Lower Extremity Lymphatic Flow/Drainage Assessment by Indocyanine Green Fluorescent Lymphography in Heart Failure Patients.

The purpose of this study was to present a protocol for visualizing lymphatic flow in patients with heart failure (HF) by using indocyanine green fluorescence lymphography. We studied 37 subjects: 20 patients with acute heart failure (AHF) and lower limb edema, 7 patients with chronic heart failure (CHF) without lower limb edema, and 10 control subjects (no HF, no limb edema). All subjects were assessed at rest, and 11 subjects (6 control and 5 with CHF) were assessed again after a 10-minute walk. The lymph flow was visualized in all selected patients without complications. At rest, there was either no lymph flow or minimal lymph flow in all control subjects and patients with CHF, whereas the majority of patients with AHF demonstrated significant lymph flow. This study describes a new method to visualize/assess lymphatic flow in patients with HF, allowing for continuous, real-time tracking of lymphatic flow in the lower extremity.

Spot urine sodium-to-creatinine ratio surpasses sodium in identifying poor diuretic response in acute heart failure.

AIMS: We aim to identify the most accurate marker for early prediction of poor diuretic response in acute heart failure (AHF) patients with signs of congestion requiring intravenous diuretic treatment. METHODS: In this single-centre, prospective observational study, AHF patients with signs of congestion received a standardized intravenous furosemide dose (1 mg/kg of body weight; 40 mg in bolus and remaining dose in 2 h continuous infusion). Subsequently, we assessed spot urine composition at 2 h post-administration, comparing it with total urine output at 6 h. Various potential urine markers were analysed for predicting urine output using receiver operating characteristic (ROC) curves and logistic regression models. We investigated guideline-recommended markers, including spot urine sodium (UNa+) and its cut-off, and introduced the UNa+/UCr (urine creatinine concentration) ratio adjusting UNa+ for urine dilution. RESULTS: Out of 111 patients (85% males, 66.4 ± 13.9 years old, NTproBNP 7290 [4493-14 582] pg/ml), there were 18 (16%) with a poor diuretic response (cumulative urine output <600 ml during the first 6 h). The mean 6 h cumulative diuresis in patients with poor and good diuretic response was 406 ± 142 and 2114 ± 1164 ml, respectively, P < 0.005. After an initial evaluation of several potential biomarkers, only UNa+, UCr and UNa+/UCr were selected as candidates with the highest predictive value. The cut-off for UNa+ adjusted for urine dilution: UNa+/UCr ratio <0.167 mmol/mg × 10-1 was determined by ROC analysis with the highest area under the curve (95% confidence interval): 0.956 (0.915-0.997), P < 0.001. When compared with the guideline-recommended cut-off (UNa+ <50 mmol/L as a reference, specificity-0.97; sensitivity-0.83), the odds ratio (OR) for UNa+/UCreat to identify a poor diuretic response was 2.5 times greater, regardless of kidney function (OR for estimated glomerular filtration rate in the logistic regression model was 0.978 [0.945-1.013, P = 0.222]). CONCLUSIONS: The UNa+/UCr ratio in a spot urine sample 2 h after intravenous diuretic administration is a simple, highly predictive marker for the identification of AHF patients with poor diuretic response, surpassing guidelines-recommended markers like UNa+.

The role of urine chloride in acute heart failure.

In our retrospective study, we aimed to investigate the relationship between urinary chloride (uCl-) and selected clinical and laboratory biomarkers, renal function, and patient outcomes in the acute heart failure (AHF) population. We divided 248 adult patients (≥ 18 years) with AHF into two groups: low uCl- (< 115 mmol/L) and high uCl-. The mean age of the patient group was 70.2 ± 12.6, and 182 patients were male (73.4%). Clinical endpoints included in-hospital mortality, one-year mortality, and a composite endpoint of one-year mortality and rehospitalization for heart failure. Patients were followed up for at least one year. Relevant clinical and baseline biomarker data were collected, including markers concerning inflammation, liver and kidney function, perfusion and congestion, iron status, cardiac remodeling, gasometry, renin and aldosterone. Low uCl- was associated with worse in-hospital outcomes, including higher in-hospital mortality (7.7% vs. 1.4%, p = 0.014), the need for inotropic support (20.19% vs. 2.08%, p ≤ 0.001), worsening of HF during therapy (17.31% vs. 4.86%, p ≤ 0.001), and the need for treatment in an intensive cardiac care unit (33.65% vs. 15.28%, p ≤ 0.001). Low uCl- was a significant predictor of one-year mortality (40.4% vs. 16.7%, p < 0.05) and the composite outcome (HR 2.42, 95% CI 1.43-4.08, p < 0.001). In the multivariable analysis, uCl- was independently associated with the risk of one-year mortality (HR 0.92, 95% CI 0.87-0.98, p < 0.05) and the composite outcome (HR 0.95, 95% CI 0.92-0.99, p < 0.05). Our findings suggest that low uCl- is a marker of more advanced heart failure, activation of the renin-angiotensin-aldosterone system and is related to worse one-year outcomes.

