Circulating Biomarkers in Pulmonary Arterial Hypertension: An Update.

Pulmonary arterial hypertension (PAH) is a rare subtype of group 1 pulmonary hypertension (PH) diseases, characterized by high pulmonary artery pressure leading to right ventricular dysfunction and potential life-threatening consequences. PAH involves complex mechanisms: vasoconstriction, vascular remodeling, endothelial dysfunction, inflammation, oxidative stress, fibrosis, RV remodeling, cellular hypoxia, metabolic imbalance, and thrombosis. These mechanisms are mediated by several pathways, involving molecules like nitric oxide and prostacyclin. PAH diagnosis requires clinical evaluation and right heart catheterization, confirming a value of mPAP ≥ 20 mmHg at rest and often elevated pulmonary vascular resistance (PVR). Even if an early and accurate diagnosis is crucial, PAH still lacks effective biomarkers to assist in its diagnosis and prognosis. Biomarkers could contribute to arousing clinical suspicion and serve for prognosis prediction, risk stratification, and dynamic monitoring in patients with PAH. The aim of the present review is to report the main novelties on new possible biomarkers for the diagnosis, prognosis, and treatment monitoring of PAH.

Prognostic implication of lung ultrasound in heart failure: pooled analysis of international cohorts.

BACKGROUND: Lung ultrasound (LUS) is often used to assess congestion in heart failure (HF). In this study, we assessed the prognostic role of LUS in HF patients at admission and hospital discharge, and in an out-patient setting and explored whether clinical factors (age, sex, left ventricular ejection fraction (LVEF) and atrial fibrillation) impact the prognostic value of LUS findings. Further, we assessed the incremental prognostic value of LUS on top of AHEAD and MAGGIC clinical risk scores. METHODS AND RESULTS: We pooled data of patients hospitalized for HF or followed-up in out-patient clinics from international cohorts. We enrolled 1,947 patients, at admission (n=578), discharge (n=389) and in out-patient clinic (n=980). Total LUS B-line count was calculated for the 8-zone scanning protocol. The primary outcome was a composite of re-hospitalization for HF and all-cause death. Compared to those in the lower tertiles of B-lines, patients in the highest tertile were older, more likely to have signs of HF and higher NT-proBNP levels. A higher number of B-lines was associated with increased risk of primary outcome at discharge (Tertile3 vs Tertile1: adjustedHR= 5.74 (3.26- 10.12), p<0.0001) and in out-patients (Tertile3 vs Tertile1: adjustedHR= 2.66 (1.08- 6.54), p=0.033). Age and LVEF did not influence the prognostic capacity of LUS in different clinical settings. Adding B-line count to MAGGIC and AHEAD scores improved net reclassification significantly in all three clinical settings. CONCLUSION: A higher number of B-lines in patients with HF was associated with increased risk of morbidity and mortality, regardless of the clinical setting.

Right ventricular dysfunction in chronic heart failure: clinical laboratory and echocardiographic characteristics. (the RIVED-CHF registry).

BACKGROUND: Right ventricular dysfunction (RVD) and pulmonary hypertension have been recognized as two important prognostic features in patients with left side heart failure. Current literature does not distinguish between right heart failure (RHF) and RVD, and the two terms are used indiscriminately to describe pulmonary hypertension and RVD as well as clinical sign of RHF. Therefore, the right ventricle (RV) adaptation across the whole spectrum of left ventricular ejection fraction (LVEF) values has been poorly investigated. METHODS: This is a multicenter observational prospective study endorsed by the Italian Society of Cardiology aiming to analyze the concordance between the signs and symptoms of RHF and echocardiographic features of RVD. The protocol will assess patients affected by chronic heart failure in stable condition regardless of the LVEF threshold by clinical, laboratory, and detailed echocardiographic study. During the follow-up period, patients will be observed by direct check-up visit and/or virtual visits every 6 months for a mean period of 3 years. All clinical laboratory and echocardiographic data will be recorded in a web platform system accessible for all centers included in the study. RESULTS: The main study goals are: to investigate the concordance and discordance between clinical signs of RHF and RVD measured by ultrasonographic examination; to evaluate prognostic impact (in terms of cardiovascular mortality and heart failure hospitalization) of RVD and RHF during a mean follow-up period of 3 years; to investigate the prevalence of different right ventricular maladaptation (isolated right ventricular dilatation, isolated pulmonary hypertension, combined pattern) and the related prognostic impact. CONCLUSIONS: With this protocol, we would investigate the three main RVD patterns according to heart failure types and stages; we would clarify different RVD and pulmonary hypertension severity according to the heart failure types. Additionally, by a serial multiparametric analysis of RV, we would provide a better definition of RVD stage and how much is it related with clinical signs of RHF (ClinicalTrials.gov Identifier: NCT06002321).

