OBJECTIVE: Despite availability of an array of antihypertensive drugs, malignant hypertension remains a life-threatening condition, and new therapeutic strategies for the treatment of malignant hypertension and malignant hypertension-associated organ damage are needed. The aim of the present study was to assess the effects of nitric oxide (NO)-independent soluble guanylyl cyclase (sGC) stimulator on the course of malignant hypertension. The second aim was to investigate if the treatment with sodium-glucose cotransporter type 2 (SGLT2) inhibitor would augment the expected beneficial actions of the sGC stimulation on the course of malignant hypertension. METHODS: As a model of malignant hypertension, Ren-2 transgenic rats (TGR) treated with nonspecific NO synthase inhibitor (Nω-nitro- l -arginine methyl ester, l -NAME) was used. Blood pressure (BP) was monitored by radiotelemetry, and the treatment was started 3 days before administration of l -NAME. RESULTS: The treatment with sGC stimulator BAY 41-8543, alone or combined with SGLT2 inhibitor empagliflozin, abolished malignant hypertension-related mortality in TGR receiving l -NAME. These two treatment regimens also prevented BP increases after l -NAME administration in TGR, and even decreased BP below values observed in control TGR, and prevented cardiac dysfunction and malignant hypertension-related morbidity. The treatment with the SGLT2 inhibitor empagliflozin did not further augment the beneficial actions of sGC stimulator on the course of malignant hypertension-related mortality. CONCLUSION: The treatment with NO-independent sGC stimulator displayed marked protective actions on the course of malignant hypertension-related mortality and malignant hypertension-related cardiac damage. This suggests that application of sGC stimulator could be a promising therapeutic means for the treatment of malignant hypertension.

• Keywords
• malignant hypertension, renin–angiotensin system, sodium-glucose cotransporter type 2 inhibitor, soluble guanylyl cyclase stimulator,
• MeSH
• Benzhydryl Compounds pharmacology   MeSH
• Sodium-Glucose Transporter 2 Inhibitors MeSH
• Glucosides pharmacology   therapeutic use   MeSH
• Hypertension, Malignant * prevention & control   drug therapy   MeSH
• Blood Pressure drug effects   MeSH
• Rats MeSH
• Morpholines MeSH
• NG-Nitroarginine Methyl Ester pharmacology   MeSH
• Rats, Transgenic MeSH
• Pyrazoles * pharmacology   therapeutic use   MeSH
• Pyrimidines * therapeutic use   pharmacology   MeSH
• Soluble Guanylyl Cyclase * metabolism   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• BAY 41-8543 MeSH Browser
• Benzhydryl Compounds MeSH
• empagliflozin MeSH Browser
• Sodium-Glucose Transporter 2 Inhibitors MeSH
• Glucosides MeSH
• Morpholines MeSH
• NG-Nitroarginine Methyl Ester MeSH
• Pyrazoles * MeSH
• Pyrimidines * MeSH
• Soluble Guanylyl Cyclase * MeSH

Heart failure (HF) is a clinical syndrome characterized by the inability of the heart to provide adequate perfusion to tissues and organs, resulting in typical symptoms such as fatigue, dyspnea, dyspepsia, or swelling due to decreased cardiac output. With its increasing prevalence, heart failure has become one of the leading causes of morbidity and mortality worldwide, imposing a significant burden on the population by reducing long-term life expectancy and raising hospital costs. Indeed, over 20 million people worldwide suffer from heart failure, with a 5-year mortality rate of 60-70%. As heart failure progresses, various structural and metabolic changes occur within the myocardium and organ systems. In the past two decades, therapeutic options for heart failure patients have significantly expanded. In addition to novel pharmacological treatment, advanced surgical methods such as heart transplantation (HTx) and the implantation of durable left ventricular assist devices (LVADs) are available for patients with end-stage heart failure. This review discusses the pathophysiological aspects and metabolic consequences of heart failure and metabolic changes, as well as the benefits and challenges of implanting a left ventricular assist device. Furthermore, future targets for heart failure diagnostics and therapy will be highlighted.