The early safety profile of simultaneous vaccination against influenza and Respiratory Syncytial Virus (RSV) in patients with high-risk heart failure.

The safety of simultaneous vaccination for Respiratory Syncytial Virus (RSV) and influenza in vulnerable high-risk heart failure (HF) patients remains unclear. In an open-label, prospective study, 105 patients received concurrent influenza (Vaxigrip Tetra, season 2023/2024, Sanofi) and RSV (Arexvy, GSK) vaccinations from September 15th to November 17th, 2023. Adverse events were collected on the fourth-day post-vaccination. Overall, the vaccination was well tolerated, with the most common reaction being injection site pain (63 %). General symptoms occurred in 33 % of patients, predominantly fatigue (23 %), myalgia (12 %), and headache (9 %). Grade 3 reactions were observed in 6 % of patients, and a few experienced temperature elevation or flu-like symptoms, managing them with antipyretics. Notably, there were no exacerbations of HF, hospitalizations, or deaths within a week post-vaccination. This study indicates the safety of simultaneous influenza and RSV vaccination in high-risk HF patients, with a low incidence of mild adverse events.

Spot urine sodium as a marker of urine dilution and decongestive abilities in acute heart failure.

The decongestion ability in response to diuretic treatment plays a crucial role in the treatment of acute heart failure. This effectiveness is evaluated through the assessment of sodium concentration and urine volume, which are also treatment goals themselves. However, the bidirectional interconnection between these factors remains not fully understood. The objective of this study is to provide mechanistic insights into the correlation between spot urine sodium concentrations (UNa+) and urine dilution. This aims to better understand of the decongestive abilities in acute heart failure (AHF). The study was single-center, prospective, conducted on a group of 50 AHF patients. Each participant received a standardized furosemide dose of 1 mg per kg of body weight. Hourly diuresis was measured in the first 6 h of the study, and urine composition was assessed at predefined timepoints. The study group presented the exponential (rather than linear) pattern of relationship between UNa+ and 6-h urine volume, whereas relationship between eGFR and 6-h urine volume was linear (r = 0.61, p < 0.001). The relationship between UNa+ and all other analyzed indices of urine dilution, including the change from baseline in urine creatinine concentration, urine osmolarity, and urine osmolarity corrected for urine sodium, also exhibited an exponential relationship. Patients who were chronically exposed to furosemide demonstrated a significantly lower urine dilution (1.78 [1.18-3.54] vs 11.58 [3.9-17.88]; p < 0.001) in comparison to naïve individuals. In conclusion, it should be noted that in AHF higher UNa+ is associated with disproportionally higher urine dilution, and patients naïve to furosemide have significantly greater ability to dilute urine when compare to chronic furosemide users.

Prognostic significance and clinical determinants of residual dyspnoea at discharge in acute heart failure: a single-centre, prospective observational study.

