Different methods of bone marrow harvesting influence cell characteristics and purity, affecting clinical outcomes.

Background: Bone marrow (BM)-derived stem cells were implanted to induce angiogenesis in patients with no-option critical limb-threatening ischemia. Considering the potential for this therapy, conflicting results related to BM harvesting methods have been reported that could affect stem cell concentrations and quality. Methods: A total of 75 patients with no-option critical limb-threatening ischemia were treated with BM implantation. For 58 patients, BM was harvested using a BM aspirate concentrate system (Harvest Technologies; group HT) with a standard aspiration needle, followed by an automated centrifugation process, to produce BM aspirate concentrate. For 17 patients, BM was harvested using the Marrow Cellution system (Aspire Medical Innovation; group MC). CD34+ cells/mL, CD117+ cells/mL, CD133+ cells/mL, CD309+ cells/mL, hematocrit, and BM purity were compared between the two BM preparations. Results: The retrospective analysis of a subset group after adjustment for age shows that the quality of BM obtained using the Marrow Cellution system is better, in terms of purity, than the classic harvesting method before centrifugation. Harvested BM before centrifugation is characterized by a higher percentage of CD133+ cells compared with BM after centrifugation. In contrast, the MC aspirate had a larger amount of very small embryonic-like cells, as indicated by the higher percentage of CD133+, CD34+, and CD45- cells. These differences translated into an increased occurrence of leg amputations in group HT than in group MC and an increase in transcutaneous oxygen pressure in patients treated with BM aspirated using MC. Conclusions: BM manipulation, such as centrifugation, affects the quality and number of stem cells, with detrimental consequences on clinical outcomes, as reflected by the different amputation rates between the two groups.

Renal effects of SGLT2 inhibitors in cardiovascular patients with and without chronic kidney disease: focus on heart failure and renal outcomes.

The kidney has a prominent role in maintaining glucose homeostasis by using glucose as a metabolic substrate. This occurs by generating glucose through gluconeogenesis, and by reuptaking filtered glucose through the sodium-glucose cotransporters SGLT1 and SGLT2 located in the proximal tubule. In recent studies, the administration of sodium-glucose cotransporters inhibitors demonstrated that inhibition of renal glucose reabsorption significantly reduces adverse renal events and heart failure exacerbations, in type 2 diabetic patients with and without cardiovascular damage as well as in advanced chronic kidney disease and heart failure patients with reduced ejection fraction with and without diabetes. The benefit was consistent throughout the different investigated clinical conditions, ameliorating overall patient outcome. The efficacy of sodium glucose cotransporters inhibitors was prominently linked to the limitation of renal damage as highlighted by the significant reduction on global mortality achieved in the studies investigating diabetic and not diabetic populations with advanced chronic kidney disease. Both studies were halted at the interim analysis because of unquestionable evidence of treatment benefit. In current review, we examine the role of SGLT2 and SGLT1 in the regulation of renal glucose reabsorption in health and disease and the effect of SGLT2 inhibition on clinical outcomes of populations with different cardiovascular conditions investigated with large-scale outcome trials.

N-Acetylcysteine Antagonizes NGF Activation of TrkA through Disulfide Bridge Interaction, an Effect Which May Contribute to Its Analgesic Activity.

N-acetylcysteine (NAC), a mucolytic agent and an antidote to acetaminophen intoxication, has been studied in experimental conditions and trials exploring its analgesic activity based on its antioxidant and anti-inflammatory properties. The purpose of this study is to investigate additional mechanisms, namely, the inhibition of nerve growth factor (NGF) and the activation of the Tropomyosin receptor kinase A (TrkA) receptor, which is responsible for nociception. In silico studies were conducted to evaluate dithiothreitol and NAC's interaction with TrkA. We also measured the autophosphorylation of TrkA in SH-SY5Y cells via ELISA to assess NAC's in vitro activity against NGF-induced TrkA activation. The in silico and in vitro tests show that NAC interferes with NGF-induced TrkA activation. In particular, NAC breaks the disulfide-bound Cys 300-345 of TrkA, perturbing the NGF-TrkA interaction and producing a rearrangement of the binding site, inducing a consequent loss of their molecular recognition and spatial reorganization, which are necessary for the induction of the autophosphorylation process. The latter was inhibited by 40% using 20 mM NAC. These findings suggest that NAC could have a role as a TrkA antagonist, an action that may contribute to the activity and use of NAC in various pain states (acute, chronic, nociplastic) sustained by NGF hyperactivity and/or accompanied by spinal cord sensitization.