Poor in-hospital congestion improvement in acute heart failure patients classified according to LVEF: prognostic implications.

BACKGROUND: Residual congestion in acute heart failure (AHF) is associated with poor prognosis. However, there is a lack of data on the prognostic value of changes in a combined assessment of in-hospital congestion. The present study sought to assess the association between in-hospital congestion changes and subsequent prognosis according to left ventricular ejection fraction (LVEF) classification. METHODS: Patients (N=244, 80.3±7.6 years, 50.8% male) admitted for acute HF in two European tertiary care centers underwent clinical assessment (congestion score included dyspnea at rest, rales, third heart sound, jugular venous distention, peripheral edema and hepatomegaly; simplified congestion score included rales and peripheral edema), echocardiography, lung ultrasound (LUS) and natriuretic peptides (NP) measurement at admission and discharge. The primary outcome was a composite of all-cause mortality and/or HF re-hospitalization. RESULTS: In the 244 considered patients (95 HF with reduced EF, 57 HF with mildly reduced EF and 92 HF with preserved EF), patients with limited improvement in clinical congestion score (hazard ratio 2.33, 95%CI 1.51 to 3.61, p=0.0001), NP levels (2.29, 95%CI 1.55 to 3.38, p<0.0001) and the number of B-lines (6.44, 95%CI 4.19 to 9.89, p<0.001) had a significantly higher risk of outcome compared to patients experiencing more sizeable decongestion. The same pattern of association was observed when adjusting for confounding factors. A limited improvement in clinical congestion score and in the number of B-lines was related to poor prognosis for all LVEF categories. CONCLUSIONS: In AHF, the degree of congestion reduction assessed over the in-hospital stay period can stratify the subsequent event risk. Limited reduction in both clinical congestion and B-lines number are related to poor prognosis, irrespective of HF subtype.

Beyond Natriuretic Peptides: Unveiling the Power of Emerging Biomarkers in Heart Failure.

Heart failure (HF) represents a significant global health challenge, characterized by high morbidity and mortality rates, and imposes considerable burdens on healthcare systems and patient quality of life. Traditional management strategies, primarily relying on clinical assessments and standard biomarkers like natriuretic peptides, face limitations due to the heterogeneity of HF. This review aims to delve into the evolving landscape of non-natriuretic biomarkers and the transformative potential of omics technologies, underscoring their roles in advancing HF treatment towards precision medicine. By offering novel insights into the biological underpinnings of HF, including inflammation, myocardial stress, fibrosis, and metabolic disturbances, these advancements facilitate more accurate patient phenotyping and individualized treatment strategies. The integration of non-natriuretic biomarkers and omics technologies heralds a pivotal shift in HF management, enabling a move towards tailored therapeutic interventions. This approach promises to enhance clinical outcomes by improving diagnostic accuracy, risk stratification, and monitoring therapeutic responses. However, challenges such as the variability in biomarker levels, cost-effectiveness, and the standardization of biomarker testing across different healthcare settings pose hurdles to their widespread adoption. Despite these challenges, the promise of precision medicine in HF, driven by these innovative biomarkers and technologies, offers a new horizon for improving patient care and outcomes. This review advocates for the further integration of these advancements into clinical practice, highlighting the need for ongoing research to fully realize their potential in transforming the landscape of heart failure management.