OBJECTIVE: This study aimed to assess the prognostic significance of residual (discharge) dyspnoea in acute heart failure (AHF) patients. DESIGN: Single-centre, prospective observational study. SETTING: Patients hospitalised for decompensated AHF in a single cardiology centre, in Poland. PARTICIPANTS: All patients (n=202) who survived the hospitalisation with the primary diagnosis of AHF and were discharged from the hospital. PRIMARY AND SECONDARY OUTCOME MEASURES: 1-year all-cause mortality; and the composite endpoint of 1-year all-cause mortality and rehospitalisation for the HF (whichever occurred first). RESULTS: On admission, 159 (78.7%) AHF patients presented dyspnoea at rest, while residual resting dyspnoea at discharge was present in 16 patients (7.9%). There were 48 (24%) patients with moderate/severe exertional dyspnoea at discharge. In the multivariable model, the resting dyspnoea at discharge was related to a higher risk of both 1-year mortality and composite outcome, with HR (95% CI) 8.0 (3.7 to 17.3) and 5.1 (2.6 to 10.2), respectively, both p<0.0001. Analogically, moderate or severe residual dyspnoea at discharge was related to the heightened risk of study both outcomes, with HR (95% CI) 3.1 (1.8 to 5.4) and 1.8 (1.1 to 2.9), respectively, p<0.01. CONCLUSIONS: Among AHF patients the residual dyspnoea at discharge was unexpectedly common and was associated with an unfavourable outcome during 1-year follow-up.

Sex-stratified patterns of emergency cardiovascular admissions prior and during the COVID-19 pandemic.

The COVID-19 pandemic has had a significant impact on global public health, with long-term consequences that are still largely unknown. This study aimed to assess the data regarding acute cardiovascular hospital admissions in five European centers before and during the pandemic. A multicenter, multinational observational registry was created, comparing admissions to the emergency departments during a 3-months period in 2020 (during the pandemic) with the corresponding period in 2019 (pre-pandemic). Data on patient demographics, COVID-19 test results, primary diagnosis, comorbidities, heart failure profile, medication use, and laboratory results were collected. A total of 8778 patients were included in the analysis, with 4447 patients in 2019 and 4331 patients in 2020. The results showed significant differences in the distribution of cardiovascular diseases between the two years. The frequency of pulmonary embolism (PE) increased in 2020 compared to 2019, while acute heart failure (AHF) and other cardiovascular diseases decreased. The odds of PE incidence among hospitalized patients in 2020 were 1.316-fold greater than in 2019. The incidence of AHF was 50.83% less likely to be observed in 2020, and the odds for other cardiovascular diseases increased by 17.42% between the 2 years. Regarding acute coronary syndrome (ACS), the distribution of its types differed between 2019 and 2020, with an increase in the odds of ST-segment elevation myocardial infarction (STEMI) in 2020. Stratification based on sex revealed further insights. Among men, the incidence of AHF decreased in 2020, while other cardiovascular diseases increased. In women, only the incidence of STEMI showed a significant increase. When analyzing the influence of SARS-CoV-2 infection, COVID-positive patients had a higher incidence of PE compared to COVID-negative patients. COVID-positive patients with ACS also exhibited symptoms of heart failure more frequently than COVID-negative patients. These findings provide valuable information on the impact of the COVID-19 pandemic on acute cardiovascular hospital admissions. The increased incidence of PE and changes in the distribution of other cardiovascular diseases highlight the importance of monitoring and managing cardiovascular health during and post pandemic period. The differences observed between sexes emphasize the need for further research to understand potential sex-specific effects of COVID-19 on cardiovascular outcomes.

The blunted loop diuretic response in acute heart failure is driven by reduced tubular responsiveness rather than insufficient tubular delivery. The role of furosemide urine excretion on diuretic and natriuretic response in acute heart failure.

AIMS: Diuretic response in heart failure is blunted when compared to healthy individuals, but the pathophysiology underlying this phenomenon is unclear. We aimed to investigate whether the diuretic resistance mechanism is related to insufficient furosemide tubular delivery or low tubular responsiveness. METHODS AND RESULTS: We conducted a prospective, observational study of 50 patients with acute heart failure patients divided into two groups based on previous furosemide use (furosemide naïve: n = 28 [56%] and chronic furosemide users: n = 22 [44%]). Each patient received a protocol-derived, standardized furosemide dose based on body weight. We measured diuretic response and urine furosemide concentrations. The furosemide naïve group had significantly higher urine volumes and natriuresis when compared to chronic users at all timepoints (all p < 0.05). Urine furosemide delivery was similar in furosemide naïve versus chronic users after accounting for differences in estimated glomerular filtration rate (28.02 [21.03-35.89] vs. 29.70 [18.19-34.71] mg, p = 0.87). However, the tubular response to delivered diuretic was dramatically higher in naïve versus chronic users, that is the urine volume per 1 µg/ml of urine furosemide at 2 h was 148.6 ± 136.1 versus 50.6 ± 56.1 ml (p = 0.005). CONCLUSIONS: Patients naïve to furosemide have significantly better diuresis and natriuresis when compared to chronic furosemide users. The blunted diuretic response in patients with chronic loop diuretic exposure is driven by decreased tubular responsiveness rather than insufficient furosemide tubular delivery.

