty: Beginner.), Graphical abstract, Myocardial infarction with nonobstructed coronary arteries (MINOCA) can be triggered by intense emotions. We report 5 cases of emotional…

The significant morbidity and mortality associated with heart failure with reduced ejection fraction (HFrEF) or heart failure with preserved ejection fraction (HFpEF) justify the search for novel therapeutic agents. Reduced cyclic guanosine monophosphate levels contribute to HF progression. Among molecules modulating the nitric oxide (NO)–GMP–phosphodiesterase (PDE) pathway, the evaluation of nitrates, synthetic natriuretic peptides (NP), and NP analogs has yielded mixed results. Conversely, sacubitril/valsartan, combining NP degradation inhibition through neprilysin and angiotensin receptor blockade, has led to groundbreaking findings in HFrEF. Other strategies to increase tissue cyclic guanosine monophosphate have been attempted, such as PDE-3 or PDE-5 inhibition (with negative or neutral results), NO-independent soluble guanylate cyclase (sGC) activation, or enhancement of sGC sensitivity to endogenous NO. Following the positive results of the phase 3 VICTORIA (A Study of Vericiguat in Participants With Heart Failure With Reduced Ejection Fraction) trial on the sGC stimulator vericiguat in HFrEF, the main open questions are the efficacy of the sacubitril/valsartan-vericiguat combination in HFrEF and of vericiguat in HFpEF.

Accurate and reproducible diagnostic techniques are essential to detect left-sided cardiac thrombi [either in the left ventricle (LV) or in the left atrial appendage (LAA)] and to guide the onset and duration of antithrombotic treatment while minimizing the risk for thromboembolic and hemorrhagic events. We conducted a systematic review and meta-analysis aiming to compare the diagnostic performance of transthoracic echocardiography (TTE) vs. cardiac magnetic resonance (CMR) for the detection of LV thrombi, and transesophageal echocardiography (TEE) vs. computed tomography (CT) for the detection of LAA thrombi. Six studies were included in the first meta-analysis (TTE vs. CMR for LV thrombosis). Pooled sensitivity and specificity values were 62% [95% confidence interval (CI), 37–81%] and 97% (95% CI, 94–99%). The shape of the hierarchical summary receiver operating characteristic (HSROC) curve and the area under the curve (AUC) of 0.96 suggested a high accuracy. Ten studies were included in the second meta-analysis (CT versus TEE for LAA thrombosis). The pooled values of sensitivity and specificity were 97% (95% CI, 77–100%) and 94% (95% CI, 87–98%). The pooled diagnostic odds ratio (DOR) was 500 (95% CI, 52–4810), and the pooled likelihood ratios (LR + and LR−) were 17% (95% CI, 7–40%) and 3% (95% CI, 0–28%). The shape of the HSROC curve and 0.99 AUC suggested a high accuracy of CT vs. TEE. TTE is a fair alternative to DE-CMR for the identification of LV thrombi, while CT has a good accuracy compared to TEE for the detection of LAA thrombosis. CRD42020185842.

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Graphical abstract

In non-ischaemic dilated cardiomyopathy (NIDCM), it is uncertain which late gadolinium enhancement (LGE) pattern, extent and location predict ventricular arrhythmias.We analysed 183 NIDCM patients (73% men, median age 66 years) receiving an implantable cardioverter defibrillator (ICD) for primary prevention, undergoing cardiac magnetic resonance within 1 month before implantation. The primary endpoint was appropriate ICD shock, the secondary endpoint was a composite of appropriate ICD shock and cardiac death.LGE was found in 116 patients (63%), accounting for 9% of LV mass (5-13%). Over a 30-month follow-up (10-65), 20 patients (11%) experienced the primary and 30 patients (16%) the secondary endpoint. LGE presence, inferior wall LGE, diffuse (≥2 wall) LGE, the number of segments with LGE, the number of segments with 50-75% transmural LGE, and percent LGE mass were univariate predictors of both endpoints. Also septal LGE predicted the primary, and lateral LGE predicted the secondary endpoint. LGE limited to right ventricular insertion points did not predict any endpoint. Percent LGE mass had an area under the curve of 0.734 for the primary endpoint, with 13% as the best cut-off (55% sensitivity, 86% specificity, 32% PPV, 94% NPV), conferring a 7-fold higher risk compared to patients with no LGE or LGE13%. Survival free from both endpoints was significantly worse for patients with LGE ≥13%.In patients with NIDCM receiving a defibrillator for primary prevention, LGE presence and extent predicted appropriate ICD shock and cardiac mortality; also specific LGE patterns and locations predicted a worse prognosis.

