Biomarkers for the diagnosis and management of heart failure

Heart failure (HF) is a significant cause of morbidity and mortality worldwide. Circulating biomarkers reflecting pathophysiological pathways involved in HF development and progression may assist clinicians in early diagnosis and management of HF patients. Natriuretic peptides (NPs) are cardioprotective hormones released by cardiomyocytes in response to pressure or volume overload. The roles of B-type NP (BNP) and N-terminal pro-B-type NP (NT-proBNP) for diagnosis and risk stratification in HF have been extensively demonstrated, and these biomarkers are emerging tools for population screening and as guides to the start of treatment in subclinical HF. On the contrary, conflicting evidence exists on the role of NPs as a guide to HF therapy. Among the other biomarkers, high-sensitivity troponins and soluble suppression of tumorigenesis-2 are the most promising biomarkers for risk stratification, with independent value to NPs. Other biomarkers evaluated as predictors of adverse outcome are galectin-3, growth differentiation factor 15, mid-regional pro-adrenomedullin, and makers of renal dysfunction. Multi-marker scores and genomic, transcriptomic, proteomic, and metabolomic analyses could further refine HF management

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 >500 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

The place of vericiguat in the landscape of treatment for heart failure with reduced ejection fraction

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

Biopsy Evidence of Sequential Transthyretin and Immunoglobulin Light-Chain Cardiac Amyloidosis in the Same Patient

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.

CaCO3 as an environmentally friendly renewable material for drug delivery systems: Uptake of HSA-CaCO3 nanocrystals conjugates in cancer cell lines

Chemical and biochemical functionalization of nanoparticles (NPs) can lead to an active cellular uptake enhancing their efficacy thanks to the targeted localization in tumors. In the present study calcium carbonate nano-crystals (CCNs), stabilized by an alcohol dehydration method, were successfully modified by grafting human serum albumin (HSA) on the surface to obtain a pure protein corona. Two types of CCNs were used: naked CaCO3 and the (3-aminopropyl)triethoxysilane (APTES) modified CaCO3-NH2. The HSA conjugation with naked CCN and amino-functionalized CCN (CCN-NH2) was established through the investigation of modification in size, zeta potential, and morphology by Transmission Electron Microscopy (TEM). The amount of HSA coating on the CCNs surface was assessed by spectrophotometry. Thermogravimetric analysis (TGA) and Differential scanning calorimetry (DSC) confirmed the grafting of APTES to the surface and successive adsorption of HSA. Furthermore, to evaluate the effect of protein complexation of CCNs on cellular behavior, bioavailability, and biological responses, three human model cancer cell lines, breast cancer (MCF7), cervical cancer (HeLa), and colon carcinoma (Caco-2) were selected to characterize the internalization kinetics, localization, and bio-interaction of the protein-enclosed CCNs. To monitor internalization of the various conjugates, chemical modification with fluorescein-isothiocyanate (FITC) was performed, and their stability over time was measured. Confocal microscopy was used to probe the uptake and confirm localization in the perinuclear region of the cancer cells. Flow cytometry assays confirmed that the bio-functionalization influence cellular uptake and the CCNs behavior depends on both cell line and surface features

Contribution of the lung to the genesis of cheyne-stokes respiration in heart failure: Plant gain beyond chemoreflex gain and circulation time

Background-The contribution of the lung or the plant gain (PG; ie, change in blood gases per unit change in ventilation) to Cheyne-Stokes respiration (CSR) in heart failure has only been hypothesized by mathematical models, but never been directly evaluated.Methods and Results-Twenty patients with systolic heart failure (age, 72.4 +/- 6.4 years; left ventricular ejection fraction, 31.5 +/- 5.8%), 10 with relevant CSR (24-hour apnea-hypopnea index [AHI] >= 10 events/h) and 10 without (AHI <10 events/h) at 24-hour cardiorespiratory monitoring underwent evaluation of chemoreflex gain (CG) to hypoxia (CG(O2)) and hypercapnia (CG(CO2)) by rebreathing technique, lung-to-finger circulation time, and PG assessment through a visual system. PG test was feasible and reproducible (intraclass correlation coefficient, 0.98; 95% CI, 0.91-0.99); the best-fitting curve to express the PG was a hyperbola (R-2 >= 0.98). Patients with CSR showed increased PG, CG(CO2) (but not CG(O2)), and lung-to-finger circulation time, compared with patients without CSR (all P<0.05). PG was the only predictor of the daytime AHI (R=0.56, P=0.01) and together with the CG(CO2) also predicted the nighttime AHI (R=0.81, P=0.0003) and the 24-hour AHI (R=0.71, P=0.001). Lung-to-finger circulation time was the only predictor of CSR cycle length (R=0.82, P=0.00006).Conclusions-PG is a powerful contributor of CSR and should be evaluated together with the CG and circulation time to individualize treatments aimed at stabilizing breathing in heart failure

Discharge FGF23 level predicts one year outcome in patients admitted with acute heart failure

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) 5844 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

Thromboembolism and bleeding in systemic amyloidosis: a review

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