The Changing Role of Loop Diuretics in Heart Failure Management across the Last Century.

Congestion is the main therapeutic target of acute heart failure (HF) treatment, and loop diuretics (LDs) are widely used drugs for this purpose. Despite their extensive use, these agents remain largely understudied in terms of modality administration, treatment duration, and escalation dose for subjects responding poorly to therapy. LDs were initially investigated in several edematous statuses such as cirrhosis, nephrotic syndrome, and congestive HF and initially approved for the treatment of cardiogenic congestion in 1966. Despite the long history and the undoubted role in congestion management, the use of LDs in the acute phase is mostly based on the physician's experience, the oral amount chronically administered, and clinical decongestion response. Recent literature suggests monitoring diuretic activity by the evaluation of daily diuresis, weight loss, and sample urinary sodium assessment after early intravenous LD administration. More recently, the measurement of urinary sodium integrated with urinary and blood creatinine values and fluid status has been suggested as optimal marker to predict whole diuretic efficiency and to target the optimal dose. However, this method is not easily available in the chronic setting or in patients with recurrent hospitalization taking a high loop diuretic amount. Since high loop diuretic dose is related to diuretic resistance (DR) and poorer outcome, additional diuretics acting in different nephron sites are often required. Current sequential nephron blockade can stimulate diuresis by synergic mechanisms. This strategy is attempted in patients with poor response, revealing good results in the early period, but the effects of neuro-endocrine stimulation and electrolyte balance across long-term follow-up are still questioned. This paper reviews the historical course of loop diuretics and highlights the need for a universal approach based on clinical conditions, cardio-renal interactions, and HF phenotypes.

Cardiovascular Biomarkers in Cardio-Oncology: Antineoplastic Drug Cardiotoxicity and Beyond.

Serum biomarkers represent a reproducible, sensitive, minimally invasive and inexpensive method to explore possible adverse cardiovascular effects of antineoplastic treatments. They are useful tools in risk stratification, the early detection of cardiotoxicity and the follow-up and prognostic assessment of cancer patients. In this literature review, we aim at describing the current state of knowledge on the meaning and the usefulness of cardiovascular biomarkers in patients with cancer; analyzing the intricate relationship between cancer and cardiovascular disease (especially HF) and how this affects cardiovascular and tumor biomarkers; exploring the role of cardiovascular biomarkers in the risk stratification and in the identification of chemotherapy-induced cardiotoxicity; and providing a summary of the novel potential biomarkers in this clinical setting.

Multi-modality assessment of congestion in acute heart failure: Associations with left ventricular ejection fraction and prognosis.

BACKGROUND: Integrating clinical examination with ultrasound measures of congestion could improve risk stratification in patients hospitalized with acute heart failure (AHF). AIM: To investigate the prevalence of clinical, echocardiographic and lung ultrasound (LUS) signs of congestion according to left ventricular ejection fraction (LVEF) and their association with prognosis in patients with AHF. METHODS: We pooled the data of four cohorts of patients (N = 601, 74.9±10.8 years, 59 % men) with AHF and analysed six features of congestion at enrolment: clinical (peripheral oedema and respiratory rales), biochemical (BNP/NT-proBNP≥median), echocardiographic (inferior vena cava (IVC)≥21 mm, pulmonary artery systolic pressure (PASP)≥40 mmHg, E/e'≥15) and B-lines ≥25 (8-zones) in those with reduced (<40 %, HFrEF), mildly reduced (40-49 %, HFmrEF and preserved (≥50 %HFpEF) LVEF. RESULTS: Compared to patients with HFmrEF (n = 110) and HFpEF (n = 201), those with HFrEF (N = 290) had higher natriuretic peptides, but prevalence of clinical (39 %), echocardiographic (IVC≥21 mm: 56 %, E/e'≥15: 57 %, PASP≥40 mmHg: 76 %) and LUS (48 %) signs of congestion was similar. In multivariable analysis, clinical (HR: 3.24(2.15-4.86), p < 0.001), echocardiographic [(IVC≥21 mm (HR:1.91, 1.21-3.03, p=0.006); E/e'≥15 (HR:1.54, 1.04-2.28, p = 0.031)] and LUS (HR:2.08, 1.34-3.24, p = 0.001) signs of congestion were significantly associated with all-cause mortality and/or HF re-hospitalization. Adding echocardiographic and LUS features of congestion to a model than included age, sex, systolic blood pressure, clinical congestion and natriuretic peptides, improved prediction at 90 and 180 days. CONCLUSIONS: Clinical and ultrasound signs of congestion are highly prevalent in patients with AHF, regardless of LVEF and their combined assessment improves risk stratification.