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.

Background & Aims: In the direct-acting antiviral era, treatment of genotype-3 HCV (HCV-GT3) is still challenging. Real-life comparisons between recommended regimens, sofosbuvir (SOF)+daclatasvir (DAC), SOF/velpatasvir (VEL), glecaprevir/pibrentasvir (GLE/PIB), are scarce. We aimed at filling this data gap. Methods: Sustained virological response 12weeks after treatment completion (SVR12) was assessed for all HCV-GT3 patients consecutively treated within the Lombardia web-based Navigatore HCV-Network; differences in SVR12 across regimens were evaluated by logistic regression. Results: Of the 2082 subjects with HCV-GT3, 1544 were evaluable for comparisons between regimens: SOF+DAC (1023, 66.2%), SOF/VEL (369, 23.9%), GLE/PIB (152, 9.8%). Patients treated with former regimens were more frequently male, cirrhotic, HIV-positive, pretreated, used ribavirin in their regimen, and had lower baseline HCV-RNA. SVR12 was similar across groups: 94.8% in SOF+DAC, 97.6% in SOF/VEL, 96.7% in GLE/PIB (P=.065). At univariate analysis, SVR12 was associated with female gender (97.9% vs 94.8%, P=.007) and lower median pretreatment Log10HCV-RNA (5.87 vs 6.20, P=.001). At multivariate logistic regression analysis, treatment with SOF/VEL was associated with a higher likelihood of SVR12 than SOF+DAC, but only in the absence of ribavirin (98% vs 90.3%). Female gender and lower pretreatment HCV-RNA were independently associated with SVR12. Conclusions: In a large real-life setting of HCV-GT3-infected patients with a high proportion of cirrhosis, the success rate was remarkable. The slight advantage of SOF/VEL on SOF+DAC was significant only without ribavirin. The current prescription shift towards novel regimens (ie SOF/VEL and GLE/PIB) in easier-to-treat patients allows ribavirin-free and shorter schedules without mining SVR12 in this <> genotype.

The significant morbidity and mortality associated with heart failure with reduced (HFrEF) or preserved ejection fraction (HFpEF) justify the search for novel therapeutic agents. The nitric oxide (NO)–soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) pathway plays an important role in the regulation of cardiovascular function. This pathway is disrupted in HF resulting in decreased protection against myocardial injury. The sGC activator cinaciguat increases cGMP levels by direct, NO-independent activation of sGC, and may be particularly effective in conditions of increased oxidative stress and endothelial dysfunction, and then reduced NO levels, but this comes at the expense of a greater risk of hypotension. Conversely, sGC stimulators (riociguat and vericiguat) enhance sGC sensitivity to endogenous NO, and then exert a more physiological action. The phase 3 VICTORIA trial found that vericiguat is safe and effective in patients with HFrEF and recent HF decompensation. Therefore, adding vericiguat may be considered in individual patients with HFrEF, particularly those at higher risk of HF hospitalization; the efficacy of the sacubitril/valsartan-vericiguat combination in HFrEF is currently unknown.

The urinary bladder is markedly enlarged in the type 1 diabetes mellitus model of streptozotocin (STZ)-injected rats, but much less data exist for models of type 2 diabetes (T2DM). Diabetic polyuria has been proposed to explain bladder enlargement. We have collected data on bladder weight and blood glucose from 16 studies representing 9 distinct rodent diabetes (7 T2DM) and obesity models; some included arms with diets and/or pharmacological treatments. Data were analyzed for bladder enlargement and for correlations between bladder weight on the one and glucose levels on the other hand. Our data confirm major bladder enlargements in STZ rats, minor if any enlargement in fructose-fed rats, db/db mice and mice on a high-fat diet. For the first time we report bladder weight data on 5 other models with presence and degree of bladder enlargement being heterogeneous across models. Bladder weight was correlated with plasma glucose in some but not other models, but correlations were moderate to weak except for RIP-LMCV mice. We conclude that the presence and extent of bladder enlargement varies markedly across diabetes models, particularly TD2M models; our data do not support the idea that bladder enlargement is primarily driven by glucose levels/glucosuria.

