Conduit Flow Compensates for Impaired Left Atrial Passive and Booster Functions in Advanced Diastolic Dysfunction.

BACKGROUND: Quantification of left atrial (LA) conduit function and its contribution to left ventricular (LV) filling is challenging because it requires simultaneous measurements of both LA and LV volumes. The functional relationship between LA conduit function and the severity of diastolic dysfunction remains controversial. We studied the role of LA conduit function in maintaining LV filling in advanced diastolic dysfunction. METHODS: We performed volumetric and flow analyses of LA function across the spectrum of LV diastolic dysfunction, derived from a set of consecutive patients undergoing multiphasic cardiac computed tomography scanning (n=489). From LA and LV time-volume curves, we calculated 3 volumetric components: (1) early passive emptying volume; (2) late active (booster) volume; and (3) conduit volume. Results were prospectively validated on a group of patients with severe aortic stenosis (n=110). RESULTS: The early passive filling progressively decreased with worsening diastolic function (P<0.001). The atrial booster contribution to stroke volume modestly increases with impaired relaxation (P=0.021) and declines with more advanced diastolic function (P<0.001), thus failing to compensate for the reduction in early filling. The conduit volume increased progressively (P<0.001), accounting for 75% of stroke volume (interquartile range, 63-81%) with a restrictive filling pattern, compensating for the reduction in both early and booster functions. Similar results were obtained in patients with severe aortic stenosis. The pulmonary artery systolic pressure increased in a near-linear fashion when the conduit contribution to stroke volume increased above 60%. Maximal conduit flow rate strongly correlated with mitral E-wave velocity (r=0.71; P<0.0001), indicating that the increase in mitral E wave in diastolic dysfunction represents the increased conduit flow. CONCLUSIONS: An increase in conduit volume contribution to stroke volume represents a compensatory mechanism to maintain LV filling in advanced diastolic dysfunction. The increase in conduit volume despite increasing LV diastolic pressures is accomplished by an increase in pulmonary venous pressure.

Diuresis Efficacy in Ambulatory Congested Heart Failure Patients: Intra-patient Comparison of Three Diuretic Regimens (DEA-HF).

BACKGROUND: Limited evidence exists regarding efficacy and safety of diuretic regimens in ambulatory, congestion-refractory, chronic heart failure (CHF) patients. OBJECTIVE: To compare the potency and safety of commonly used diuretic regimens in CHF patients. METHODS: A prospective, randomized, open-label, crossover study conducted in NYHA class II-IV CHF patients, treated in an ambulatory day-care unit. Each patient received 3 different diuretic regimens: intravenous (IV) furosemide 250mg; IV furosemide 250mg plus oral metolazone 5mg; and IV furosemide 250mg plus IV acetazolamide 500mg. Treatments were administered once a week, in one of six randomized sequences. The primary endpoint was total sodium excretion, and the secondary was total urinary volume excreted, both measured for 6 hours post-treatment initiation. RESULTS: A total of 42 patients were recruited. Administration of furosemide plus metolazone resulted in the highest weight of sodium excreted, 4691 mg (95% CI: 4153-5229) compared to furosemide alone 3835 mg (95% CI: 3279-4392), P=0.015 and to furosemide plus acetazolamide 3584 mg (95% CI: 3020-4148), P=0.001. Furosemide plus metolazone resulted in 1.84 liters of urine (95% CI: 1.63-2.05), compared to 1.58 liters (95% CI: 1.37-1.8) P=0.039 collected following administration of furosemide plus acetazolamide and 1.71 liters (95% CI 1.49-1.93) following furosemide alone. The incidence of worsening renal function (WRF) was significantly higher when adding metolazone (41%) to furosemide compared to furosemide alone (17%) and to furosemide plus acetazolamide (2.6%), P<0.001. CONCLUSIONS: In ambulatory CHF patients, furosemide plus metolazone resulted in a significantly higher natriuresis compared to IV furosemide alone or furosemide plus acetazolamide.

Utilizing Human-Induced Pluripotent Stem Cells to Study Cardiac Electroporation Pulsed-Field Ablation.