The role and application of current pharmacological management in patients with advanced heart failure.

In the last decades, several classifications and definitions have been proposed for advanced heart failure (ADVHF) patients, including clinical, functional, hemodynamic, imaging, and electrocardiographic features. Despite different inclusion criteria, ADVHF is characterized by some common items, such as drug intolerance, low arterial pressure, multiple organ dysfunction, chronic kidney disease, and diuretic use dependency. Additional features include fatigue, hypotension, hyponatremia, and unintentional weight loss associated with a specific laboratory profile reflecting systemic multiorgan dysfunction. Notably, studies evaluating guideline-directed medical therapy recently endorsed by guidelines in stable HF, including the 4 drug classes all together (i.e., betablocker, mineral corticoid antagonist, renin angiotensin inhibitors/neprilysin inhibitors, and sodium glucose transporter inhibitors), remain scarcely analyzed in ADVHF and New York Heart Association (NYHA) Class IV. Additionally, due to the common conditions associated with advanced stages, the balance between drug tolerance and potential benefits of the contemporary use of all agents is questioned. Therefore, less hard endpoints, such as exercise tolerance, quality of life (QoL) and self-competency, are not clearly demonstrated. Specific analyses evaluating outcome and rehospitalization of each drug provided conflicting results and are often limited to subjects with stable conditions and less advanced NYHA class. Current European Society of Cardiology/American Heart Association (ESC/AHA) Guidelines do not indicate the type of treatment, dosage, and administration modalities, and they do not suggest specific indications for ADVHF patients. Due to these concerns, there is an impelling need to understand what drugs may be used as the first line, what management leads to the better outcome, and what is the best treatment algorithm in this setting. In this paper, we summarize the most common pitfalls and limitations for the use of the traditional agents, and we propose a personalized approach aiming at preserve drug tolerance and maintaining adverse event protection and satisfactory QoL.

Patient phenotype profiling using echocardiography and natriuretic peptides to personalise heart failure therapy.

Heart failure (HF) is a progressive condition with a clinical picture resulting from reduced cardiac output (CO) and/or elevated left ventricular (LV) filling pressures (LVFP). The original Diamond-Forrester classification, based on haemodynamic data reflecting CO and pulmonary congestion, was introduced to grade severity, manage, and risk stratify advanced HF patients, providing evidence that survival progressively worsened for those classified as warm/dry, cold/dry, warm/wet, and cold/wet. Invasive haemodynamic evaluation in critically ill patients has been replaced by non-invasive haemodynamic phenotype profiling using echocardiography. Decreased CO is not infrequent among ambulatory HF patients with reduced ejection fraction, ranging from 23 to 45%. The Diamond-Forrester classification may be used in combination with the evaluation of natriuretic peptides (NPs) in ambulatory HF patients to pursue the goal of early identification of those at high risk of adverse events and personalise therapy to antagonise neurohormonal systems, reduce congestion, and preserve tissue/renal perfusion. The most benefit of the Guideline-directed medical treatment is to be expected in stable patients with the warm/dry profile, who more often respond with LV reverse remodelling, while more selective individualised treatments guided by echocardiography and NPs are necessary for patients with persisting congestion and/or tissue/renal hypoperfusion (cold/dry, warm/wet, and cold/wet phenotypes) to achieve stabilization and to avoid further neurohormonal activation, as a result of inappropriate use of vasodilating or negative chronotropic drugs, thus pursuing the therapeutic objectives. Therefore, tracking the haemodynamic status over time by clinical, imaging, and laboratory indicators helps implement therapy by individualising drug regimens and interventions according to patients' phenotypes even in an ambulatory setting.