Background The relative contribution of amyloid and fibrosis to extracellular volume expansion in cardiac amyloidosis (CA) has never been defined. Methods and Results We included all patients diagnosed with amyloid light‐chain (AL) or transthyretin cardiac amyloidosis at a tertiary referral center between 2014 to 2020 and undergoing a left ventricular endomyocardial biopsy. Patients (n=37) were more often men (92%), with a median age of 72 years (interquartile range, 68–81). Lambda‐positive AL was found in 14 of 19 AL cases (38%) and kappa‐positive AL in 5 of 19 (14%), while transthyretin was detected in the other 18 cases (48%). Amyloid deposits accounted for 15% of tissue sample area (10%–30%), without significant differences between AL and transthyretin amyloidosis. All patients displayed myocardial fibrosis, with a median extent of 15% of tissue samples (10%–23%; range, 5%–60%), in the absence of spatial overlap with amyloid deposits. Interstitial fibrosis was often associated with mild and focal subendocardial fibrosis. The extent of fibrosis or the combination of amyloidosis and fibrosis did not differ significantly between transthyretin amyloidosis and AL subgroups. In 20 patients with myocardial T1 mapping at cardiac magnetic resonance, the combined amyloid and fibrosis extent displayed a modest correlation with extracellular volume ( r =0.661, P =0.001). The combined amyloid and fibrosis extent correlated with high‐sensitivity troponin T ( P =0.035) and N‐terminal pro‐B‐type natriuretic peptide ( P =0.002) serum levels. Conclusions Extracellular spaces in cardiac amyloidosis are enlarged to a similar extent by amyloid deposits and fibrotic tissue. Their combination can better explain the increased extracellular volume at cardiac magnetic resonance and circulating biomarkers than amyloid extent alone.

Background Soluble suppression of tumorigenesis-2 (sST2) is released in response to inflammation and vascular injury, and holds prognostic value in heart failure (HF). Type 2 diabetes (T2D) is characterized by a pro-inflammatory status and is highly prevalent among HF patients, with adverse impact on outcomes. The clinical value of sST2 in HF patients with T2D has never been characterized. Purpose We aimed to assess sST2 clinical correlates and prognostic value in HF patients with T2D. Methods Individual data of 3476 patients with stable chronic HF from 5 cohorts from the BIOS (Biomarkers In Heart Failure Outpatient Study) dataset were analysed, with available N-terminal fraction of pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity troponin T (hs-TnT), and sST2 levels. Results Mean age was 65±12 years (75% males). T2D was present in 1386 patients (40%), who had higher body mass index (BMI, 27 [24–30] vs. 26 [23–29] kg/m2, p Conclusions sST2 is higher in HF patients with T2D and likely linked to a pro-inflammatory status. sST2 maintains its prognostic value both in diabetic and non-diabetic HF patients, independently of NT-proBNP, hs-TnT and hs-CRP. Funding Acknowledgement Type of funding sources: None. Figure 1

Background Patients with acute heart failure (AHF) show high levels of fibroblast growth factor-23 (FGF23) on admission. We examined if plasma FGF23 changes during an episode of AHF, and if FGF23 holds prognostic significance in this setting. Methods Consecutive AHF patients were enrolled. Blood samples were collected on admission and at discharge. Patients were then followed for all-cause death or HF hospitalization. Results Patients (n=125; median age 76 years [interquartile interval 71–83], 63% men, left ventricular ejection fraction 35% [25–56%]) had median admission FGF23 70 ng/L (47–100), N-terminal pro-B-type natriuretic peptide (NT-proBNP) 5,844 ng/L (2,503–10,468), high-sensitivity troponin T (hs-TnT) 40 ng/L (25–72), and soluble suppression of tumorigenesis-2 (sST2) 26 ng/mL (17–37). While other biomarkers decreased, FGF23 increased by 15% from admission to discharge (p=0.033), with a significant correlation with percent changes in estimated glomerular filtration rate (rho=0.306, p=0.001). Over a 12-month follow-up, 64 patients (51%) experienced the endpoint. They were more often men, older, with higher systolic pulmonary artery pressure (sPAP), higher NT-proBNP, hs-TnT and discharge FGF23. The best FGF23 cut-off at discharge from receiver operating characteristics analysis was 78 ng/L. Both discharge FGF23 and the 78 ng/L cut-off independently predicted outcome in models including gender, sPAP, age, and 1) admission NT-proBNP, 2) discharge NT-proBNP, 3) admission NT-proBNP and hs-TnT, 4) discharge NT-proBNP and hs-TnT. The 78 ng/L cut-off also refined risk reclassification. Conclusions During an AHF episode, FGF23 increases from admission to discharge, and patients with higher discharge FGF23 have a higher risk of worse outcome. Funding Acknowledgement Type of funding sources: None.