The Benefit of Sodium-Glucose Co-Transporter Inhibition in Heart Failure: The Role of the Kidney.

In the essential homeostatic role of kidney, two intrarenal mechanisms are prominent: the glomerulotubular balance driving the process of Na+ and water reabsorption in the proximal tubule, and the tubuloglomerular feedback which senses the Na+ concentration in the filtrate by the juxtaglomerular apparatus to provide negative feedback on the glomerular filtration rate. In essence, the two mechanisms regulate renal oxygen consumption. The renal hyperfiltration driven by increased glomerular filtration pressure and by glucose diuresis can affect renal O2 consumption that unleashes detrimental sympathetic activation. The sodium-glucose co-transporters inhibitors (SGLTi) can rebalance the reabsorption of Na+ coupled with glucose and can restore renal O2 demand, diminishing neuroendocrine activation. Large randomized controlled studies performed in diabetic subjects, in heart failure, and in populations with chronic kidney disease with and without diabetes, concordantly address effective action on heart failure exacerbations and renal adverse outcomes.

Prevalence of asymptomatic atrial fibrillation among multimorbid elderly patients: diagnostic implications.

Advancing age of the global population is one of the main reasons for the uprising trend in atrial fibrillation (AF) prevalence worldwide leading to a proper "AF epidemic". Strictly related to the increasing prevalence of AF in the elderly is the relevant burden of cardiac end extra-cardiac comorbidities that these patients show. Patients with AF are frequently asymptomatic (i.e., asymptomatic or silent AF) and thus the arrhythmia is generally underdiagnosed. Detainment of proper treatment in elderly and comorbid patients may potentially result in significant morbidity and mortality. Therefore, in recent years, several screening strategies (systematic vs opportunistic screening) for asymptomatic AF have been developed and early diagnosis of AF is an important treatment goal that can improve prognosis. This review will focus on the prevalence of asymptomatic AF in the elderly, frequently associated comorbidities, screening strategies, and implications for a correct AF diagnosis.

Use of dual-flow bioreactor to develop a simplified model of nervous-cardiovascular systems crosstalk: A preliminary assessment.

Chronic conditions requiring long-term rehabilitation therapies, such as hypertension, stroke, or cancer, involve complex interactions between various systems/organs of the body and mutual influences, thus implicating a multiorgan approach. The dual-flow IVTech LiveBox2 bioreactor is a recently developed inter-connected dynamic cell culture model able to mimic organ crosstalk, since cells belonging to different organs can be connected and grown under flow conditions in a more physiological environment. This study aims to setup for the first time a 2-way connected culture of human neuroblastoma cells, SH-SY5Y, and Human Coronary Artery Smooth Muscle Cells, HCASMC through a dual-flow IVTech LiveBox2 bioreactor, in order to represent a simplified model of nervous-cardiovascular systems crosstalk, possibly relevant for the above-mentioned diseases. The system was tested by treating the cells with 10nM angiotensin II (AngII) inducing PKCßII/HuR/VEGF pathway activation, since AngII and PKCßII/HuR/VEGF pathway are relevant in cardiovascular and neuroscience research. Three different conditions were applied: 1- HCASMC and SH-SY5Y separately seeded in petri dishes (static condition); 2- the two cell lines separately seeded under flow (dynamic condition); 3- the two lines, seeded in dynamic conditions, connected, each maintaining its own medium, with a membrane as interface for biohumoral changes between the two mediums, and then treated. We detected that only in condition 3 there was a synergic AngII-dependent VEGF production in SH-SY5Y cells coupled to an AngII-dependent PKCßII/HuR/VEGF pathway activation in HCASMC, consistent with the observed physiological response in vivo. HCASMC response to AngII seems therefore to be generated by/derived from the reciprocal cell crosstalk under the dynamic inter-connection ensured by the dual flow LiveBox 2 bioreactor. This system can represent a useful tool for studying the crosstalk between organs, helpful for instance in rehabilitation research or when investigating chronic diseases; further, it offers the advantageous opportunity of cultivating each cell line in its own medium, thus mimicking, at least in part, distinct tissue milieu.

