Hyperkalaemia in Cardiological Patients: New Solutions for an Old Problem.

Hyperkalaemia is one of the most common electrolyte disorders in patients with cardiovascular disease (CVD). The true burden of hyperkalaemia in the real-world setting can be difficult to assess, but in population-based cohort studies up to 4 in 10 patients developed hyperkalaemia. In addition to drugs interfering with potassium metabolism and food intake, several conditions can cause or worsen hyperkalaemia, such as advanced age, diabetes, and chronic kidney disease. Mortality, cardiovascular morbidity, and hospitalisation are higher in patients with hyperkalaemia. Hyperkalaemia represents a major contraindication or a withholding cause for disease-modifying therapies like renin-angiotensin-aldosterone inhibitors (RAASi), mainly mineralocorticoid receptor antagonists. Hyperkalaemia can be also classified as acute and chronic, according to the onset. Acute hyperkalaemia is often a life-threatening emergency requiring immediate treatment to avoid lethal arrhythmias. Therapy goal is cell membrane stabilisation by calcium administration, cellular intake, shift of extracellular potassium to the intracellular space (insulin, beta-adrenergic agents, sodium bicarbonate), and increased elimination with diuretics or dialysis. Chronic hyperkalaemia was often managed with dietary counselling to prevent potassium-rich food intake and tapering of potassium-increasing drugs, mostly RAASi. Sodium polystyrene sulphonate, a potassium binder, was the only therapeutic option. Recently, new drugs such as patiromer and sodium zirconium cyclosilicate give new opportunities for the treatment of hyperkalaemia, as they proved to be safe, well tolerated, and effective. Aim of this review is to describe the burden of hyperkalaemia in cardiovascular patients, its direct and indirect effects, and the therapeutic options now available in the acute and chronic setting.

Rationale and Design of PURE: A Randomized Controlled Trial to Evaluate Peritoneal Ultrafiltration with PolyCore™ in Refractory Congestive Heart Failure.

INTRODUCTION: Peritoneal ultrafiltration (PUF) has been proposed as an additional therapeutic option for refractory congestive heart failure (RCHF) patients. Despite promising observational studies and/or case report results, limited clinical trial data exist, and so far, PUF solutions remain only indicated for chronic kidney diseases. In this article, we described a multicenter, randomized, controlled, unblinded, adaptive design clinical trial, about to start, investigating the effects of PolyCore™, an innovative PUF solution, in the treatment of RCHF patients. METHODS: The Peritoneal Ultrafiltration in Cardiorenal Syndrome (PURE) study is a phase II, multicenter, randomized, controlled, unblinded, adaptive design clinical trial that aims to evaluate the safety and efficacy of PUF, using PolyCore™ as the investigational solution, in the treatment of RCHF patients who present with prominent right ventricular failure due to afterload mismatch, functional tricuspid regurgitation and enlarged cava vein consequent to intravascular fluid overload. Approximately 84 patients will be randomized 1:1 either to continue with their prescribed guideline-directed medical therapy or to add the PUF treatment on top of it. The primary objective is to evaluate if PUF treatment has an impact on the composite endpoint of the patient's mortality or worsening of the patient's condition such as hospitalization for cardiovascular causes, increasing the initial daily dose of loop diuretic or worsening of renal function. Statistical analysis for the primary endpoint will be standard survival analysis to estimate the failure rate at month 7 for each group via Kaplan-Meier curves. Sensitivity analysis and various secondary analyses, including a multiple events analysis, will be conducted to evaluate the robustness of the primary endpoint results. Safety will be evaluated for up to 12 months. CONCLUSION: The PURE study was designed to evaluate the safety and efficacy of peritoneal ultrafiltration with PolyCore™ on top of guideline-directed medical therapy in patients with RCHF, assuming a combined clinical endpoint of mortality or worsening patients' condition. If successful, the treatment should allow for an improvement of the RCHF symptoms, decreasing hospitalization rate of patients.

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.

Renal Oxygen Demand and Nephron Function: Is Glucose a Friend or Foe?