Heart failure 'the cancer of the heart': the prognostic role of the HLM score.

AIMS: The multi-systemic effects of heart failure (HF) resemble the spread observed during cancer. We propose a new score, named HLM, analogous to the TNM classification used in oncology, to assess the prognosis of HF. HLM refers to H: heart damage, L: lung involvement, and M: systemic multiorgan involvement. The aim was to compare the HLM score to the conventional New York Heart Association (NYHA) classification, American College of Cardiology/American Heart Association (ACC/AHA) stages, and left ventricular ejection fraction (LVEF), to assess the most accurate prognostic tool for HF patients. METHODS AND RESULTS: We performed a multicentre, observational, prospective study of consecutive patients admitted for HF. Heart, lung, and other organ function parameters were collected. Each patient was classified according to the HLM score, NYHA classification, ACC/AHA stages, and LVEF assessed by transthoracic echocardiography. The follow-up period was 12 months. The primary endpoint was a composite of all-cause death and rehospitalization due to HF. A total of 1720 patients who completed the 12 month follow-up period have been enrolled in the study. 520 (30.2%) patients experienced the composite endpoint of all-cause death and rehospitalization due to HF. 540 (31.4%) patients were female. The mean age of the study population was 70.5 ± 12.9. The mean LVEF at admission was 42.5 ± 13%. Regarding the population distribution across the spectrum of HLM score stages, 373 (21.7%) patients were included in the HLM-1, 507 (29.5%) in the HLM-2, 587 (34.1%) in the HLM-3, and 253 (14.7%) in the HLM-4. HLM was the most accurate score to predict the primary endpoint at 12 months. The area under the receiver operating characteristic curve (AUC) was greater for the HLM score compared with the NYHA classification, ACC/AHA stages, or LVEF, regarding the composite endpoint (HLM = 0.645; NYHA = 0.580; ACC/AHA = 0.589; LVEF = 0.572). The AUC of the HLM score was significantly better compared with the LVEF (P = 0.002), ACC/AHA (P = 0.029), and NYHA (P = 0.009) AUC. CONCLUSIONS: The HLM score has a greater prognostic power compared with the NYHA classification, ACC/AHA stages, and LVEF assessed by transthoracic echocardiography in terms of the composite endpoint of all-cause death and rehospitalization due to HF at 12 months of follow-up.

Usefulness of Combined Ultrasound Assessment of E/e' Ratio, Pulmonary Pressure, and Cava Vein Status in Patients With Acute Heart Failure.

