Cardiac diastolic maladaptation is associated with the severity of exercise intolerance in sickle cell anemia patients.

This pilot study focusing on Sickle Cell Anemia (SCA) patients offers a comprehensive and integrative evaluation of respiratory, cardiovascular, hemodynamic, and metabolic variables during exercise. Knowing that diastolic dysfunction is frequent in this population, we hypothesize that a lack of cardiac adaptation through exercise might lead to premature increase in blood lactate concentrations in SCA patients, a potential trigger for acute disease complication. SCA patients were prospectively included in PHYSIO-EXDRE study and underwent a comprehensive stress test with a standardized incremental exercise protocol up to 4 mmol L-1 blood lactate concentration (BL4). Gas exchange, capillary lactate concentration and echocardiography were performed at baseline, during stress test (at ∼ 2 mmol L-1) and BL4. The population was divided into two groups and compared according to the median value of percentage of theoretical peak oxygen uptake (% V ˙ O 2 p e a k t h ) at BL4. Twenty-nine patients were included (42 ± 12 years old, 48% of women). Most patients reached BL4 at low-intensity exercise [median value of predicted power output (W) was 37%], which corresponds to daily life activities. The median value of % V ˙ O 2 p e a k t h at BL4 was 39%. Interestingly, diastolic maladaptation using echocardiography during stress test along with hemoglobin concentration were independently associated to early occurrence of BL4. As BL4 occurs for low-intensity exercises, SCA patients may be subject to acidosis-related complications even during their daily life activities. Beyond assessing physical capacities, our study underlines that diastolic maladaptation during exercise is associated with an early increase in blood lactate concentration.

Endurance training improves oxygen uptake/demand mismatch, metabolic flexibility and recovery in patients with sickle cell disease.

Patients with sickle cell disease (SCD) display lower slope coefficients of the oxygen uptake (V_O2) vs. work rate (W) relationship (delineating an O2 uptake/demand mismatch) and a poor metabolic flexibility. Because endurance training (ET) increases the microvascular network and oxidative enzymes activity including one involved in lipid oxidation, ET might improve the slope coefficient of the V_O2 vs. W curve and the metabolic flexibility of SCD patients. ET may also contribute to improve patient post-exercise cardiopulmonary and metabolic recovery. Fifteen patients with SCD performed a submaximal incremental test on a cycle ergometer before (SIT1) and after (SIT2) 8 weeks of ET. Minute ventilation, ventilation rate (VR), heart rate (HR), V_O2, CO2 production, respiratory exchange ratio, carbohydrate/lipid utilization and partitioning (including %Lipidox) and blood lactate concentration ([lactate]b) were measured during and after SIT1 and SIT2. At baseline, the slope coefficient of the V_O2 vs. W curve positively correlated with total hemoglobin, mean corpuscular hemoglobin and percentage of HbF. After training, the slope coefficient of the V_O2 vs. W curve was significantly higher and the [lactate]b increase was delayed. If patients' energy metabolism apparently relied largely on carbohydrate sources during SIT1, %Lipidox tended to increase at low exercise intensities during SIT2, supporting a training-induced improvement of metabolic flexibility in patients with SCD. Post-exercise recovery of VR, V_E/V_CO2, HR and [lactate]b was faster after training. We concluded that ET in patients with SCD i) ameliorated the oxygen uptake/demand mismatch, ii) blunted the metabolic inflexibility, and iii) improved post-exercise cardiopulmonary and metabolic responses.

Combined effects of smoking and HIV infection on the occurrence of aging-related manifestations.