COVID-19 Related Myocarditis in Adults: A Systematic Review of Case Reports.

Despite the progress of its management, COVID-19 maintains an ominous condition which constitutes a threat, especially for the susceptible population. The cardiac injury occurs in approximately 30% of COVID-19 infections and is associated with a worse prognosis. The clinical presentation of cardiac involvement can be COVID-19-related myocarditis. Our review aims to summarise current evidence about that complication. The research was registered at PROSPERO (CRD42022338397). We performed a systematic analysis using five different databases, including i.a. MEDLINE. Further, the backward snowballing technique was applied to identify additional papers. Inclusion criteria were: full-text articles in English presenting cases of COVID-19-related myocarditis diagnosed by the ESC criteria and patients over 18 years old. The myocarditis had to occur after the COVID-19 infection, not vaccination. Initially, 1588 papers were screened from the database search, and 1037 papers were revealed in the backward snowballing process. Eventually, 59 articles were included. Data about patients' sex, age, ethnicity, COVID-19 confirmation technique and vaccination status, reported symptoms, physical condition, laboratory and radiological findings, applied treatment and patient outcome were investigated and summarised. COVID-19-related myocarditis is associated with the risk of sudden worsening of patients' clinical status, thus, knowledge about its clinical presentation is essential for healthcare workers.

Serum Osmolarity and Vasopressin Concentration in Acute Heart Failure-Influence on Clinical Course and Outcome.

Neurohormone activation plays an important role in Acute Heart Failure (AHF) pathophysiology. Serum osmolarity can affect this activation causing vasopressin excretion. The role of serum osmolarity and vasopressin concentration and its interaction remain still unexplored in AHF. The objective of our study was to evaluate the relationship of serum osmolarity with clinical parameters, vasopressin concentration, in-hospital course, and outcomes in AHF patients. The study group consisted of 338 AHF patients (male (76.3%), mean age of 68 ± 13 years) with serum osmolarity calculated by the equation: 1.86 × sodium [mmol/L] + (glucose [mg/dL]/18) + (urea [mg/dL]/2.8) + 9 and divided into osmolarity quartiles marked as: low: <287 mOsm/L, intermediate low: 287−294 mOsm/L, intermediate high: 295−304 mOsm/L, and high: >304 mOsm/L. There was an increasing age gradient in the groups and patients differed in the occurrence of comorbidities and baseline clinical and laboratory parameters. Importantly, analysis revealed that vasopressin presented a linear correlation with osmolarity (r = −0.221, p = 0.003) and its concentration decreased with quartiles (61.6 [44.0−81.0] vs. 57.8 [50.0−77.3] vs. 52.7 [43.1−69.2] vs. 45.0 [30.7−60.7] pg/mL, respectively, p = 0.034). This association across quartiles was observed among de novo AHF (63.6 [55.3−94.5] vs. 58.0 [50.7−78.6] vs. 52.0 [46.0−58.0] vs. 38.0 [27.0−57.0] pg/mL, respectively, p = 0.022) and was not statistically significant in patients with acute decompensated heart failure (ADHF) (59.5 [37.4−80.0] vs. 52.0 [38.0−74.5] vs. 57.0 [38.0−79.0] vs. 50.0 [33.0−84.0] pg/mL, respectively, p = 0.849). The worsening of renal function episodes were more frequent in quartiles with higher osmolarity (4 vs. 2 vs. 13 vs. 11%, respectively, p = 0.018) and patients that belonged to the quartiles with low and high osmolarity were characterized more often by incidence of worsening heart failure (20 vs. 9 vs. 10 vs. 22%, respectively, p = 0.032). There was also a U-shape distribution in relation to one-year mortality (31 vs. 19 vs. 23 vs. 37%, respectively, p = 0.022). In conclusion, there was an association of serum osmolarity with clinical status and both in-hospital and out-of-hospital outcomes. Moreover, the linear dependence between vasopressin concentration and serum osmolarity in the AHF population was identified and was driven mainly by patients with de novo AHF which suggests different pathophysiological paths in ADHF and AHF de novo.