Background The relative contribution of amyloid and fibrosis to extracellular volume expansion in cardiac amyloidosis (CA) has never been defined. Methods We included all patients diagnosed with amyloid light-chain or transthyretin (AL/ATTR) CA at a tertiary referral center between 2014 to 2020 and undergoing a left ventricular (LV) endomyocardial biopsy (EMB). Results Patients (n=37) were more often male (92%), with a median age of 72 years (68–81). Lambda+ AL was found in 14/19 AL cases (38%) and kappa+ AL in 5/19 (14%), while TTR was detected in the other 18 cases (48%). Amyloid deposits accounted for 15% of tissue sample area (10–30%), without significant differences between AL and ATTR. All patients displayed myocardial fibrosis, with a median extent of 15% of tissue samples (10–23%, range 5–60%), in the absence of spatial overlap with amyloid deposits. Interstitial fibrosis was often associated with mild and focal subendocardial fibrosis. The extent of fibrosis or the combination of amyloidosis and fibrosis did not differ significantly between ATTR and AL subgroups. In 20 patients with myocardial T1 mapping at cardiac magnetic resonance (CMR), the combined amyloid and fibrosis extent displayed a modest correlation with extracellular volume (ECV; r=0.661, p=0.001). The combined amyloid and fibrosis extent correlated with high-sensitivity troponin T (p=0.035) and N-terminal pro-B-type natriuretic peptide (p=0.002) serum levels. Conclusions Extracellular spaces in CA are enlarged to a similar extent by amyloid deposits and fibrotic tissue. Their combination can better explain the increased ECV at CMR and circulating biomarkers than amyloid extent alone. Funding Acknowledgement Type of funding sources: None.

The assessment of both thromboembolic and haemorrhagic risks and their management in systemic amyloidosis have been poorly emphasized so far. This narrative review summarizes main evidence from literature with clinical perspective. The rate of thromboembolic events is as high as 5–10% amyloidosis patients, at least in patients with cardiac involvement, with deleterious impact on prognosis. The most known pro‐thrombotic factors are heart failure, atrial fibrillation, and atrial myopathy. Atrial fibrillation could occur in 20% to 75% of systemic amyloidosis patients. Cardiac thrombi are frequently observed in patients, particularly in immunoglobulin light chains (AL) amyloidosis, up to 30%, and it is advised to look for them systematically before cardioversion. In AL amyloidosis, nephrotic syndrome and the use of immunomodulatory drugs also favour thrombosis. On the other hand, the bleeding risk increases because of frequent amyloid digestive involvement as well as factor X deficiency, renal failure, and increased risk of dysautonomia‐related fall.

Background Infective endocarditis (IE) is characterized by high rates of in-hospital death, and Staphylococcus aureus infection predicts a worse prognosis. We aimed to assess if admission inflammatory biomarkers (white blood cell – WBC – count, C-reactive protein — CRP, and procalcitonin) are informative on microbiological etiology and short-term outcomes. Methods Data from 236 patients admitted for IE from January 2013 to June 2018 were retrieved from a multicenter registry. Results Fifty-two patients (22%) were infected by S. aureus. WBC, CRP and procalcitonin had area under the curve (AUC) values for S. aureus infection of 0.595, 0.675, and 0.727, respectively. Adding procalcitonin to WBC improved discrimination over WBC alone (p = 0.045), and procalcitonin predicted S. aureus infection independently from the other inflammatory biomarkers and patient characteristics. Patients with WBC ≥ 12,800/mm3, CRP ≥ 130 mg/L, and procalcitonin ≥ 1.7 ng/mL had an almost 20-fold higher risk of S. aureus infection than patients with all biomarkers Conclusions Among patients with IE, high levels of inflammatory biomarkers on admission, particularly procalcitonin, are associated with a higher likelihood of S. aureus infection, and a higher risk of in-hospital mortality.