The PARAGON-HF trial: the sacubitril/valsartan in heart failure with preserved ejection fraction.

Heart failure (HF) with preserved ejection fraction (HFpEF) is a clinical condition characterized by large pathophysiology heterogeneity with lack of effective therapies as proven by the disappointing results generated by randomized controlled trials. The innovative therapeutic concept provided by sacubitril-valsartan, a molecule combining angiotensin receptor blocking agent and neprilysin inhibitor has suggested the hypothesis it would have led to a reduced risk of hospitalization for HF or death from cardiovascular causes among patients with HF and preserved ejection fraction. The PARAGON-HF (ClinicalTrials.gov number, NCT01920711) investigated HF subjects class II to IV HF, ejection fraction of 45% or higher, elevated level of natriuretic peptides, and structural heart disease to receive sacubitril-valsartan (target dose, 97 mg of sacubitril with 103 mg of valsartan twice daily) or valsartan (target dose, 160 mg twice daily). The trial missed the primary outcome of cardiovascular death and HF hospitalization (HFH) in the overall study population. A subgroup analysis addressed significant decrease of HFH in subjects with left ventricular ejection fraction below the median 57% value in the study. The data were consistent with previous post hoc analysis performed in studies where candesartan and spironolactone were investigated in HFpEF. Those results open the door to investigate angiotensin aldosterone and peptidases inhibition efficacy in the unexplored HF middle range ejection fraction, currently lacking of valid evidence.

Risk of heart failure progression in patients with reduced ejection fraction: mechanisms and therapeutic options.

Transition from stage C to stage D of heart failure (HF) represents an irreversible process toward end-stage disease. Crucial interventions to be adopted in the attempt to interfere with this process are represented by the identification of patients at high risk to develop HF progression and by an effective and prompt management. Markers of worse prognosis and disease progression are well established and include recurrence of HF decompensation, intolerance to the neurohormonal standard pharmacological treatment, and resistance to loop diuretics. In addition, both NT-proBNP and sympathetic nervous system (SNS) overdrive are strong predictors of adverse clinical outcome and allow to identify high-risk HF patients even in the presence of mild symptoms. To counteract the deleterious effects of the SNS activation, new strategies such as a new drug combining angiotensin receptor and neprilysin inhibition and baroreceptor stimulation therapy (BAT) have been investigated. Inability to properly counteract the SNS overdrive leads to acute HF decompensation by different mechanisms. The leading ones are represented by the progressive sodium and water retention with fluid overload and by the blood volume redistribution between splanchnic and non-splanchnic regions. The correct understanding of these mechanisms, together with the availability of new therapeutic options such as peritoneal ultrafiltration, represent the rationale but not infrequently overlooked therapeutic options to improve congestion management in HF patients.

CardioMEMS, the real progress in heart failure home monitoring.

The burden of hospitalizations driven by exacerbation of acute heart failure remains unacceptably high. The associated use of hospital resources drives increasing patient, caregiver, and economic costs. Noninvasive telemedical systems investigated in randomized controlled trials have failed to demonstrate to reduce hospitalization rates probably because of the indirect (non-linear) relationship of the measured biological signals with the patient congestion status. Instead, there is increasing evidence that direct measure of intracardiac and pulmonary artery pressure can effectively guide heart failure management and reduce hospitalizations. Early studies adopting implantable hemodynamic monitors in the right heart unveiled the potential of pressure-based heart failure management, whereas subsequent investigations showed the powerful preemptive approach for heart failure exacerbations. One large randomized trial (CHAMPION) proved that a direct pulmonary pressure monitor system (CardioMEMS) substantially reduced heart failure hospitalizations in subjects randomized to active pulmonary pressure-guided management. The system monitoring safety and efficacy were also excellent. The study proved that early management in response to increased pulmonary pressure is able to provide the most effective therapeutic intervention to prevent heart failure exacerbations.