BACKGROUND: Electroporation is a promising nonthermal ablation method for cardiac arrhythmia treatment. Although initial clinical studies found electroporation pulsed-field ablation (PFA) both safe and efficacious, there are significant knowledge gaps concerning the mechanistic nature and electrophysiological consequences of cardiomyocyte electroporation, contributed by the paucity of suitable human in vitro models. Here, we aimed to establish and characterize a functional in vitro model based on human-induced pluripotent stem cells (hiPSCs)-derived cardiac tissue, and to study the fundamentals of cardiac PFA. METHODS: hiPSC-derived cardiomyocytes were seeded as circular cell sheets and subjected to different PFA protocols. Detailed optical mapping, cellular, and molecular characterizations were performed to study PFA mechanisms and electrophysiological outcomes. RESULTS: PFA generated electrically silenced lesions within the hiPSC-derived cardiac circular cell sheets, resulting in areas of conduction block. Both reversible and irreversible electroporation components were identified. Significant electroporation reversibility was documented within 5 to 15-minutes post-PFA. Irreversibly electroporated regions persisted at 24-hours post-PFA. Per single pulse, high-frequency PFA was less efficacious than standard (monophasic) PFA, whereas increasing pulse-number augmented lesion size and diminished reversible electroporation. PFA augmentation could also be achieved by increasing extracellular Ca2+ levels. Flow-cytometry experiments revealed that regulated cell death played an important role following PFA. Assessing for PFA antiarrhythmic properties, sustainable lines of conduction block could be generated using PFA, which could either terminate or isolate arrhythmic activity in the hiPSC-derived cardiac circular cell sheets. CONCLUSIONS: Cardiac electroporation may be studied using hiPSC-derived cardiac tissue, providing novel insights into PFA temporal and electrophysiological characteristics, facilitating electroporation protocol optimization, screening for potential PFA-sensitizers, and investigating the mechanistic nature of PFA antiarrhythmic properties.

Diagnostic Value of High-Sensitivity Cardiac Troponin-I in Patients After Out-of-Hospital Cardiac Arrest.

Knowing the etiology of cardiac arrest (CA) is important for treatment decisions. Results of previous studies on the diagnostic role of cardiac troponin in patients resuscitated from CA are controversial, few studies were done during the era of high-sensitivity cardiac troponin-I (hs-cTnI), and kinetics of hs-cTnI was not thoroughly investigated. We aimed to explore the diagnostic value of hs-cTnI in patients resuscitated from out-of-hospital CA (OHCA). This retrospective study included 201 consecutive patients after OHCA admitted to the intensive cardiac care unit at Rambam Health Care Campus from 2016 to 2021. Patients were divided into 2 groups according to etiology of CA: group 1-patients with definite acute myocardial infarction (AMI), group 2-patients in whom AMI was excluded. Values of hs-cTnI on admission, peak hs-cTnI, and hs-cTnI upslope were compared between patients with AMI and non-AMI. Peak hs-cTnI and hs-cTnI upslope differed significantly between patients with non-AMI versus AMI CA (median 1,424 vs 32,558 ng/L, p <0.0001 and median 109 vs 2,322 ng/L/h, p <0.0001, respectively). Moreover, peak hs-cTnI and hs-cTnI upslope were found to have good discrimination performance between patients with non-AMI and AMI, with area under the curve receiver operating characteristics (ROC) curves of 0.83 and 0.80, respectively. In conclusion, in patients resuscitated from OHCA values of peak hs-cTnI and hs-cTnI upslope could be helpful in the diagnosis of etiology of CA as adjunct to other diagnostic methods.

Effects of Angiotensin 1-7 and Mas Receptor Agonist on Renal System in a Rat Model of Heart Failure.