Evidence of sympathetic and renin-angiotensin-aldosterone system activation provided a rationale for neurohormonal antagonism in heart failure with reduced ejection fraction (HFrEF), while no data are available in patients with milder degree of systolic dysfunction. We aimed to investigate neurohormonal function in HF with preserved and mid-range EF (HFpEF/HFmrEF).Three cohorts (n = 189/each) of stable HFpEF, HFmrEF and HFrEF patients were selected (median age 70, 67 and 67 years; male 56%, 73% and 74%, respectively). Patients received a baseline clinical assessment including plasma renin activity (PRA), aldosterone, catecholamines, and N-terminal fraction of pro-B-type natriuretic peptide (NT-proBNP) assays, and were followed-up for all-cause death.Neuroendocrine profile was similar between HFpEF and HFmrEF, while all neurohormones except epinephrine were higher in HFrEF than in HFmrEF (NT-proBNP 2332 ng/L, IQR 995-5666 vs 575 ng/L, 205-1714; PRA 1.7 ng/mL/h, 0.4-5.6 vs 0.6 ng/mL/h, 0.2-2.6; aldosterone 153 ng/L, 85-246 vs 113 ng/L, 72-177; norepinephrine 517 ng/L, 343-844 vs 430 ng/L, 259-624; all p 0.001, epinephrine 31 ng/L, 10-63 vs 25 ng/L, 10-44; p = 0.319). These findings were unrelated to treatment heterogeneity. Ten percent of HFpEF patients had elevated PRA, aldosterone and norepinephrine vs. 8% in HFmrEF and 21% in HFrEF. During a 5-year follow-up, survival decreased with the number of neurohormones elevated (HFpEF: log-rank 7.8, p = 0.048; HFmrEF: log-rank 11.8, p = 0.008; HFrEF: log-rank 8.1, p = 0.044).Neurohormonal activation is present only in a subset of patients with HFpEF and HFmrEF, and may hold clinical significance. Neurohormonal antagonism may be useful in selected HFpEF/HFmrEF population.

Negative T waves in the inferior leads in an asymptomatic 17-year-old female patient prompted a diagnostic evaluation disclosing the presence of multiple cardiac glomangiomas. The combination of different imaging modalities (echocardiography, magnetic resonance, and positron emission tomography/computed tomography) and myocardial biopsy was crucial to establishing the correct diagnosis. (Level of Difficulty: Advanced.), Graphical abstract, Negative T waves in the inferior leads in an asymptomatic 17-year-old female patient prompted a diagnostic evaluation disclosing the presence of…

OBJECTIVE Diabetes is a major risk factor for renal function decline and failure. The availability of multiplex panels of biochemical markers provides the opportunity to identify novel biomarkers that can better predict changes in renal function than routinely available clinical markers. RESEARCH DESIGN AND METHODS The concentration of 239 biochemical markers was measured in stored serum from participants in the biomarker substudy of Outcome Reduction With Initial Glargine Intervention (ORIGIN) trial. Repeated-measures mixed-effects models were used to compute the annual change in eGFR (measured as mL/min/1.73 m2/year) for the 7,482 participants with a recorded baseline and follow-up eGFR. Linear regression models using forward selection were used to identify the independent biomarker determinants of the annual change in eGFR after accounting for baseline HbA1c, baseline eGFR, and routinely measured clinical risk factors. The incidence of the composite renal outcome (i.e., renal replacement therapy, renal death, renal failure, albuminuria progression, doubling of serum creatinine) and death within each fourth of change in eGFR predicted from these models was also estimated. RESULTS During 6.2 years of median follow-up, the median annual change in eGFR was −0.18 mL/min/1.73 m2/year. Fifteen biomarkers independently predicted eGFR decline after accounting for cardiovascular risk factors, as did 12 of these plus 1 additional biomarker after accounting for renal risk factors. Every 0.1 mL/min/1.73 m2 predicted annual fall in eGFR predicted a 13% (95% CI 12, 14%) higher mortality. CONCLUSIONS Adding up to 16 biomarkers to routinely measured clinical risk factors improves the prediction of annual change in eGFR in people with dysglycemia.