Congestion is poorly investigated by ultrasound scans during acute heart failure (AHF) and systematic studies evaluating ultrasound indexes of cardiac pulmonary and systemic congestion during early hospital admission are lacking. We aimed to investigate the prevalence of ultrasound cardiac pulmonary and systemic congestion in a consecutive cohort of hospitalized patients with AHF, analyzing the relevance of each ultrasound congestion component (cardiac, pulmonary, and systemic) in predicting the risk of death and rehospitalization. This is a prospective research study of a single center that evaluates patients with an AHF diagnosis who are divided according to the left ventricular ejection fraction in patients with heart failure with preserved ejection fraction or reduced ejection fraction. We performed a complete bedside echocardiography and lung ultrasound analyses within the first 24 hours of hospital admission. The ultrasound congestion score was preliminarily established by measuring the following parameters: cardiac congestion, which was defined as the contemporary presence of E/e' >15 and pulmonary systolic pressure >35 mm Hg and the pulmonary congestion, defined as the total B-line number >25 at the lung ultrasound performed in 8 chest sites; moreover, the systemic congestion was defined if the inferior vena cava (IVC) was >21 mm and if it was associated with a reduced inspiratory collapse >50%. We thoroughly assessed 230 patients and evaluated their results. Of these patients, 135 had heart failure with reduced ejection fraction and there were 95 patients with heart failure with preserved ejection fraction; 122 patients experienced adverse events during the 180-day follow-up. The receiver operating characteristic curve analysis showed that the tricuspid annular peak systolic excursion (TAPSE) (area under the curve [AUC] 0.34 [0.26 to 0.41], p <0.001), E/e' (AUC 0.62 [0.54 to 0.69], p = 0.003), and IVC (AUC 0.70 [0.63 to 0.77], p <0.001) were all significantly related to poor prognosis detection. The univariate Cox regression analysis revealed that cardiac congestion in terms of E/e' and pulmonary systolic pressure (hazard ratio [HR] 1.49 [1.02 to 2.17], p = 0.037), TAPSE (HR 0.90 [0.85 to 0.94], p <0.001), and systemic congestion (HR 2.64 [1.53 to 4.56], p <0.001) were all significantly related to the 180-day outcome. After adjustment for potential confounders, only TAPSE (HR 0.92 [0.88 to 0.98], p = 0.005) and IVC (HR 1.92 [1.07 to 3.46], p = 0.029) confirmed their prognostic role. The multivariable analysis of multiple congestion levels in terms of systemic plus cardiac (HR 1.54 [1.05 to 2.25], p = 0.03), systemic plus pulmonary (HR 2.26 [1.47 to 3.47], p <0.001), and all 3 congestion features (HR 1.53 [1.06 to 2.23], p = 0.02) revealed an incremental prognostic role for each additional determinant. In conclusion, among the ultrasound indexes of congestion, IVC and TAPSE are related to adverse prognosis, and the addition of pulmonary and cardiac congestion indexes increases the risk prediction accuracy. Our data confirmed that right ventricular dysfunction and systemic congestion are the most powerful predictive factors in AHF.

Risk Factors and Cellular Differences in Heart Failure: The Key Role of Sex Hormones.

Patients with heart failure are conventionally stratified into phenotypic groups based on their ejection fraction. The aim of this stratification is to improve disease management with a more targeted therapeutic approach. A further subdivision based on patient gender is justified. It is recognized that women are underrepresented in randomized controlled clinical trials, resulting in limited clinical and molecular differentiation between males and females. However, many observational studies show that the onset, development, and clinical course of the disease may substantially differ between the two sexes. According to the emerging concept of precision medicine, investigators should further explore the mechanisms responsible for the onset of heart failure due to sex differences. Indeed, the synergistic or opposing effects of sex hormones on the cardiovascular system and underlying heart failure mechanisms have not yet been clarified. Sex hormones, risk factors impact, and cardiovascular adaptations may be relevant for a better understanding of the intrinsic pathophysiological mechanisms in the two sexes. Despite the differences, treatment for HF is similar across the whole population, regardless of sex and gender. In our review, we describe the main differences in terms of cardiovascular dysfunction, risk factors, and cellular signaling modifications related to the hormonal pattern.

Effect of sacubitril/valsartan on cardiac remodeling compared with other renin-angiotensin system inhibitors: a difference-in-difference analysis of propensity-score matched samples.