Congestive heart failure (CHF) is often associated with impaired kidney function. Over- activation of the renin-angiotensin-aldosterone system (RAAS) contributes to avid salt/water retention and cardiac hypertrophy in CHF. While the deleterious effects of angiotensin II (Ang II) in CHF are well established, the biological actions of angiotensin 1-7 (Ang 1-7) are not fully characterized. In this study, we assessed the acute effects of Ang 1-7 (0.3, 3, 30 and 300 ng/kg/min, IV) on urinary flow (UF), urinary Na+ excretion (UNaV), glomerular filtration rate (GFR) and renal plasma flow )RPF) in rats with CHF induced by the placement of aortocaval fistula. Additionally, the chronic effects of Ang 1-7 (24 µg/kg/h, via intra-peritoneally implanted osmotic minipumps) on kidney function, cardiac hypertrophy and neurohormonal status were studied. Acute infusion of either Ang 1-7 or its agonist, AVE 0991, into sham controls, but not CHF rats, increased UF, UNaV, GFR, RPF and urinary cGMP. In the chronic protocols, untreated CHF rats displayed lower cumulative UF and UNaV than their sham controls. Chronic administration of Ang 1-7 and AVE 0991 exerted significant diuretic, natriuretic and kaliuretic effects in CHF rats, but not in sham controls. Serum creatinine and aldosterone levels were significantly higher in vehicle-treated CHF rats as compared with controls. Treatment with Ang 1-7 and AVE 0991 reduced these parameters to comparable levels observed in sham controls. Notably, chronic administration of Ang 1-7 to CHF rats reduced cardiac hypertrophy. In conclusion, Ang 1-7 exerts beneficial renal and cardiac effects in rats with CHF. Thus, we postulate that ACE2/Ang 1-7 axis represents a compensatory response to over-activity of ACE/AngII/AT1R system characterizing CHF and suggest that Ang 1-7 may be a potential therapeutic agent in this disease state.

What drives performance in machine learning models for predicting heart failure outcome?

Aims: The development of acute heart failure (AHF) is a critical decision point in the natural history of the disease and carries a dismal prognosis. The lack of appropriate risk-stratification tools at hospital discharge of AHF patients significantly limits clinical ability to precisely tailor patient-specific therapeutic regimen at this pivotal juncture. Machine learning-based strategies may improve risk stratification by incorporating analysis of high-dimensional patient data with multiple covariates and novel prediction methodologies. In the current study, we aimed at evaluating the drivers for success in prediction models and establishing an institute-tailored artificial Intelligence-based prediction model for real-time decision support. Methods and results: We used a cohort of all 10 868 patients AHF patients admitted to a tertiary hospital during a 12 years period. A total of 372 covariates were collected from admission to the end of the hospitalization. We assessed model performance across two axes: (i) type of prediction method and (ii) type and number of covariates. The primary outcome was 1-year survival from hospital discharge. For the model-type axis, we experimented with seven different methods: logistic regression (LR) with either L1 or L2 regularization, random forest (RF), Cox proportional hazards model (Cox), extreme gradient boosting (XGBoost), a deep neural-net (NeuralNet) and an ensemble classifier of all the above methods. We were able to achieve an area under receiver operator curve (AUROC) prediction accuracy of more than 80% with most prediction models including L1/L2-LR (80.4%/80.3%), Cox (80.2%), XGBoost (80.5%), NeuralNet (80.4%). RF was inferior to other methods (78.8%), and the ensemble model was slightly superior (81.2%). The number of covariates was a significant modifier (P < 0.001) of prediction success, the use of multiplex-covariates preformed significantly better (AUROC 80.4% for L1-LR) compared with a set of known clinical covariates (AUROC 77.8%). Demographics followed by lab-tests and administrative data resulted in the largest gain in model performance. Conclusions: The choice of the predictive modelling method is secondary to the multiplicity and type of covariates for predicting AHF prognosis. The application of a structured data pre-processing combined with the use of multiple-covariates results in an accurate, institute-tailored risk prediction in AHF.

Enhancing Sweat Rate Using a Novel Device for the Treatment of Congestion in Heart Failure.

BACKGROUND: Current treatment of fluid retention in heart failure relies primarily on diuretics. However, adequate decongestion is not achieved in many patients. We aimed to study the feasibility and short-term performance of a novel approach to remove fluids and sodium directly from the interstitial compartment by enhancing sweat rate. METHODS: We used a device designed to enhance fluid and salt loss via the eccrine sweat glands. Skin temperature in the lower body was increased from 35 °C to 38 °C, where the slope of the relationship between temperature and sweat production is linear. The sweat evaporates instantaneously, thus avoiding the awareness of perspiration. The primary efficacy endpoint was the ability to increase skin temperature to the desired range. A secondary efficacy endpoint was a clinically meaningful hourly sweat output, defined as ≥150 mL/h. The primary safety endpoint was any procedure-related adverse events. RESULTS: We studied 6 normal subjects and 18 patients with congestion. Participants underwent 3 treatment sessions of up to 4 hours. Skin temperature increased to a median of 37.5 °C (interquartile range, 37.1-37.9 °C) with the median core temperature increasing by 0.2 °C (interquartile range, 0.1-0.3 °C). The median hourly weight loss during treatment was 215 g/h (interquartile range, 165-285; range, 100-344 g/h). In 80% of treatment procedures, the average sweat rate was ≥150 mL/h. There were no significant changes in hemodynamic variables or renal function and no procedure-related adverse events. CONCLUSIONS: Enhancing sweat rate was safe and resulted in a clinically meaningful fluid removal and weight loss. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT04578353.