Current challenges in sudden cardiac death prevention.

Ischemic heart disease and non-ischemic dilated cardiomyopathy are the most common causes of arrhythmic sudden cardiac death (SCD). Implantable cardioverter defibrillator (ICD) therapy is the only strategy that proved to be effective in preventing SCD in high-risk individuals while the role of antiarrhythmic drugs is limited to symptoms relief. Current guidelines recommend selecting candidates to ICD implantation based on etiology, symptoms of heart failure (NYHA class), and severely depressed left ventricular ejection fraction, but these parameters are neither sensitive nor specific. The review addresses the mechanisms of SCD in patients with heart failure of either ischemic or non-ischemic etiology, risk stratification, and strategies for prevention of SCD in the clinical practice (including optimization of heart failure therapy, avoidance of triggering factors, antiarrhythmic drugs, ICD therapy, early resuscitation, and public access defibrillators).

Cardiovascular autonomic individual profile of relapsing-remitting multiple sclerosis patients and risk of extending cardiac monitoring after first dose fingolimod.

Fingolimod exerts its therapeutic effect in multiple sclerosis by modulating sphingosine-1P receptors which are expressed in the heart mediating fingolimod first dose effects. Understanding potential interactions of baseline characteristics and autonomic profile with fingolimod first dose effects may add novel safety information and help explain cases requiring extension of the 6-hour ECG monitoring period. We aimed at characterizing the patient population treated with the first dose of fingolimod in clinical practice in an observational, multicenter, prospective 6-hours (up to 24) study. ECG was recorded for 15 min before first fingolimod administration and for 6 h after. Heart rate (HR) and HR variability in the frequency domain were derived from ECG traces. Out of the 625 enrolled patients, 580 (92.8%) were discharged at the sixth hour after fingolimod first dose; 45 (7.2%) required monitoring extension. Data confirm the well characterized cardiovascular fingolimod profile upon treatment initiation. Ten (1.6%) patients showed an atrioventricular block, all asymptomatic and self-resolving. Normalized spectral power in the High Frequency band (marking vagal modulation) and previous annualized relapse rate were independently correlated with the probability of undergoing extended monitoring. Our results could provide useful information for the stratification and individualized monitoring of MS patients prescribed with fingolimod.

Unresolved issues in left ventricular postischemic remodeling and progression to heart failure.

: In the past decades, myocardial infarction periacute mortality markedly declined since coronary reperfusion therapy has been adopted. Despite immediate benefits of coronary blood flow restoration, the percentage of new onset heart failure has increased over time suggesting that ischemia can run detrimental consequences beyond the immediate anoxic hit. By accepting to aggregate all types of heart failure regardless of underlying cause, the current practice did not help to shed light on the complex postischemic cardiac biology indicating that heart failure is somewhat unavoidable. In the ischemic sequel, the activated mechanisms aim to repair the infarcted zone and to compensate for the lost myocyte functions, thus allowing the heart to maintain the efficient cardiac output for vital organs. The variety of underlying preexisting conditions, as well as the multifaceted components of cardiac molecular structure, cellular state, and electrophysiological postischemic events pave the way for long-term adverse cardiac remodeling. We focused our attention on multiple factors, which include myocyte loss, hypertrophy, hyperplasia, extracellular matrix changes linked to myocardial fibrosis and scar, metabolic imbalance, as well as immunologic response occurring in the acute myocardial aftermath. Moreover, we reported both current pharmacological strategies and future perspectives that might be useful in clinical practice. Furthermore, we discussed the cardiac magnetic resonance as the most promising noninvasive imaging tool, which could be helpful in identifying the amount of myocardial damage. Despite the redundancy of molecular pathogenic mechanisms making it impossible to estimate the proportionate contributions in generating the heart failure phenotype, a deeper understanding will contribute to more customized patient management.