BACKGROUND: In patients with heart failure with reduced ejection fraction (HFrEF), treatment with sacubitril-valsartan (S/V) may reverse left ventricular remodeling (rLVR). Whether this effect is superior to that induced by other renin-angiotensin system (RAS) inhibitors is not well known. METHODS: HFrEF patients treated with S/V (n = 795) were compared, by propensity score matching, with a historical cohort of 831 HFrEF patients (non-S/V group) treated with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (RAS inhibitors). All patients were also treated with beta-blockers and shared the same protocol with repeat echocardiogram 8-12 months after starting therapy. The difference-in-difference (DiD) analysis was used to evaluate the impact of S/V on CR indices between the two groups. RESULTS: After propensity score matching, compared to non-S/V group (n = 354), S/V group (n = 354) showed a relative greater reduction in end-diastolic and end-systolic volume index (ESVI), and greater increase in ejection fraction (DiD estimator = + 5.42 mL/m2, P = 0.0005; + 4.68 mL/m2, P = 0.0009, and + 1.76%, P = 0.002, respectively). Reverse LVR (reduction in ESVI ≥ 15% from baseline) was more prevalent in S/V than in non-S/V group (34% vs 26%, P = 0.017), while adverse LVR (aLVR, increase in ESVI at follow-up ≥ 15%) was more frequent in non-S/V than in S/V (16% vs 7%, P < 0.001). The beneficial effect of S/V on CR over other RAS inhibitors was appreciable across a wide range of patient's age and baseline end-diastolic volume index, but it tended to attenuate in more dilated left ventricles (P for interaction = NS for both). CONCLUSION: In HFrEF patients treated with beta-blockers, sacubitril/valsartan is associated with a relative greater benefit in LV reverse remodeling indices than other RAS inhibitors.

Different right ventricular dysfunction and pulmonary coupling in acute heart failure according to the left ventricular ejection fraction.

BACKGROUND: Right ventricular (RV) dysfunction and pulmonary uncoupling are two acknowledged features associated with poor outcome, however few data defined RV adaptation across the different left ventricular ejection fraction (EF) cut-off. Additionally, less data are reported in patients with acute heart failure (AHF). AIMS: The aim of present study was to analyse RV function in AHF patients presenting with either reduced or preserved EF. METHODS: This is a multi-center observational study including 380 patients affected by AHF: 235 had AHF with reduced EF (AHFrEF) and 145 had AHF with preserved EF (AHFpEF). Pulmonary artery systolic pressure (PASP), tricuspid annular plane systolic excursion (TAPSE), S' wave velocity, and the RV end-diastolic diameter (RVEDD) were measured by echocardiography. TAPSE/PASP and S'/PASP ratios were calculated as non-invasive surrogates of RV-pulmonary arterial coupling. RESULTS: Factors associated with poor outcome were higher values of PASP (45 [40-55] mmHg vs 40 [35-46] mmHg; p < 0.001), RVEDD (44 [38-47] mm vs 37 [35-42] mm; p < 0.001), lower TAPSE values (17 [15-20] mm vs 20 [18-22] mm; p < 0.001) and S' wave (10 [8-12] cm/s vs 11 [10-13] cm/s; p < 0.001), reduced TAPSE/PASP (0.37 [0.29-0.47] vs 0.50 [0.40-0.60]; p < 0.001) and S'/PASP ratios (0.22 [0.18-0.28] vs 0.28 [0.22-0.34]; p < 0.001). However, the prognostic parameters differed according to the LVEF value: in AHFpEF S'/PASP between 0.22 and 0.29 and > 0.29 demonstrated a protective prognostic value (Respectively HR 0.29 (0.16-0.53), p < 0.001 and HR 0.22 [0.12-0.42], p < 0.001). Conversely, in AHFrEF, TAPSE <16 mm (HR 2.59 [1.67-4.03], p < 0.001), ICV > 21 mm (HR 1.17 [1.17-1.28], p = 0.001) and TAPSE/PASP <0.49 HR 1.92 [1.10-3.37], p = 0.023) were related to adverse outcome. CONCLUSIONS: RV adaptation and RV pulmonary coupling differ in AHF according to the level of LVEF. S' wave, and S'/PASP are associated with adverse outcome in patients with preserved EF; reduced TAPSE and TAPSE/PASP are better prognostic predictors in patients with reduced EF.

Vitamin D Deficiency and Cardiovascular Mortality: Retrospective Analysis "Siena Osteoporosis" Cohort.