Adherence to Guidelines in Heart Failure, Is It Valid for Elderly Patients?

BACKGROUND: Current guidelines for the treatment of heart failure with reduced ejection fraction (HFrEF) are based on studies that have excluded or underrepresented older patients. OBJECTIVES: To assess the value of guideline directed medical therapy (GDMT) in HFrEF patients 80 years of age and older. METHODS: A single-center retrospective study included patients hospitalized with a first and primary diagnosis of acute decompensated heart failure (ADHF) and ejection fraction (EF) of ≤ 40%. Patients 80 years of age and older were stratified into two groups: GDMT, defined as treatment at hospital discharge with at least two drugs of the following groups: beta-blockers, angiotensin converting enzyme inhibitor (ACEI), angiotensin receptor blocker (ARB), or mineralocorticoid antagonists; and a personalized medicine group, which included patients who were treated with up to one of these drug groups. The primary outcomes were 90-day all-cause mortality, 90-day rehospitalization, and 3-years mortality. RESULTS: The study included 1152 patients with HFrEF. 254 (22%) patients who were at least 80 years old. Of the group, 123 were GDMT at discharge. When GDMT group was compared to the personalized medicine group, there were no statistically significant differences in terms 90-day mortality (17% vs. 13%, P = 0.169), 90-day readmission (51 % vs. 45.6%, P = 0.27), or 3-year mortality (64.5% vs. 63.3%, P = 0.915). CONCLUSIONS: Adherence to guidelines in the older adult population may not have the same effect as in younger patients who were studied in the randomized clinical trials. Larger prospective studies are needed to further address this issue.

Edema formation in congestive heart failure and the underlying mechanisms.

Congestive heart failure (HF) is a complex disease state characterized by impaired ventricular function and insufficient peripheral blood supply. The resultant reduced blood flow characterizing HF promotes activation of neurohormonal systems which leads to fluid retention, often exhibited as pulmonary congestion, peripheral edema, dyspnea, and fatigue. Despite intensive research, the exact mechanisms underlying edema formation in HF are poorly characterized. However, the unique relationship between the heart and the kidneys plays a central role in this phenomenon. Specifically, the interplay between the heart and the kidneys in HF involves multiple interdependent mechanisms, including hemodynamic alterations resulting in insufficient peripheral and renal perfusion which can lead to renal tubule hypoxia. Furthermore, HF is characterized by activation of neurohormonal factors including renin-angiotensin-aldosterone system (RAAS), sympathetic nervous system (SNS), endothelin-1 (ET-1), and anti-diuretic hormone (ADH) due to reduced cardiac output (CO) and renal perfusion. Persistent activation of these systems results in deleterious effects on both the kidneys and the heart, including sodium and water retention, vasoconstriction, increased central venous pressure (CVP), which is associated with renal venous hypertension/congestion along with increased intra-abdominal pressure (IAP). The latter was shown to reduce renal blood flow (RBF), leading to a decline in the glomerular filtration rate (GFR). Besides the activation of the above-mentioned vasoconstrictor/anti-natriuretic neurohormonal systems, HF is associated with exceptionally elevated levels of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP). However, the supremacy of the deleterious neurohormonal systems over the beneficial natriuretic peptides (NP) in HF is evident by persistent sodium and water retention and cardiac remodeling. Many mechanisms have been suggested to explain this phenomenon which seems to be multifactorial and play a major role in the development of renal hyporesponsiveness to NPs and cardiac remodeling. This review focuses on the mechanisms underlying the development of edema in HF with reduced ejection fraction and refers to the therapeutic maneuvers applied today to overcome abnormal salt/water balance characterizing HF.

The interstitial compartment as a therapeutic target in heart failure.