• Keywords
• cachexia, diabetes, gliflozins, heart failure, left ventricular assist device, mechanical circulatory support, metabolism, obesity,
• Publication type
• Journal Article MeSH
• Review MeSH

Despite improvements over recent years, morbidity and mortality associated with heart failure (HF) are higher in countries in the Central and Eastern Europe and Baltic region than in Western Europe. With the goal of improving the standard of HF care and patient outcomes in the Central and Eastern Europe and Baltic region, this review aimed to identify the main barriers to optimal HF care and potential areas for improvement. This information was used to suggest methods to improve HF management and decrease the burden of HF in the region that can be implemented at the national and regional levels. We performed a literature search to collect information about HF epidemiology in 11 countries in the region (Bulgaria, Croatia, Czechia, Estonia, Hungary, Latvia, Lithuania, Poland, Romania, Serbia, and Slovenia). The prevalence of HF in the region was 1.6-4.7%, and incidence was 3.1-6.0 per 1000 person-years. Owing to the scarcity of published data on HF management in these countries, we also collected insights on local HF care and management practices via two surveys of 11 HF experts representing the 11 countries. Based on the combined results of the literature review and surveys, we created national HF care and management profiles for each country and developed a common patient pathway for HF for the region. We identified five main barriers to optimal HF care: (i) lack of epidemiological data, (ii) low awareness of HF, (iii) lack of national HF strategies, (iv) infrastructure and system gaps, and (v) poor access to novel HF treatments. To overcome these barriers, we propose the following routes to improvement: (i) establish regional and national prospective HF registries for the systematic collection of epidemiological data; (ii) establish education campaigns for the public, patients, caregivers, and healthcare professionals; (iii) establish formal HF strategies to set clear and measurable policy goals and support budget planning; (iv) improve access to quality-of-care centres, multidisciplinary care teams, diagnostic tests, and telemedicine/telemonitoring; and (v) establish national treatment monitoring programmes to develop policies that ensure that adequate proportions of healthcare budgets are reserved for novel therapies. These routes to improvement represent a first step towards improving outcomes in patients with HF in the Central and Eastern Europe and Baltic region by decreasing disparities in HF care within the region and between the region and Western Europe.

• Keywords
• Central and Eastern Europe and Baltic region, Heart failure management, Heart failure nursing, Multidisciplinary care, Patient pathway, Registries,
• MeSH
• Humans MeSH
• Disease Management MeSH
• Morbidity trends   MeSH
• Prevalence MeSH
• Heart Failure * epidemiology   therapy   MeSH
• Quality Improvement MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Geographicals
• Europe epidemiology   MeSH
• Baltic States epidemiology   MeSH
• Europe, Eastern epidemiology   MeSH

BACKGROUND: The increased diuresis after sodium-glucose cotransporter 2 inhibitor (SGLT2i) was associated with a reduction of the estimated plasma volume (ePV) in type 2 diabetic patients. HYPOTHESIS: We hypothesized that the early effect of SGLT2i on ePV may be monitored by the change of biomarkers of hemoconcentration. PATIENTS AND METHODS: We analyzed the early- and long-term effect of SGLT2i empagliflozin on the ePV as assessed by biomarkers of hemoconcentration in a nondiabetic patient with heart failure and reduced ejection fraction (HFrEF) and a nondiabetic patient with heart failure and preserved ejection fraction (HFpEF). The ePV was calculated from hemoglobin and hematocrit levels by Duarte formula and ePV change was calculated by Strauss formula. RESULTS: The ePV change was -22.56% between baseline and 1 month, and -37.60% between baseline and 12 months follow-up in a patient with HFrEF, and -6.18% and -16.40% in a patient with HFpEF, respectively. CONCLUSION: The early effect of SGLT2i on ePV in patients with heart failure may be monitored by biomarkers of hemoconcentration.

• Keywords
• biomarker, heart failure, hemoconcentration, plasma volume, sodium−glucose co‐transporter‐2 inhibitor,
• MeSH
• Benzhydryl Compounds therapeutic use   MeSH
• Biomarkers blood   MeSH
• Time Factors MeSH
• Diabetes Mellitus, Type 2 drug therapy   complications   blood   physiopathology   MeSH
• Ventricular Function, Left drug effects   physiology   MeSH
• Sodium-Glucose Transporter 2 Inhibitors * therapeutic use   MeSH
• Glucosides therapeutic use   pharmacology   MeSH
• Middle Aged MeSH
• Humans MeSH
• Plasma Volume * MeSH
• Aged MeSH
• Heart Failure * physiopathology   drug therapy   blood   MeSH
• Stroke Volume * physiology   drug effects   MeSH
• Treatment Outcome MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Case Reports MeSH
• Names of Substances
• Benzhydryl Compounds MeSH
• Biomarkers MeSH
• empagliflozin MeSH Browser
• Sodium-Glucose Transporter 2 Inhibitors * MeSH
• Glucosides MeSH