The kidneys and heart work together to balance the body's circulation, and although their physiology is based on strict inter dependence, their performance fulfills different aims. While the heart can rapidly increase its own oxygen consumption to comply with the wide changes in metabolic demand linked to body function, the kidneys physiology are primarily designed to maintain a stable metabolic rate and have a limited capacity to cope with any steep increase in renal metabolism. In the kidneys, glomerular population filters a large amount of blood and the tubular system has been programmed to reabsorb 99% of filtrate by reabsorbing sodium together with other filtered substances, including all glucose molecules. Glucose reabsorption involves the sodium-glucose cotransporters SGLT2 and SGLT1 on the apical membrane in the proximal tubular section; it also enhances bicarbonate formation so as to preserve the acid-base balance. The complex work of reabsorption in the kidney is the main factor in renal oxygen consumption; analysis of the renal glucose transport in disease states provides a better understanding of the renal physiology changes that occur when clinical conditions alter the neurohormonal response leading to an increase in glomerular filtration pressure. In this circumstance, glomerular hyperfiltration occurs, imposing a higher metabolic demand on kidney physiology and causing progressive renal impairment. Albumin urination is the warning signal of renal engagement over exertion and most frequently heralds heart failure development, regardless of disease etiology. The review analyzes the mechanisms linked to renal oxygen consumption, focusing on sodium-glucose management.

Noncardiac comorbidity clustering in heart failure: an overlooked aspect with potential therapeutic door.

Heart failure is associated with a range of comorbidities that have the potential to impair both quality of life and clinical outcome. Unfortunately, noncardiac diseases are underrepresented in large randomized clinical trials, and their management remains poorly understood. In clinical practice, the prevalence of comorbidities in heart failure is high. Although the prognostic impact of comorbidities is well known, their prevalence and impact in specific heart failure settings have been overlooked. Many studies have described specific single noncardiac conditions, but few have examined their overall burden and grading in patients with multiple comorbidities. The risk of comorbidities in patients with heart failure rises with more advanced disease, older age, and increased frailty-three conditions that are poorly represented in clinical trials. The pathogenic links between comorbidities and heart failure involve many pathways and include neurohormonal overdrive, inflammatory activation, oxidative stress, and endothelial dysfunction. Such interactions may worsen prognoses, but details of these relationships are still under investigation. We propose a shift from cardiac-focused care to a more systemic approach that considers all noncardiac diseases and related medications. Some new drugs class such as ARNI or SGLT2 inhibitors could change prognosis by acting directly or indirectly on metabolic disorders and related vascular consequences.

Combining home monitoring temporal trends from implanted defibrillators and baseline patient risk profile to predict heart failure hospitalizations: results from the SELENE HF study.

AIMS: We developed and validated an algorithm for prediction of heart failure (HF) hospitalizations using remote monitoring (RM) data transmitted by implanted defibrillators. METHODS AND RESULTS: The SELENE HF study enrolled 918 patients (median age 69 years, 81% men, median ejection fraction 30%) with cardiac resynchronization therapy (44%), dual-chamber (38%), or single-chamber defibrillators with atrial diagnostics (18%). To develop a predictive algorithm, temporal trends of diurnal and nocturnal heart rates, ventricular extrasystoles, atrial tachyarrhythmia burden, heart rate variability, physical activity, and thoracic impedance obtained by daily automatic RM were combined with a baseline risk-stratifier (Seattle HF Model) into one index. The primary endpoint was the first post-implant adjudicated HF hospitalization. After a median follow-up of 22.5 months since enrolment, patients were randomly allocated to the algorithm derivation group (n = 457; 31 endpoints) or algorithm validation group (n = 461; 29 endpoints). In the derivation group, the index showed a C-statistics of 0.89 [95% confidence interval (CI): 0.83-0.95] with 2.73 odds ratio (CI 1.98-3.78) for first HF hospitalization per unitary increase of index value (P < 0.001). In the validation group, sensitivity of predicting primary endpoint was 65.5% (CI 45.7-82.1%), median alerting time 42 days (interquartile range 21-89), and false (or unexplained) alert rate 0.69 (CI 0.64-0.74) [or 0.63 (CI 0.58-0.68)] per patient-year. Without the baseline risk-stratifier, the sensitivity remained 65.5% and the false/unexplained alert rates increased by ≈10% to 0.76/0.71 per patient-year. CONCLUSION: With the developed algorithm, two-thirds of first post-implant HF hospitalizations could be predicted timely with only 0.7 false alerts per patient-year.

Mechanisms of action of SGLT2 inhibitors and their beneficial effects on the cardiorenal axis.