Congestion is the single most important contributor to heart failure (HF) decompensation. Most of the excess volume in patients with HF resides in the interstitial compartment. Inadequate decongestion implies persistent interstitial congestion and is associated with worse outcomes. Therefore, effective interstitial decongestion represents an unmet need to improve quality of life and reduce clinical events. The key processes that underlie incomplete interstitial decongestion are often ignored. In this review, we provide a summary of the pathophysiology of the interstitial compartment in HF and the factors governing the movement of fluids between the interstitial and vascular compartments. Disruption of the extracellular matrix compaction occurs with edema, such that the interstitium becomes highly compliant, and large changes in volume marginally increase interstitial pressure and allow progressive capillary filtration into the interstitium. Augmentation of lymph flow is required to prevent interstitial edema, and the lymphatic system can increase fluid removal by at least 10-fold. In HF, lymphatic remodeling can become insufficient or maladaptive such that the capacity of the lymphatic system to remove fluid from the interstitium is exceeded. Increased central venous pressure at the site of the thoracic duct outlet also impairs lymphatic drainage. Owing to the kinetics of extracellular fluid, microvascular absorption tends to be transient (as determined by the revised Starling equation). Therefore, effective interstitial decongestion with adequate transcapillary plasma refill requires a substantial reduction in plasma volume and capillary pressure that are prolonged and sustained, which is not always achieved in clinical practice. The critical importance of the interstitium in the congestive state underscores the need to directly decongest the interstitial compartment without relying on the lowering of intracapillary pressure with diuretics. This unmet need may be addressed by novel device therapies in the near future.

The two envelopes method for active learning.

Purpose: Active learning improves knowledge acquisition and provides medical students with learning habits that become an integral part of their behavior. As an integral element of our institution's transition from a lecture hall teaching culture to active learning, the current project, conducted with fourth year students, aimed to examine the effects of the two envelopes method of teaching on students' knowledge. Method: The class of 120 students was divided into 12 groups of 10 students each. Six experienced senior cardiologists were assigned to teach the 12 groups. When the students arrived at the classroom, they received two envelopes. Students were instructed to open the first envelope and answer a 10-question test in 15 minutes. After completing the test, they returned the tests to the envelope, sealed it, and then opened the second envelope which included the same test and relevant patient information. They then spent the next 30 minutes discussing the test as a group and familiarizing themselves with the patients' case histories and clinical data. After completion of the group discussion, the tutor entered the room for a two-hour discussion of the patients' disease entities including the anatomy, physiology, pathology, clinical presentation, diagnostic measures, and potential therapies. Results: We compared grades and standard deviations of grades between two classes: one learned in the lecture hall format (2018) and the other learned employing the two-envelopes method (2019). There was a non-statistically significant trend toward better grades with reduced dispersion of grades in the class that learned with the two-envelope method. Conclusions: We describe a novel method for active learning that enhances self-learning and peer learning, and we observed better knowledge acquisition and reduced knowledge dispersion that were not statistically significant.

Comparison Between Echocardiography and Cardiac Computed Tomography in the Evaluation of Diastolic Dysfunction and Prediction of Heart Failure.

Recent data indicate that left atrial (LA) function assessment by cardiac computed tomography (CT) is closely related to diastolic dysfunction (DD). Therefore, we aimed to perform a direct comparison between CT and echocardiography for diagnosis of advanced DD and prediction of future heart failure or cardiovascular death. We identified 340 patients who had both spiral cardiac CT and a proximate echocardiogram. LA total emptying fraction (LATEF), a measure of global LA function, was automatically calculated from CT data, as a surrogate for diastolic function and was compared with echocardiographic grades of diastolic function. The area under the receiver operating characteristic curve for LATEF to differentiate between advanced DD (grades 2 and 3) and all other grades was 0.84 (0.79 to 0.88). Over a median of 4 years, 69 events (admissions for heart failure and cardiovascular deaths) occurred. By multivariate Cox analysis, LATEF <40% provided incremental prognostic information after adjustments for advanced DD by echocardiography (hazard ratio 2.15, 95% confidence interval 1.13 to 3.94). There was a significant interaction (p = 0.03) between LATEF and echocardiography-based diastolic grades. Stratified analyses within the diastolic function groups revealed that LATEF <40% was equivalent to echocardiography in predicting events in the subgroup with advanced DD by echocardiography (p = 0.20) but was associated with a significantly higher event rates in patients with normal filling pressures (p = 0.0001) or indeterminate diastolic function (p = 0.04) by echocardiography. In conclusion, LA function derived from CT can accurately detect advanced DD diagnosed by echocardiography and has additive value to echocardiography-derived DD.