Proarrhythmic proclivity of left-stellate ganglion stimulation in a canine model of drug-induced long-QT syndrome type 1.

BACKGROUND: Left-stellate ganglion stimulation (LSGS) can modify regional dispersion of ventricular refractoriness, promote triggered activity, and reduce the threshold for ventricular fibrillation (VF). Sympathetic hyperactivity precipitates torsades de pointes (TdP) and VF in susceptible patients with long-QT syndrome type 1 (LQT1). We investigated the electromechanical effects of LSGS in a canine model of drug-induced LQT1, gaining novel arrhythmogenic insights. METHODS: In nine mongrel dogs, the left and right stellate ganglia were exposed for electrical stimulation. ECG, left- and right-ventricular endocardial monophasic action potentials (MAPs) and pressures (LVP, RVP) were recorded. The electromechanical window (EMW; Q to LVP at 90% relaxation minus QT interval) was calculated. LQT1 was mimicked by infusion of the KCNQ1/IKs blocker HMR1556. RESULTS: At baseline, LSGS and right-stellate ganglion stimulation (RSGS) caused similar heart-rate acceleration and QT shortening. Positive inotropic and lusitropic effects were more pronounced under LSGS than RSGS. IKs blockade prolonged QTc, triggered MAP-early afterdepolarizations (EADs) and rendered the EMW negative, but no ventricular tachyarrhythmias occurred. Superimposed LSGS exaggerated EMW negativity and evoked TdP in 5/9 dogs within 30 s. Preceding extrasystoles originated mostly from the outflow-tracts region. TdP deteriorated into therapy-refractory VF in 4/5 animals. RSGS did not provoke TdP/VF. CONCLUSIONS: In this model of drug-induced LQT1, LSGS readily induced TdP and VF during repolarization prolongation and MAP-EAD generation, but only if EMW turned from positive to very negative. We postulate that altered mechano-electric coupling can exaggerate regional dispersion of refractoriness and facilitates ventricular ectopy.

AnatoMy and physIopathoLogy of the heArt in a ceNtenarian cOhort (MILANO study).

Background: Centenarians are increasingly being encountered in clinical practice. The aim of the study was to characterize centenarians' clinical features and cardiovascular system. Methods: A prospective, observational, cross-sectional, case-control study included 118 hospitalized >100-year-old patients compared to 50 octogenarians, selected in Milan (Italy) from December 2010 to December 2017, to assess their clinical and echocardiographic characteristics. Results: Centenarians were mostly women with small body surface area; long history of hypertension; chronic renal failure; and low incidence of smoking, diabetes, dyslipidemia, hyperuricemia, coronary artery disease, atrial fibrillation, and cerebrovascular disease. They showed high prevalence of severe cognitive impairment and disability. Almost half of patients (46%) were hospitalized for congestive heart failure (HF), mostly diastolic (80% of cases). Centenarians' hearts had reduced left ventricular end-diastolic dimensions (25.3 ± 3.8 mm/m^2), increased septal thickness (13.3 ± 1.9 mm), and higher relative wall thickness (0.58 ± 0.1). The ejection fraction was usually normal and rarely depressed (57.1% ± 11.7%), whereas the E/e' ratio was considerably increased (17.0 ± 6.0). Noninvasive evaluation of ventricular-arterial coupling parameters revealed significantly higher values of LV end-diastolic elastance in all centenarians versus octogenarians (0.4 ± 01 mm Hg/mL/m^2 vs 0.18 ± 0.2 mm Hg/mL/m^2, P < .0001) and in centenarians with HF versus those without HF (0.5 ± 0.1 mm Hg/mL/m^2 vs 0.34 ± 0.1 mm Hg/mL/m^2, P < .0001). Conclusions: The centenarians' cardiovascular system manifested a significant increase in LV diastolic stiffness with consequent susceptibility to diastolic HF. A progressive afterload increase and a passive load independent mechanism could have contributed to such changes.