High-sensitivity troponin T (hs-TnT) reflects the severity of ongoing myocardial damage. In acute heart failure (AHF), its additive prognostic value over B-type natriuretic peptides is unclear.Individual data of 1499 AHF patients with admission hs-TnT were collected from 3 cohorts.Patients (78 ± 10 years, 51% men, N-terminal fragment of pro-B-type natriuretic peptide - NT-proBNP - 5660 [2693-12,466], hs-TnT 43 ng/L [26-69]) experiencing in-hospital death (n = 187, 13%) had significantly higher hs-TnT and NT-proBNP on admission (both p 0.001). Patients with hs-TnT ≥43 ng/L and NT-proBNP ≥5660 ng/L had a 2.7-fold higher risk of in-hospital death (relative risk - RR 2.7, 95% confidence interval - CI 1.7-4.5). Among discharged patients, 1024 deaths (81%) occurred over 11 months (4-22). In the whole population, hs-TnT ≥43 ng/L predicted all-cause death at 6, 12 and 24 months independently from NT-proBNP ≥5660 ng/L. The best NT-proBNP cut-off for in-hospital mortality (4382 ng/L) independently predicted this endpoint, while the best hs-TnT cut-off (55 ng/L) did not. Patients with NT-proBNP ≥4382 ng/L and hs-TnT ≥55 ng/L had a 12-fold higher risk of in-hospital death (RR 11.7, 95% CI 6.9-19.7). The best hs-TnT cut-offs independently predicted all post-discharge outcomes.The best NT-proBNP cut-off (4382 ng/L) independently predicts outcome, while the best hs-TnT (55 ng/L) does not; patients with both biomarkers ≥best cut-offs have a 12-fold higher risk of in-hospital mortality. Admission hs-TnT ≥43 ng/L and the best hs-TnT cut-offs hold independent prognostic significance for post-discharge outcome, while hs-TnT seems less predictive than NT-proBNP when considering absolute values.

Soluble suppression of tumorigenesis-2 (sST2) is released in response to vascular congestion and inflammatory and pro-fibrotic stimuli, and is a strong, independent predictor of mortality and heart failure (HF) hospitalization in patients with acute or chronic HF. sST2 meets 2 fundamental criteria for clinically useful biomarkers: accurate, repeated measurements are available at a reasonable cost, and the biomarker provides information not already available from a careful clinical assessment. In particular, the prognostic value of sST2 is additive to natriuretic peptides and (in the case of chronic HF) to high-sensitivity troponin T. Nevertheless, the need for a multibiomarker approach to risk stratification and the role of sST2 as a guide to therapy decision-making remain to be established. Four years after a consensus document on sST2, and following major advances in the comprehension of the clinical value of this biomarker, the authors felt it worthwhile to reappraise current knowledge on sST2 in HF.

Both oxidative stress and inflammation are enhanced in chronic heart failure. Dysfunction of cardiac mitochondria is a hallmark of heart failure and a leading cause of oxidative stress, which in turn exerts detrimental effects on cellular components, including mitochondria themselves, thus generating a vicious circle. Oxidative stress also causes myocardial tissue damage and inflammation, contributing to heart failure progression. Furthermore, a subclinical inflammatory state may be caused by heart failure comorbidities such as obesity, diabetes mellitus or sleep apnoeas. Some markers of both oxidative stress and inflammation are enhanced in chronic heart failure and hold prognostic significance. For all these reasons, antioxidants or anti-inflammatory drugs may represent interesting additional therapies for subjects either at high risk or with established heart failure. Nonetheless, only a few clinical trials on antioxidants have been carried out so far, with several disappointing results except for vitamin C, elamipretide and coenzyme Q10. With regard to anti-inflammatory drugs, only preliminary data on the interleukin-1 antagonist anakinra are currently available. Therefore, a comprehensive, deep understanding of our current knowledge on oxidative stress and inflammation in chronic heart failure is key to providing some suggestions for future research on this topic.