Hyperlactataemia and acid-base disturbances in normotensive patients with acute heart failure.

AIMS: Acute heart failure (AHF) may be associated with low-tissue perfusion and/or hypoxaemia leading to increased lactate levels and acid-base perturbations. Few data are available on the clinical significance of elevated lactate levels and primary acid-base disorders in the setting of AHF. METHODS AND RESULTS: Arterial blood gas was obtained at admission in 4012 normotensive (systolic blood pressure ≥ 90 mmHg) patients with AHF. The association between lactate levels and acid-base status and in-hospital mortality was determined using multivariable logistic regression. Hyperlactataemia (>2 mmol/L) was present in 38.0% of patients and was strongly associated with markers of sympathetic activation, such as hyperglycaemia. Hyperlactataemia was present in 31.0%, 43.7%, and 42.0% of patients with normal pH, acidosis, and alkalosis, respectively. In-hospital mortality occurred in 16.4% and 11.1% of patients with and without hyperlactataemia [adjusted odds ratio (OR) 1.49; 95% confidence interval (CI) 1.22-1.82, P < 0.0001]. Compared with normal pH, the OR for in-hospital mortality was 2.48 (95% CI 1.95-3.16, P < 0.0001) in patients with acidosis and 1.77 (95% CI 1.32-2.26, P < 0.0001) in patients with alkalosis. The risk for in-hospital mortality was high with acidosis (18.1%) or alkalosis (10.4%) even with normal lactate. The most common primary acid-base disturbances included metabolic acidosis, respiratory acidosis, and metabolic alkalosis with respiratory acidosis having the highest risk for in-hospital mortality. CONCLUSION: Hyperlactataemia was common in patients without hypotension and was associated with increased risk for in-hospital mortality. Hyperlactataemia is not associated with any specific acid-base disorder. Acute heart failure patients also present with diverse acid-base disorders portending increased in-hospital mortality.

Left atrial function by cardiac computed tomography is a predictor of heart failure and cardiovascular death.

OBJECTIVES: We sought to evaluate cardiac CT angiography (CCTA)-based assessment of left atrial (LA) function as a predictor of hospitalizations for heart failure (HF) and cardiovascular (CV) mortality. METHODS: LA function was evaluated using automatic derivation of LA volumes to calculate LA total emptying fraction (LATEF) in 788 consecutive patients with normal sinus rhythm who had undergone spiral CT scans. The relationship between LATEF evaluated by CCTA and the composite endpoint of admission for HF or CV mortality was analyzed using Cox models. RESULTS: During a median follow-up of 4 years, there were 100 events, 62 HF hospitalizations, and 38 cardiovascular deaths. Mean LATEF was 30.7 ± 10.7% and 40.5 ± 11.2% in patients with and without events, respectively (p < 0.0001). A high LATEF (upper tertile > 46%) was associated with a very low event rate (3.5% at 6 years [95% CI 1.7-7.1%]). The adjusted HR for HF or CV mortality was 4.37 (95% CI 1.99-9.60) in the lowest LATEF tertile, and 2.29 (95% CI 1.03-5.14) in the middle tertile, relative to the highest tertile. For the endpoint of HF alone, adjusted HR for the lowest LATEF tertile was 5.93 (95% CI 2.23-15.82) and for the middle tertile 2.89 (95% CI 1.06-7.86). The association of LATEF with outcome was similar for patients with both reduced and preserved left ventricular (LV) ejection fraction (Pinteraction = 0.724). Reduced LATEF was associated with a high event rate, even when coupled with normal LA volume. CONCLUSION: CCTA-derived LA function is a predictor of HF hospitalization or CV death, independent of clinical risk factors, LA volume, and LV systolic function. KEY POINTS: • Left atrial function can be automatically derived from cardiac CTA scans. • Cardiac CTA-derived left atrial function is a predictor of hospitalization for heart failure and cardiovascular death. • Evaluation of left atrial function could be useful in identifying patients at risk of heart failure.

Distribution of Cardiac and Renal Corin and Proprotein Convertase Subtilisin/Kexin-6 in the Experimental Model of Cardio-Renal Syndrome of Various Severities.