Vitamin D is a fat-soluble vitamin that plays a key role in bone metabolism, particularly concerning the regulation of calcium and phosphate homeostasis. Cardiovascular disease (CVD) is the main cause of morbidity and mortality in Western countries. Knowledge of the role of vitamin D in CVD arose from evidence of the vitamin D receptor (VDR) inside the cardiovascular system. In this retrospective analysis, we investigated the relationships between vitamin D status and hospitalization for heart failure (HF), overall mortality and cardiovascular mortality. Between 2004 and 2009, age-stratified, random sampling of elderly men and postmenopausal women in the primary care registers of Siena residents was performed. In total, 174 males (mean ± SD, 65.9 ± 6 years) and 975 females (62.5 ± 6 years) were enrolled in the study. We investigated the association between 25OHD status and hospitalization for HF or causes of mortality. A total of 51 subjects (12 males and 39 females) had been hospitalized for acute HF. At the end of the survey, 931 individuals were alive, while 187 had died (43 males and 144 females). A greater proportion of deceased patients showed low 25OHD (particularly patients with levels below 20 ng/mL). A similar trend was observed concerning the prevalence of patients with 25OHD levels below 20 ng/mL who died from stroke (RR = 2.15; 95% CIs 0.98-4.69; p = 0.06). Low 25OHD levels may be predictive of cardiovascular mortality. Whether vitamin deficiency represents a primitive cause or is a simple bystander in increased cardiovascular mortality should be further investigated in prospective large cohort studies specifically designed to assess CVD risk, including a detailed assessment of cardiac dysfunction and the characterization of atherosclerotic lesions.

The role of fibrosis, inflammation, and congestion biomarkers for outcome prediction in candidates to cardiac resynchronization therapy: is "response" the right answer?

Background: Cardiac resynchronization therapy (CRT) is an established treatment in selected patients suffering from heart failure with reduced ejection fraction (HFrEF). It has been proposed that myocardial fibrosis and inflammation could influence CRT "response" and outcome. Our study investigated the long-term prognostic significance of cardiac biomarkers in HFrEF patients with an indication for CRT. Methods: Consecutive patients referred for CRT implantation were retrospectively evaluated. The soluble suppression of tumorigenicity 2 (sST2), galectin-3 (Gal-3), N-terminal portion of the B-type natriuretic peptide (NT-proBNP), and estimated glomerular filtration rate (eGFR) were measured at baseline and after 1 year of follow-up. Multivariate analyses were performed to evaluate their correlation with the primary composite outcome of cardiovascular mortality and heart failure hospitalizations at a mean follow-up of 9 ± 2 years. Results: Among the 86 patients enrolled, 44% experienced the primary outcome. In this group, the mean baseline values of NT-proBNP, Gal-3, and sST2 were significantly higher compared with the patients without cardiovascular events. At the multivariate analyses, baseline Gal-3 [cut-off: 16.6 ng/ml, AUC: 0.91, p < 0.001, HR 8.33 (1.88-33.33), p = 0.005] and sST2 [cut-off: 35.6 ng/ml AUC: 0.91, p < 0.001, HR 333 (250-1,000), p = 0.003] significantly correlated with the composite outcome in the prediction models with high likelihood. Among the parameters evaluated at 1-year follow-up, sST2, eGFR, and the variation from baseline to 1-year of Gal-3 levels showed a strong association with the primary outcome [HR 1.15 (1.08-1.22), p < 0.001; HR: 0.84 (0.74-0.91), p = 0.04; HR: 1.26 (1.10-1.43), p ≤ 0.001, respectively]. Conversely, the echocardiographic definition of CRT response did not correlate with any outcome. Conclusion: In HFrEF patients with CRT, sST2, Gal-3, and renal function were associated with the combined endpoint of cardiovascular death and HF hospitalizations at long-term follow-up, while the echocardiographic CRT response did not seem to influence the outcome of the patients.

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.