BACKGROUND: Sodium-glucose cotransporter 2 inhibitors (SGLT-2i) are glucose-lowering agents used for the treatment of type 2 diabetes mellitus, which also improve heart failure and decrease the risk of cardiovascular complications. Epicardial adipose tissue (EAT) dysfunction was suggested to contribute to the development of heart failure. We aimed to elucidate a possible role of changes in EAT metabolic and inflammatory profile in the beneficial cardioprotective effects of SGLT-2i in subjects with severe heart failure. METHODS: 26 subjects with severe heart failure, with reduced ejection fraction, treated with SGLT-2i versus 26 subjects without treatment, matched for age (54.0 ± 2.1 vs. 55.3 ± 2.1 years, n.s.), body mass index (27.8 ± 0.9 vs. 28.8 ± 1.0 kg/m2, n.s.) and left ventricular ejection fraction (20.7 ± 0.5 vs. 23.2 ± 1.7%, n.s.), who were scheduled for heart transplantation or mechanical support implantation, were included in the study. A complex metabolomic and gene expression analysis of EAT obtained during surgery was performed. RESULTS: SGLT-2i ameliorated inflammation, as evidenced by the improved gene expression profile of pro-inflammatory genes in adipose tissue and decreased infiltration of immune cells into EAT. Enrichment of ether lipids with oleic acid noted on metabolomic analysis suggests a reduced disposition to ferroptosis, potentially further contributing to decreased oxidative stress in EAT of SGLT-2i treated subjects. CONCLUSIONS: Our results show decreased inflammation in EAT of patients with severe heart failure treated by SGLT-2i, as compared to patients with heart failure without this therapy. Modulation of EAT inflammatory and metabolic status could represent a novel mechanism behind SGLT-2i-associated cardioprotective effects in patients with heart failure.

• Keywords
• Adipose tissue, Ether lipids, Heart failure, Inflammation, Sodium-glucose cotransporter 2 inhibitors,
• MeSH
• Anti-Inflammatory Agents therapeutic use   pharmacology   MeSH
• Biomarkers blood   MeSH
• Diabetes Mellitus, Type 2 drug therapy   metabolism   diagnosis   MeSH
• Epicardial Adipose Tissue MeSH
• Ventricular Function, Left drug effects   MeSH
• Sodium-Glucose Transporter 2 Inhibitors * therapeutic use   pharmacology   adverse effects   MeSH
• Middle Aged MeSH
• Humans MeSH
• Inflammation Mediators * metabolism   MeSH
• Metabolomics MeSH
• Pericardium * metabolism   drug effects   MeSH
• Heart Failure * metabolism   physiopathology   drug therapy   MeSH
• Severity of Illness Index * MeSH
• Stroke Volume drug effects   MeSH
• Adipose Tissue * drug effects   metabolism   MeSH
• Treatment Outcome MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Anti-Inflammatory Agents MeSH
• Biomarkers MeSH
• Sodium-Glucose Transporter 2 Inhibitors * MeSH
• Inflammation Mediators * MeSH

The 9th Cardiovascular Outcome Trial (CVOT) Summit: Congress on Cardiovascular, Kidney, and Metabolic Outcomes was held virtually on November 30-December 1, 2023. This reference congress served as a platform for in-depth discussions and exchange on recently completed outcomes trials including dapagliflozin (DAPA-MI), semaglutide (SELECT and STEP-HFpEF) and bempedoic acid (CLEAR Outcomes), and the advances they represent in reducing the risk of major adverse cardiovascular events (MACE), improving metabolic outcomes, and treating obesity-related heart failure with preserved ejection fraction (HFpEF). A broad audience of endocrinologists, diabetologists, cardiologists, nephrologists and primary care physicians participated in online discussions on guideline updates for the management of cardiovascular disease (CVD) in diabetes, heart failure (HF) and chronic kidney disease (CKD); advances in the management of type 1 diabetes (T1D) and its comorbidities; advances in the management of CKD with SGLT2 inhibitors and non-steroidal mineralocorticoid receptor antagonists (nsMRAs); and advances in the treatment of obesity with GLP-1 and dual GIP/GLP-1 receptor agonists. The association of diabetes and obesity with nonalcoholic steatohepatitis (NASH; metabolic dysfunction-associated steatohepatitis, MASH) and cancer and possible treatments for these complications were also explored. It is generally assumed that treatment of chronic diseases is equally effective for all patients. However, as discussed at the Summit, this assumption may not be true. Therefore, it is important to enroll patients from diverse racial and ethnic groups in clinical trials and to analyze patient-reported outcomes to assess treatment efficacy, and to develop innovative approaches to tailor medications to those who benefit most with minimal side effects. Other keys to a successful management of diabetes and comorbidities, including dementia, entail the use of continuous glucose monitoring (CGM) technology and the implementation of appropriate patient-physician communication strategies. The 10th Cardiovascular Outcome Trial Summit will be held virtually on December 5-6, 2024 ( http://www.cvot.org ).