Congestive heart failure (CHF) often leads to progressive cardiac hypertrophy and salt/water retention. However, its pathogenesis remains largely unclarified. Corin, a cardiac serine protease, is responsible for converting proANP and proBNP to biologically active peptides. Although the involvement of corin in cardiac hypertrophy and heart failure was extensively studied, the alterations in corin and proprotein convertase subtilisin/kexin-6 (PCSK6), a key enzyme in the conversion of procorin to corin, has not been studied simultaneously in the cardiac and renal tissues in cardiorenal syndrome. Thus, this study aims to examine the status of PCSK6/corin in the cardiac and renal tissues of rats with CHF induced by the creation of aorto-caval fistula (ACF). We divided rats with ACF into two subgroups based on the pattern of their urinary sodium excretion, namely, compensated and decompensated. Placement of ACF led to cardiac hypertrophy, pulmonary congestion, and renal dysfunction, which were more profound in the decompensated subgroup. Corin immunoreactive peptides were detected in all heart chambers at the myocyte membranal and cytosolic localization and in the renal tissue, especially in the apical membrane of the proximal tubule, mTAL, and the collecting duct. Interestingly, the expression and abundance of corin in both the cardiac ventricles and renal tissues were significantly increased in compensated animals as compared with the decompensated state. Noteworthy, the abundance of PCSK6 in these tissues followed a similar pattern as corin. In contrast, furin expression was upregulated in the cardiac and renal tissues in correlation with CHF severity. We hypothesize that the obtained upregulation of cardiac and renal PCSK6/corin in rats with compensated CHF may represent a compensatory response aiming at maintaining normal Na+ balance, whereas the decline in these two enzymes may contribute to the pathogenesis of avid sodium retention, cardiac hypertrophy, and blunted atrial natriuretic peptide/brain natriuretic peptide actions in decompensated CHF.

Risk of Worsening Renal Function Following Repeated Exposures to Contrast Media During Percutaneous Coronary Interventions.

Background Multiple contrast media exposures are common, but their cumulative effect on renal function is unknown. We aimed to investigate the renal consequences of repeated exposures to contrast media with coronary interventions. Methods and Results We studied 2942 patients who underwent between 1 and 9 procedures. The primary end point was a persistent creatinine increase of ≥50% above baseline at ≥90 days after the last procedure. The effect of cumulative contrast media dose was assessed using Cox models, with cumulative exposure as a time-dependent variable, and propensity score matching. The primary end point occurred in 190 patients (6.5%), with 6.1%, 6.8%, and 6.2% of patients with 1, 2 or 3, and ≥4 procedures, respectively (P=0.75). In the multivariable Cox model, baseline renal function, diabetes, anemia, acute coronary syndrome, and heart failure were independent predictors of the primary end point (all P≤0.01), whereas cumulative contrast dose was not (hazard ratio [HR], 1.29 [95% CI, 0.89-1.88] for the fourth contrast quartile [>509 mL] versus first contrast quartile [<233 mL]). Propensity score matching yielded 384 patient pairs with similar characteristics and either 1 or 2 to 9 contrast exposures (median cumulative dose, 160 and 480 mL, respectively). Despite large differences in the cumulative contrast exposure, there were similar rates of the primary end points (7.3% versus 6.3%, respectively; HR, 0.76 [95% CI, 0.44-1.32]). Conclusions In patients with multiple exposures to contrast media, worsening of renal function over time is associated with known risk factors for the progression of kidney disease but not with cumulative contrast volume.

Environmental factors, winter respiratory infections and the seasonal variation in heart failure admissions.