Large clinical studies conducted with sodium-glucose co-transporter 2 inhibitors (SGLT2i) in patients with type 2 diabetes and heart failure with reduced ejection fraction have demonstrated their ability to achieve both cardiac and kidney benefits. Although there is huge evidence on SGLT2i-mediated clinical benefits both in diabetic and non-diabetic patients, the pathophysiological mechanisms underlying their efficacy are still poorly understood. Some favorable mechanisms are likely due to the prompt glycosuric action which is associated with natriuretic effects leading to hemodynamic benefits as well as a reduction in glomerular hyperfiltration and renin-angiotensin-aldosterone system activation. In addition to the renal mechanisms, SGLT2i may play a relevant role in cardiorenal axis protection by improving the cardiomyocyte metabolism, by exerting anti-fibrotic and anti-inflammatory actions, and by increasing cardioprotective adipokine expression. New studies will be needed to better understand the specific molecular mechanisms that mediate the SGLT2i favorable effects in patients suffering diabetes. Our aim is to first discuss about the molecular mechanisms underlying the cardiovascular benefits of SGLT2i in each of the main organs involved in the cardiorenal axis. Furthermore, we update on the most recent clinical trials evaluating the beneficial effects of SGLT2i in treatment of both diabetic and non-diabetic patients suffering heart failure.

ANMCO statement on the use of sodium-glucose cotransporter 2 inhibitors in patients with heart failure: a practical guide for a streamlined implementation.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors, dapagliflozin, and empagliflozin, first developed as glucose-lowering agents for the treatment of Type 2 diabetes, have been demonstrated to improve prognosis in patients with heart failure and reduced ejection fraction (HFrEF) regardless of the presence of diabetes. Since these drugs have only recently been included among the four pillars of HFrEF treatment, cardiologists are still unfamiliar with their use in this setting. This article provides an up-to-date practical guide for the initiation and monitoring of patients treated with SGLT2 inhibitors.

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.

Recent advances in pharmacological treatment of heart failure.

BACKGROUND: Over the last years, several trials offered new evidence on heart failure (HF) treatment. DESIGN AND RESULTS: For HF with reduced left ventricular ejection fraction, type 2 sodium-glucose cotransporter inhibitors, aside from sacubitril-valsartan, demonstrated extraordinary efficacy in ameliorating patients' prognosis. Some new molecules (eg vericiguat, omecamtiv mecarbil and ferric carboxymaltose) correct iron deficiency and have shown to be capable of furthering reducing the burden of HF hospitalisation. Finally, there is new evidence on the possible therapeutic approaches of HF patients with mid-range or preserved left ventricular ejection fraction. CONCLUSIONS: This review aimed to revise the main novelties in the field of HF therapy and focus on how the daily clinical approach to patient treatment is changing.

ANMCO POSITION PAPER: on administration of type 2 sodium-glucose co-transporter inhibitors to prevent heart failure in diabetic patients and to treat heart failure patients with and without diabetes.

This ANMCO (Associazione Nazionale Medici Cardiologi Ospedalieri) position paper aims to analyse the complex action of sodium-glucose co-transporter 2 inhibitors at the level of the kidney and cardiovascular system, focusing on the effect that these molecules have shown in the prevention and treatment of heart failure in diabetic and non-diabetic subjects. The goal was pursued by comparing the data generated with pathophysiology studies and with multicentre controlled studies in large populations. In accordance with the analysis carried out in the document, the following recommendations are issued: (i) canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin are molecules recommended for the prevention of heart failure hospitalizations in type 2 diabetic subjects; (ii) canagliflozin and dapagliflozin are recommended for the prevention of heart failure hospitalizations in type 2 diabetic subjects with severe chronic kidney disease, dapagliflozin proved to be safe and effective also in diabetic subjects; and (iii) dapagliflozin and empagliflozin are recommended to reduce the combined risk of heart failure and cardiovascular death in diabetic and non-diabetic subjects with heart failure and reduced ejection fraction.

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.

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.

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).

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.

Sympathetic Response and Outcomes Following Renal Denervation in Patients With Chronic Heart Failure: 12-Month Outcomes From the Symplicity HF Feasibility Study.