• Keywords
• CGM, Cardiovascular disease, Chronic kidney disease, Diabetes, Finerenone, GLP-1 RA, Guidelines, Heart failure, MASLD, NAFLD, Obesity, SGLT2 inhibitor, Teplizumab,
• MeSH
• Renal Insufficiency, Chronic * diagnosis   epidemiology   therapy   MeSH
• Diabetes Mellitus, Type 2 * drug therapy   MeSH
• Diabetes Mellitus * drug therapy   MeSH
• Cardiovascular Diseases * diagnosis   epidemiology   prevention & control   MeSH
• Blood Glucose MeSH
• Kidney MeSH
• Humans MeSH
• Obesity complications   MeSH
• Blood Glucose Self-Monitoring MeSH
• Heart Failure * complications   MeSH
• Stroke Volume MeSH
• Check Tag
• Humans MeSH
• Publication type
• Letter MeSH
• Names of Substances
• Blood Glucose MeSH

Adverse remodelling following an initial insult is the hallmark of heart failure (HF) development and progression. It is manifested as changes in size, shape, and function of the myocardium. While cardiac remodelling may be compensatory in the short term, further neurohumoral activation and haemodynamic overload drive this deleterious process that is associated with impaired prognosis. However, in some patients, the changes may be reversed. Left ventricular reverse remodelling (LVRR) is characterized as a decrease in chamber volume and normalization of shape associated with improvement in both systolic and diastolic function. LVRR might occur spontaneously or more often in response to therapeutic interventions that either remove the initial stressor or alleviate some of the mechanisms that contribute to further deterioration of the failing heart. Although the process of LVRR in patients with new-onset HF may take up to 2 years after initiating treatment, there is a significant portion of patients who do not improve despite optimal therapy, which has serious clinical implications when considering treatment escalation towards more aggressive options. On the contrary, in patients that achieve delayed improvement in cardiac function and architecture, waiting might avoid untimely implantable cardioverter-defibrillator implantation. Therefore, prognostication of successful LVRR based on clinical, imaging, and biomarker predictors is of utmost importance. LVRR has a positive impact on prognosis. However, reverse remodelled hearts continue to have abnormal features. In fact, most of the molecular, cellular, interstitial, and genome expression abnormalities remain and a susceptibility to dysfunction redevelopment under biomechanical stress persists in most patients. Hence, a distinction should be made between reverse remodelling and true myocardial recovery. In this comprehensive review, current evidence on LVRR, its predictors, and implications on prognostication, with a specific focus on HF patients with non-ischaemic cardiomyopathy, as well as on novel drugs, is presented.

• Keywords
• Cardiac remodelling, Heart failure, Left ventricular reverse remodelling, Non-ischaemic cardiomyopathy, Predictors, Reverse remodelling,
• MeSH
• Echocardiography MeSH
• Ventricular Function, Left physiology   MeSH
• Cardiomyopathies * MeSH
• Humans MeSH
• Ventricular Remodeling physiology   MeSH
• Heart Failure * complications   etiology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

The role of metformin (MET) in the treatment of patients with advanced HFrEF and type 2 diabetes mellitus (DM) is not firmly established. We studied the impact of MET on metabolic profile, quality of life (QoL) and survival in these patients. A total of 847 stable patients with advanced HFrEF (57.4 ± 11.3 years, 67.7% NYHA III/IV, LVEF 23.6 ± 5.8%) underwent clinical and laboratory evaluation and were prospectively followed for a median of 1126 (IQRs 410; 1781) days for occurrence of death, urgent heart transplantation or mechanical circulatory support implantation. A subgroup of 380 patients (44.9%) had DM, 87 of DM patients (22.9%) were treated with MET. Despite worse insulin sensitivity and more severe DM (higher BMI, HbA1c, worse insulin resistance), MET-treated patients exhibited more stable HF marked by lower BNP level (400 vs. 642 ng/l), better LV and RV function, lower mitral and tricuspid regurgitation severity, were using smaller doses of diuretics (all p < 0.05). Further, they had higher eGFR (69.23 vs. 63.34 ml/min/1.73 m2) and better QoL (MLHFQ: 36 vs. 48 points, p = 0.002). Compared to diabetics treated with other glucose-lowering agents, MET-treated patients had better event-free survival even after adjustment for BNP, BMI and eGFR (p = 0.035). Propensity score-matched analysis with 17 covariates yielded 81 pairs of patients and showed a significantly better survival for MET-treated subgroup (p = 0.01). MET treatment in patients with advanced HFrEF and DM is associated with improved outcome by mechanisms beyond the improvement of blood glucose control.