Restoration of normal sympathetic neural function in heart failure following baroreflex activation therapy: final 43-month study report.

BACKGROUND: Baroreflex activation therapy (BAT) exerts in severe heart failure sympathoinhibitory effects, improving clinical variables and reducing hospitalization rate. The current follow-up study was aimed at determining the long-term effects of BAT, assessing whether BAT in heart failure allows to restore physiological levels of sympathetic function. METHODS: Seven patients out of the 11 heart failure patients aged 66.5 ±â€Š3 years (mean ±â€ŠSEM) in New York Heart Association Class III with left ventricular ejection fraction 40% or less and impaired functional capacity recruited in the study survived at the final follow-up (43.5 ±â€Š2.1 months). Measurements included muscle sympathetic nerve activity (MSNA, microneurography) and spontaneous baroreflex-MSNA sensitivity together with hospitalization rate, echocardiography, Minnesota score, New York Heart Association class and standard clinical data. Measurements were collected before and at 6, 21 and 43 months following BAT. Data were compared with those collected in 17 age-matched healthy controls. All assessments were made with the heart failure patient on optimal active therapy. RESULTS: In the seven patients, BAT maintained its beneficial effects over 43.5 ±â€Š2.1 months of follow-up. MSNA values underwent a progressive significant reduction from baseline to 21 and 43 months follow-up following BAT (from 46.2 ±â€Š2.4 to 31.3 ±â€Š3.0 e 26.6 ±â€Š2.0 bursts/min, P < 0.05 at least), becoming almost superimposable to the ones seen in healthy controls (25.5 ±â€Š0.8 bursts/min). Baroreflex-MSNA sensitivity improved, without achieving, however, a full normalization. Blood pressure and heart rate did not change. Left ventricular ejection fraction improved significantly from 32.3 ±â€Š2 to 36.7 ±â€Š3% (P < 0.05). Hospitalization rate decreased substantially when measured as days/year/patients it decreased from 10.3 ±â€Š2.5 preimplant to 1.01 ±â€Š1.4 at the 43.5th month follow-up (P < 0.02). No side effects were reported in the long-term period. CONCLUSION: The current study provides evidence that BAT in heart failure with reduced ejection fraction allows not only to improve hemodynamic and clinical profile but also to exert profound sympathoinhibitory effects, allowing an almost complete restoration of physiological levels of the sympathetic neural function.

Baroreflex activation therapy: a new approach to the management of advanced heart failure with reduced ejection fraction.

: Chronic heart failure is a common clinical condition characterized by persistent excessive sympathetic nervous system activation. The derangement of the sympathetic activity has relevant implications for disease progression and patient survival. Aiming to positively impact patient outcome, autonomic nervous system modulatory therapies have been developed and tested in animal and clinical studies. As a general gross assumption, direct vagal stimulation and baroreflex activation are considered equivalent. This assumption does not take into account the fact that direct cervical vagal nerve stimulation involves activation of both afferent and efferent fibers innervating not only the heart, but the entire visceral system, leading to undesired responses to and from this compartment. The different action of baroreflex activation is based on generating a centrally mediated reduction of sympathetic outflow and increasing parasympathetic activity to the heart via a physiological reflex pathway. Thus, baroreflex activation rebalances the unbalanced autonomic nervous system via a specific path. Independent and complementary investigations have shown that sympathetic nerve activity can be rebalanced via control of the arterial baroreflex in heart failure patients.Results from recent pioneering research studies support the hypothesis that baroreflex activation can add significant therapeutic benefit on top of guideline-directed medical therapy in patients with advanced heart failure. In the present review, baroreflex activation therapy results are discussed, focusing on critical aspects like patient selection rationale to support clinician orientation in opting for baroreflex activation therapy when, on top of current guideline-directed medical treatment, other therapies are to be considered.