Novel Phenotyping for Acute Heart Failure-Unsupervised Machine Learning-Based Approach.

Acute heart failure (AHF) is a life-threatening, heterogeneous disease requiring urgent diagnosis and treatment. The clinical severity and medical procedures differ according to a complex interplay between the deterioration cause, underlying cardiac substrate, and comorbidities. This study aimed to analyze the natural phenotypic heterogeneity of the AHF population and evaluate the possibilities offered by clustering (unsupervised machine-learning technique) in a medical data assessment. We evaluated data from 381 AHF patients. Sixty-three clinical and biochemical features were assessed at the admission of the patients and were included in the analysis after the preprocessing. The K-medoids algorithm was implemented to create the clusters, and optimization, based on the Davies-Bouldin index, was used. The clustering was performed while blinded to the outcome. The outcome associations were evaluated using the Kaplan-Meier curves and Cox proportional-hazards regressions. The algorithm distinguished six clusters that differed significantly in 58 variables concerning i.e., etiology, clinical status, comorbidities, laboratory parameters and lifestyle factors. The clusters differed in terms of the one-year mortality (p = 0.002). Using the clustering techniques, we extracted six phenotypes from AHF patients with distinct clinical characteristics and outcomes. Our results can be valuable for future trial constructions and customized treatment.

Novel Therapeutic Devices in Heart Failure.

Heart failure (HF) constitutes a significant clinical problem and is associated with a sizeable burden for the healthcare system. Numerous novel techniques, including device interventions, are investigated to improve clinical outcome. A review of the most notable currently studied devices targeting pathophysiological processes in HF was performed. Interventions regarding autonomic nervous system imbalance, i.e., baroreflex activation therapy; vagus, splanchnic and cardiopulmonary nerves modulation; respiratory disturbances, i.e., phrenic nerve stimulation and synchronized diaphragmatic therapy; decongestion management, i.e., the Reprieve system, transcatheter renal venous decongestion system, Doraya, preCardia, WhiteSwell and Aquapass, are presented. Each segment is divided into subsections: potential pathophysiological target, existing evidence and weaknesses or unexplained issues. Novel therapeutic devices represent great potential in HF therapy management; however, further evidence is necessary to fully evaluate their utility.

Distinct renin/aldosterone activity profiles correlate with renal function, natriuretic response, decongestive ability and prognosis in acute heart failure.

BACKGROUND: Although renin-angiotensin-aldosterone system (RAAS) activation is believed to be the major driver of acute heart failure (AHF) episodes our understanding of its prevalence and clinical relevance in contemporary settings is incomplete. METHODS: Serum renin and aldosterone were measured at day-1 and at discharge in patients (n = 211) that were hospitalized between 2016 and 2017 for AHF in a single cardiology center. The population was profiled based on upper limits of normal (ULN) of both biomarkers assessed at day-1 and linked with the clinical course and outcomes. RESULTS: The study population constituted of three profiles: RAAS-/- (n = 121 [57%]); RAAS+/- (n = 60 [28%]); and RAAS+/+ (n = 30 [14%]). The RAAS+/+ profile had the lowest blood pressure and serum sodium at admission, day-2 and discharge compared to the other profiles (p < 0.001). The RAAS+/+ patients had significantly lower urine Na+ at admission (57.8 ± 36.7 vs 97.3 ± 31.3 and 86.4 ± 35.0), day-1 (52.7 ± 32.7 vs 85.3 ± 36.3 and 75.5 ± 33.9) mmol/l, vs RAAS-/- and RAAS+/- profiles, respectively, all p < 0.001. There was also a gradual decrease of renal function across increasing RAAS profiles. The RAAS+/+ profile received higher dose of furosemide at discharge 120 [80-160] vs the other profiles 80 [40-120] mg, p < 0.01. The risks of one year mortality or HF rehospitalization increased across the RAAS profiles (p < 0.001). The trajectory of renin or aldosterone change during hospitalization was not related to outcomes. CONCLUSIONS: The RAAS overactivity is not essential for development of AHF. However, elevated RAAS is a marker of more advanced stages of heart failure, is related to low natriuresis and adverse clinical outcomes.

Differences in the Biomarker Profile of De Novo Acute Heart Failure versus Decompensation of Chronic Heart Failure.