Transthyretin (TTR) is a tetrameric protein synthesized mostly by the liver. As a result of gene mutations or as an ageing-related phenomenon, TTR molecules may misfold and deposit in the heart and in other organs as amyloid fibrils. Cardiac involvement in TTR-related amyloidosis (ATTR) manifests typically as left ventricular pseudohypertrophy and/or heart failure with preserved ejection fraction. ATTR is an underdiagnosed disorder as well as a crucial determinant of morbidity and mortality, thus justifying the current quest for a safe and effective treatment. Therapies targeting cardiac damage and its direct consequences may yield limited benefit, mostly related to dyspnoea relief through diuretics. For many years, liver or combined heart and liver transplantation have been the only available treatments for patients with mutations causing ATTR, including those with cardiac involvement. The therapeutic options now include several pharmacological agents that inhibit hepatic synthesis of TTR, stabilize the tetramer, or disrupt fibrils. Following the positive results of a phase 3 trial on tafamidis, and preliminary findings on patisiran and inotersen in patients with ATTR-related neuropathy and cardiac involvement, we provide an update on this rapidly evolving field, together with practical recommendations on the management of cardiac involvement.

OBJECTIVE Elevated glycolytic enzymes in renal glomeruli correlated with preservation of renal function in the Medalist Study, individuals with ≥50 years of type 1 diabetes. Specifically, pyruvate kinase M2 (PKM2) activation protected insulin-deficient diabetic mice from hyperglycemia-induced glomerular pathology. This study aims to extend these findings in a separate cohort of individuals with type 1 and type 2 diabetes and discover new circulatory biomarkers for renal protection through proteomics and metabolomics of Medalists’ plasma. We hypothesize that increased glycolytic flux and improved mitochondrial biogenesis will halt the progression of diabetic nephropathy. RESEARCH DESIGN AND METHODS Immunoblots analyzed selected glycolytic and mitochondrial enzymes in postmortem glomeruli of non-Medalists with type 1 diabetes (n = 15), type 2 diabetes (n = 19), and no diabetes (n = 5). Plasma proteomic (SOMAscan) (n = 180) and metabolomic screens (n = 214) of Medalists with and without stage 3b chronic kidney disease (CKD) were conducted and significant markers validated by ELISA. RESULTS Glycolytic (PKM1, PKM2, and ENO1) and mitochondrial (MTCO2) enzymes were significantly elevated in glomeruli of CKD− versus CKD+ individuals with type 2 diabetes. Medalists’ plasma PKM2 correlated with estimated glomerular filtration rate (r2 = 0.077; P = 0.0002). Several glucose and mitochondrial enzymes in circulation were upregulated with corresponding downregulation of toxic metabolites in CKD-protected Medalists. Amyloid precursor protein was also significantly upregulated, tumor necrosis factor receptors downregulated, and both confirmed by ELISA. CONCLUSIONS Elevation of enzymes involved in the metabolism of intracellular free glucose and its metabolites in renal glomeruli is connected to preserving kidney function in both type 1 and type 2 diabetes. The renal profile of elevated glycolytic enzymes and reduced toxic glucose metabolites is reflected in the circulation, supporting their use as biomarkers for endogenous renal protective factors in people with diabetes.

Objective To assess key aspects of transportation and storage of biological therapies (BTs) on the part of the patients, from the time they collect them from the pharmacy up until the moment of administration. Methods This was a cross-sectional study in the form of a survey completed by outpatients older than 18 years who were administered BTs. The survey was carried out by the authors between August 2016 and January 2017. Results A total of 83 outpatients were interviewed (mean age, 53; standard deviation, 15; 76% female). Sixty percent had rheumatoid arthritis, 24% had psoriatic arthritis, and 16% sustained other rheumatic and inflammatory diseases. Twenty percent had not been informed of the importance of proper refrigeration when they were first prescribed BTs; 77% had acquired the medication at least 7 days before administration; 28% had misplaced the drug in the fridge (65% of them in the freezer); 90% was unaware of the temperature range at which the BT should be kept in the fridge, and only one (1%) of them had once used a thermometer to find out the fridge temperature. Fifty-three percent had suffered frequent power outages the previous summer, 22% had experienced blackouts longer than 48 hours; 37% had taken the BT to another house to avoid wasting it, and four (5%) patients had disposed of the drug due to a prolonged power outage. Conclusion Upon prescribing BTs, it is imperative that physicians brief patients on the relevance of suitable transportation and storage methods, and a treatment failure should prompt a thorough assessment of transportation and storage conditions.