BACKGROUND: Heart failure (HF) is associated with chronic sympathetic activation. Renal denervation (RDN) aims to reduce sympathetic activity by ablating the renal sympathetic nerves. We investigated the effect of RDN in patients with chronic HF and concurrent renal dysfunction in a prospective, multicenter, single-arm feasibility study. METHODS AND RESULTS: Thirty-nine patients with chronic systolic HF (left ventricular ejection fraction [LVEF] <40%, New York Heart Association class II-III,) and renal impairment (estimated glomerular filtration rate [eGFR; assessed with the use of the Modification of Diet in Renal Disease equation] < 75 mL • min-1 • 1.73 m-2) on stable medical therapy were enrolled. Mean age was 65 ± 11 years; 62% had ischemic HF. The average number of ablations per patient was 13 ± 3. No protocol-defined safety events were associated with the procedure. One subject experienced a renal artery occlusion that was possibly related to the denervation procedure. Statistically significant reductions in N-terminal pro-B-type natriuretic peptide (NT-proBNP; 1530 ± 1228 vs 1428 ± 1844 ng/mL; P = .006) and 120-minute glucose tolerance test (11.2 ± 5.1 vs 9.9 ± 3.6; P = .026) were seen at 12 months, but there was no significant change in LVEF (28 ± 9% vs 29 ± 11%; P= .536), 6-minute walk test (384 ± 96 vs 391 ± 97 m; P= .584), or eGFR (52.6 ± 15.3 vs 52.3 ± 18.5 mL • min-1 • 1.73 m-2; P= .700). CONCLUSIONS: RDN was associated with reductions in NT-proBNP and 120-minute glucose tolerance test in HF patients 12 months after RDN treatment. There was no deterioration in other indices of cardiac and renal function in this small feasibility study.

Glucagon and heart in type 2 diabetes: new perspectives.

Increased levels of glucagon in type 2 diabetes are well known and, until now, have been considered deleterious. However, glucagon has an important role in the maintenance of both heart and kidney function. Moreover, in the past, glucagon has been therapeutically used for heart failure treatment. The new antidiabetic drugs, dipeptidyl peptidase-4 inhibitors and sodium-glucose co-transporter-2 inhibitors, are able to decrease and to increase glucagon levels, respectively, while contrasting data have been reported regarding the glucagon like peptide 1 receptors agonists. The cardiovascular outcome trials, requested by the FDA, raised some concerns about the possibility that the dipeptidyl peptidase-4 inhibitors can precipitate the heart failure, while, at least for empagliflozin, a positive effect has been shown in decreasing both cardiovascular death and heart failure. The recent LEADER Trial, showed a significant reduction of cardiovascular death with liraglutide, but a neutral effect on heart failure. A possible explanation of the results with the DPPIV inhibitors and empagliflozin might be related to their divergent effect on glucagon levels. Due to unclear effects of glucagon like peptide 1 receptor agonists on glucagon, the possible role of this hormone in the Leader trial remains unclear.

Autonomic Modulation With Baroreflex Activation Therapy in Heart Failure.

Baroreflex activation therapy (BAT) produces a central inhibition of cardiac sympathetic outflow and, concomitantly, an increased cardiac vagal activity via a physiological reflex pathway. In a pilot study in 11 patients with NYHA class III heart failure (HF), BAT produced a persistent significant reduction of muscle sympathetic nerve activity over a 21-month follow-up and a dramatic decrease in the number and length of hospitalizations. In a multinational, prospective, randomized, parallel-controlled, clinical trial in 146 NYHA functional class III HF, BAT produced a significant N-terminal pro-brain natriuretic peptide reduction (p = 0.02). This was associated with a trend toward few in hospital days for HF. BAT might become a powerful tool to manipulate autonomic alterations of HF at their origin and thus profoundly affect advanced HF patient prognosis.

Novel approaches to the post-myocardial infarction/heart failure neural remodeling.

The review aims to discuss the role of nerve growth factor (NGF) as a potential novel biomarker in post-myocardial infarction (MI) and in heart failure (HF), with a specific focus on neural remodeling and sprouting processes occurring after tissue damage. Many experimental data show that MI induces nerve sprouting, leading to increased sympathetic outflow and higher risk of ventricular arrhythmias and sudden cardiac death. In this framework, cardiac and circulating NGF might be an indicator of the innervation process and neural remodeling: it dramatically increases after MI, while it declines along with advanced HF and ventricular dysfunction. The bimodal behavior of NGF in acute and chronic settings leads to the speculation that NGF modulation may be a pharmacological target for intervention in different stages of the ischemic heart disease. Specifically, a fascinating possibility is to support or to inhibit NGF receptors, in order to prevent negative cardiac remodeling after MI and consequent ventricular dysfunction.