The perception of acute heart failure (AHF) as a single entity is increasingly outdated, as distinct patient profiles can be discerned. Key heart failure (HF) studies have previously highlighted the difference in both the course and prognosis of de novo AHF and acute decompensated chronic HF (ADHF). Accordingly, distinct AHF profiles with differing underlying pathophysiologies of disease progression can be shown. We compared a range of selected biomarkers in order to better describe the profile of de novo AHF and ADHF, including the inter alia-serum lactate, bilirubin, matrix metallopeptidase 9 (MMP-9), follistatin, intercellular adhesion molecule 1 (ICAM-1), lipocalin and galectin-3. The study comprised 248 AHF patients (de novo = 104), who were followed up for one year. The biomarker data of the de novo AHF and ADHF profiles was then compared in order to link biomarkers to their prognosis. Our study demonstrated that, although there are similarities between each patient profile, key biomarker differences do exist-predominantly in terms of NTproBNP, serum lactate, bilirubin, ICAM-1, follistatin, ferritin and sTfR (soluble transferrin receptor). ADHF tended to have compromised organ function and higher risks of both one-year mortality and composite endpoint (one-year mortality or rehospitalization for heart failure) hazard ratios (HR) (95% CI): 3.4 (1.8-6.3) and 2.8 (1.6-4.6), respectively, both p < 0.0001. Among the biomarkers of interest: sTfR HR (95% CI): 1.4 (1.04-1.8), NGAL(log) (neutrophil gelatinase-associated lipocalin) HR (95% CI): 2.0 (1.3-3.1) and GDF-15(log) (growth/differentiation factor-15) HR (95% CI): 4.0 (1.2-13.0) significantly impacted the one-year survival, all p < 0.05.

Spot urine sodium in acute heart failure: differences in prognostic value on admission and discharge.

AIMS: Most studies examined spot urine sodium's (sUNa+ ) prognostic utility during the early phase of acute heart failure (AHF) hospitalization. In AHF, sodium excretion is related to clinical status; therefore, we investigated the differences in the prognostic information of spot UNa+ throughout the course of hospitalization for AHF (admission vs. discharge). METHODS AND RESULTS: The study population were AHF patients (n = 172), who survived the index hospitalization. We compared the relationship between early (on admission, at 24 and 48 h) and discharge sUNa+ measurements with post-discharge study endpoints: composite of 1 year all-cause mortality and AHF rehospitalization (with time to first event analysis) as well as with each event in separation. There were 49 (28.5%) deaths, 40 (23.3%) AHF rehospitalizations, while the composite endpoint occurred in 69 (40.1%) during 1 year follow-up. The sUNa+ had prognostic significance for the composite endpoint when assessed on admission, at 24 and at 48 h: hazard ratios (HRs) with 95% confidence intervals (CIs) (per 10 mmol/L) were 0.88 (0.82-0.94); 0.87 (0.81-0.91); 0.90 (0.84-0.96), all P < 0.005. In contrast to early, active decongestion phase, discharge sUNa+ had no prognostic significance HR (95% CI) (per 10 mmol/L): 0.99 (0.93-1.06) P = 0.79 for the composite endpoint, which was independent from the dose of oral furosemide prescribed at that timepoint (average causal mediation effects: -0.38; P = 0.71). Similarly, discharge sUNa+ was neither associated with 1 year mortality HR (95% CI) (per 10 mmol/L): 0.97 (0.89-1.05) P = 0.48 nor with AHF rehospitalizations HR (95% CI) (per 10 mmol/l): 1.03 (0.94-1.12), P = 0.56. The comparison of longitudinal profiles of sUNa+ during hospitalization showed significantly higher values within the early, active decongestive phase in those who did not experience composite endpoint when compared with those who did: admission: 94 ± 34 vs. 76 ± 35; Day 1: 85 ± 36 vs. 65 ± 37; Day 2: 84 ± 37 vs. 67 ± 35, all P < 0.005 (mmol/L), respectively. There was no difference between those groups in discharge sUNa+ : 73 ± 35 vs. 70 ± 35 P = 0.82 (mmol/L). CONCLUSIONS: Spot UNa+ assessed at early phase of hospitalization and at discharge have different prognostic significance, which confirms that it should be always interpreted along with clinical context.