Purpose of Review The nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) pathway plays an important role in the regulation of cardiovascular function, and it is disrupted in heart failure (HF), resulting in decreased protection against myocardial injury. Impaired NO-sGC-cGMP signaling in HF is secondary to reduced NO bioavailability and altered redox state of sGC, which becomes less responsive to NO. The sGC activator cinaciguat increases cGMP levels by direct NO-independent activation of sGC and may be particularly effective in conditions of increased oxidative stress and endothelial dysfunction, and therefore reduced NO levels, at the expense of a greater risk of hypotension. Conversely, sGC stimulators (riociguat and vericiguat) enhance sGC sensitivity to endogenous NO, thus exerting a more physiological action. Recent Findings Clinical trials have suggested the benefit of vericiguat in patients with high-risk HF; in particular, a lower incidence of death from cardiovascular causes or HF hospitalization. Summary Adding vericiguat may be considered in individual patients with HF, and reduced left ventricular ejection fraction (HFrEF) particularly those at higher risk of HF hospitalization.

Despite the progressive improvements in diagnosis and therapy during the first 20 years of this century, the morbidity and mortality of patients with heart failure (HF) remain high, resulting in an enormous health and economic burden. Only a further improvement in understanding the pathophysiological mechanisms related to the development of cardiac injury and dysfunction can allow more innovative and personalized approaches to HF management. The renin-angiotensin system (RAS) has a critical role in cardiovascular physiology by regulating blood pressure and electrolyte balance. The RAS is mainly regulated by both angiotensin converting enzyme (ACE) and type 2 angiotensin converting enzyme (ACE2). However, the balance between the various peptides and peptidases constituting the RAS/ACE pathway remains in great part unraveled in patients with HF. This review summarizes the role of the RAS/ACE axis in cardiac physiology and HF pathophysiology as well as some analytical issues relevant to the clinical and laboratory assessment of inter-relationships between these two systems. There is evidence that RAS peptides represent a dynamic network of peptides, which are altered in different HF states and influenced by medical therapy. However, the mechanisms of signal transduction have not been fully elucidated under physiological and pathophysiological conditions. Further investigations are necessary to explore novel molecular mechanisms related to the RAS, which will provide alternative therapeutic agents. Moreover, monitoring the circulating levels of active RAS peptides in HF patients may enable a personalized approach by facilitating assessment of the pathophysiological status of several cardiovascular diseases and thus better selection of therapies for HF patients.

After initial strategies targeting inotropism and congestion, the neurohormonal interpretative model of heart failure (HF) pathophysiology has set the basis for current pharmacological management of HF, as most of guideline recommended drug classes, including beta-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and mineralocorticoid receptor antagonists, blunt the activation of detrimental neurohormonal axes, namely sympathetic and renin–angiotensin–aldosterone (RAAS) systems. More recently, sacubitril/valsartan, a first-in-class angiotensin receptor neprilysin inhibitor, combining inhibition of RAAS and potentiation of the counter-regulatory natriuretic peptide system, has been consistently demonstrated to reduce mortality and HF-related hospitalization. A number of novel pharmacological approaches have been tested during the latest years, leading to mixed results. Among them, drugs acting directly at a second messenger level, such as the soluble guanylate cyclase stimulator vericiguat, or other addressing myocardial energetics and mitochondrial function, such as elamipretide or omecamtiv-mecarbil, will likely change the therapeutic management of patients with HF. Sodium glucose cotransporter 2 inhibitors, initially designed for the management of type 2 diabetes mellitus, have been recently demonstrated to improve outcome in HF, although mechanisms of their action on cardiovascular system are yet to be elucidated. Most of these emerging approaches have shifted the therapeutic target from neurohormonal systems to the heart, by improving cardiac contractility, metabolism, fibrosis, inflammation, and remodeling. In the present paper, we review from a pathophysiological perspective current and novel therapeutic strategies in chronic HF.