• MeSH
• Diabetes Mellitus, Type 2 * chemically induced   complications   drug therapy   MeSH
• Insulin Resistance * MeSH
• Quality of Life MeSH
• Humans MeSH
• Metformin * therapeutic use   MeSH
• Heart Failure * MeSH
• Stroke Volume MeSH
• Treatment Outcome MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Metformin * MeSH

Sodium glucose transporter type 2 (SGLT2) molecules are found in proximal tubules of the kidney, and perhaps in the brain or intestine, but rarely in any other tissue. However, their inhibitors, intended to improve diabetes compensation, have many more beneficial effects. They improve kidney and cardiovascular outcomes and decrease mortality. These benefits are not limited to diabetics but were also found in non-diabetic individuals. The pathophysiological pathways underlying the treatment success have been investigated in both clinical and experimental studies. There have been numerous excellent reviews, but these were mostly restricted to limited aspects of the knowledge. The aim of this review is to summarize the known experimental and clinical evidence of SGLT2 inhibitors' effects on individual organs (kidney, heart, liver, etc.), as well as the systemic changes that lead to an improvement in clinical outcomes.

• Keywords
• SGLT2, SGLT2 inhibitors, chronic kidney disease, diabetes, heart failure,
• MeSH
• Diabetes Mellitus, Type 2 * drug therapy   metabolism   MeSH
• Sodium-Glucose Transporter 2 Inhibitors * pharmacology   therapeutic use   MeSH
• Glucose therapeutic use   MeSH
• Cardiovascular System * metabolism   MeSH
• Humans MeSH
• Sodium metabolism   MeSH
• Sodium-Glucose Transporter 2 metabolism   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Sodium-Glucose Transporter 2 Inhibitors * MeSH
• Glucose MeSH
• Sodium MeSH
• Sodium-Glucose Transporter 2 MeSH

The sodium-glucose cotransporter 2 inhibitor empagliflozin reduces the risk of cardiovascular death or heart failure hospitalization in patients with chronic heart failure, but whether empagliflozin also improves clinical outcomes when initiated in patients who are hospitalized for acute heart failure is unknown. In this double-blind trial (EMPULSE; NCT04157751 ), 530 patients with a primary diagnosis of acute de novo or decompensated chronic heart failure regardless of left ventricular ejection fraction were randomly assigned to receive empagliflozin 10 mg once daily or placebo. Patients were randomized in-hospital when clinically stable (median time from hospital admission to randomization, 3 days) and were treated for up to 90 days. The primary outcome of the trial was clinical benefit, defined as a hierarchical composite of death from any cause, number of heart failure events and time to first heart failure event, or a 5 point or greater difference in change from baseline in the Kansas City Cardiomyopathy Questionnaire Total Symptom Score at 90 days, as assessed using a win ratio. More patients treated with empagliflozin had clinical benefit compared with placebo (stratified win ratio, 1.36; 95% confidence interval, 1.09-1.68; P = 0.0054), meeting the primary endpoint. Clinical benefit was observed for both acute de novo and decompensated chronic heart failure and was observed regardless of ejection fraction or the presence or absence of diabetes. Empagliflozin was well tolerated; serious adverse events were reported in 32.3% and 43.6% of the empagliflozin- and placebo-treated patients, respectively. These findings indicate that initiation of empagliflozin in patients hospitalized for acute heart failure is well tolerated and results in significant clinical benefit in the 90 days after starting treatment.

• MeSH
• Benzhydryl Compounds adverse effects   MeSH
• Diabetes Mellitus, Type 2 * drug therapy   MeSH
• Double-Blind Method MeSH
• Ventricular Function, Left MeSH
• Sodium-Glucose Transporter 2 Inhibitors * adverse effects   MeSH
• Glucosides MeSH
• Hospitalization MeSH
• Humans MeSH
• Heart Failure * MeSH
• Stroke Volume MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Randomized Controlled Trial MeSH
• Names of Substances
• Benzhydryl Compounds MeSH
• empagliflozin MeSH Browser
• Sodium-Glucose Transporter 2 Inhibitors * MeSH
• Glucosides MeSH