Seasonal cycles of AHF are causally attributed to the seasonal pattern of respiratory tract infections. However, this assumption has never been formally validated. We aimed to determine whether the increase in winter admissions for acute heart failure (AHF) can be explained by seasonal infectious diseases. We studied 12,147 patients admitted for AHF over a period of 11 years (2005-2015). Detailed virology and bacteriology data were collected on each patient. Meteorological information including daily temperature and relative humidity was obtained for the same period. The peak-to-low ratio, indicating the intensity of seasonality, was calculated using negative binomial regression-derived incidence rate ratios (IRR). AHF admissions occurred with a striking annual periodicity, peaking in winter (December-February) and were lowest in summer (June-August), with a seasonal amplitude (January vs. August) of 2.00 ([95% CI 1.79-2.24]. Occurrence of confirmed influenza infections was low (1.59%). Clinical diagnoses of respiratory infections, confirmed influenza infections, and influenza-like infections also followed a strong seasonal pattern (P < 0.0001; Peak/low ratio 2.42 [95% CI 1.394-3.03]). However, after exclusion of all respiratory infections, the seasonal variation in AHF remained robust (Peak/low ratio January vs. August, 1.81 [95% CI 1.60-2.05]; P < 0.0001). There was a strong inverse association between AHF admissions and average monthly temperature (IRR 0.95 per 1℃ increase; 95% CI 0.94 to 0.96). In conclusion, these is a dominant seasonal modulation of AHF admissions which is only partly explained by the incidence of winter respiratory infections. Environmental factors modify the susceptibility of heart failure patients to decompensation.

Risk of Acute Kidney Injury after Intravenous Contrast Media Administration in Patients with Suspected Pulmonary Embolism: A Propensity-Matched Study.

BACKGROUND: Although computed tomography pulmonary angiography (CTPA) is the preferred diagnostic procedure in patients with suspected pulmonary embolism (PE), some patients undergo ventilation/perfusion (V/Q) lung scan due to concern of contrast-associated acute kidney injury (AKI). METHODS: The study used a cohort of 4,565 patients with suspected PE. Patients who received contrast during CTPA were compared with propensity score-matched unexposed control patients who underwent V/Q lung scanning. AKI was defined as ≥50% increase in serum creatinine during the first 72 hours after either CTPA or V/Q lung scan. RESULTS: Classification and regression tree analysis demonstrated that baseline creatinine was the strongest determinant of the decision to use CTPA. Propensity-score matching yielded 969 patient pairs. There were 44 AKI events (4.5%) in patients exposed to contrast media (CM) and 33 events (3.4%) in patients not exposed to CM (risk difference: 1.1%, 95% confidence interval [CI]: -0.6 to 2.9%; odds ratio [OR]: 1.39, 95% CI: 0.86-2.26; p = 0.18). Using different definitions for AKI and extending the time window for AKI diagnosis gave similar results. In a sensitivity analysis with the inverse probability weighting method, the OR for AKI in the CTPA versus V/Q scan was 1.14 (95% CI: 0.72-1.78; p = 0.58). CONCLUSION: Intravenous contrast material administration was not associated with an increased risk of AKI in patients with suspected PE. Given the diagnostic superiority of CTPA, these results are reassuring with regard to the use of CTPE in patients with suspected PE perceived to be at risk for AKI.

The impact of lockdown enforcement during the SARSCoV-2 pandemic on the timing of presentation and early outcomes of patients with ST-elevation myocardial infarction.

INTRODUCTION: Early reports described decreased admissions for acute cardiovascular events during the SarsCoV-2 pandemic. We aimed to explore whether the lockdown enforced during the SARSCoV-2 pandemic in Israel impacted the characteristics of presentation, reperfusion times, and early outcomes of ST-elevation myocardial infarction (STEMI) patients. METHODS: A multicenter prospective cohort comprising all STEMI patients treated by primary percutaneous coronary intervention admitted to four high-volume cardiac centers in Israel during lockdown (20/3/2020-30/4/2020). STEMI patients treated during the same period in 2019 served as controls. RESULTS: The study comprised 243 patients, 107 during the lockdown period of 2020 and 136 during the same period in 2019, with no difference in demographics and clinical characteristics. Patients admitted in 2020 had higher admission and peak troponin levels, had a 2.4 fold greater likelihood of Door-to-balloon times> 90 min (95%CI: 1.2-4.9, p = 0.01) and 3.3 fold greater likelihood of pain-to-balloon times> 12 hours (OR 3.3, 95%CI: 1.3-8.1, p<0.01). They experienced higher rates hemodynamic instability (25.2% vs 14.7%, p = 0.04), longer hospital stay (median, IQR [4, 3-6 Vs 5, 4-6, p = 0.03]), and fewer early (<72 hours) discharge (12.4% Vs 32.4%, p<0.001). CONCLUSIONS: The lockdown imposed during the SARSCoV-2 pandemic was associated with a significant lag in the time to reperfusion of STEMI patients. Measures to improves this metric should be implemented during future lockdowns.