Both HIV-1 infection and smoking may contribute to the development of ageing-related manifestations affecting the prognosis of people living with HIV, but it is unclear whether HIV and smoking exert their effects independently or interact by potentiating each other. We conducted a cross-sectional study in 192 people living with HIV aged- and gender-matched with 192 HIV-uninfected controls, assessing the relative effect of HIV-1/smoking status on lung function (FEV1), bone mineral density (BMD), appendicular skeletal muscle mass index (ASMI), aortic pulse-wave velocity (PWV), insulin resistance (HOMA-IR) and renal function. In both unadjusted and adjusted analyses, FEV1, BMD and ASMI significantly differed according to smoking/HIV status, with the worst parameters found in HIV-1 infected patients currently smoking, and BMD and ASMI decreased to a lesser extent in HIV-1 infected patients formerly smoking (> 10 pack-years). Values in people living with HIV with < 10 pack-years exposure were of similar magnitude to those from controls. Regarding PWV, HOMA-R and eGFR, no significant differences were found, with the exception of eGFR values which were globally lower in HIV-1 infected patients. In conclusion HIV infection and smoking acted synergistically and were associated with a wasting phenotype combining muscle mass and bone mineral reduction.Clinical Trial Registration (registrar, website, and registration number), where applicable: CPP 10-023, 09-027, 10-034.

Comparison Between Lung Ultrasonography Score in the Emergency Department and Clinical Outcomes of Patients With or With Suspected COVID-19: An Observational Multicentric Study.

OBJECTIVE: Chest CT is the reference test for assessing pulmonary injury in suspected or diagnosed COVID-19 with signs of clinical severity. This study aimed to evaluate the association of a lung ultrasonography score and unfavorable clinical evolution at 28 days. METHODS: The eChoVid is a multicentric study based on routinely collected data that was conducted in 8 emergency units in France; patients were included between March 19, 2020 and April 28, 2020 and underwent lung ultrasonography, a short clinical assessment by 2 emergency physicians blinded to each other's assessment, and chest CT. Lung ultrasonography consisted of scoring lesions from 0 to 3 in 8 chest zones, thus defining a global score (GS) of severity from 0 to 24. The primary outcome was the association of lung damage severity as assessed by the GS at day 0 and patient status at 28 days. Secondary outcomes were comparing the performance between GS and CT scan and the performance between a new trainee physician and an ultrasonography expert in scores. RESULTS: For the 328 patients analyzed, the GS showed good performance in predicting clinical worsening at 28 days (area under the receiver operating characteristic curve [AUC] 0.83, sensitivity 84.2%, specificity 76.4%). The GS showed good performance in predicting the CT severity assessment (AUC 0.84, sensitivity 77.2%, specificity 83.7%). CONCLUSION: A lung ultrasonography GS is a simple tool that can be used in the emergency department to predict unfavorable assessment at 28 days in patients with COVID-19.

Determinants of ventricular arrhythmias in sickle cell anemia: toward better prevention of sudden cardiac death.

Sudden death is 1 of the leading causes of death in adults with sickle cell anemia (SCA) but its etiology remains mostly unknown. Ventricular arrhythmia (VA) carries an increased risk of sudden death; however, its prevalence and determinants in SCA are poorly studied. This study aimed to identify the prevalence and predictors of VA in patients with SCA. From 2019 to 2022, 100 patients with SCA were referred to the physiology department to specifically analyze cardiac function and prospectively included in the DREPACOEUR registry. They underwent a 24-hour electrocardiogram monitoring (24h-Holter), transthoracic echocardiography, and laboratory tests on the same day. The primary end point was the occurrence of VA, defined as sustained or nonsustained ventricular tachycardia (VT), >500 premature ventricular contractions (PVCs) on 24h-Holter, or a recent history of VT ablation. The mean patient age was 46 ± 13 years, and 48% of the patients were male. Overall, VA was observed in 22 (22%) patients. Male sex (81% vs 34%; P = .02), impaired global longitudinal strain (GLS): -16% ± 1.9% vs -18.3% ± 2.7%; P = .02), and decreased platelet count (226 ± 96 giga per liter [G/L] vs 316 ± 130 G/L) were independently associated with VA. GLS correlated with PVC load every 24 hours (r = 0.39; P < .001) and a cutoff of -17.5% could predict VA with a sensitivity of 82% and a specificity of 63%. VAs are common in patients with SCA, especially in men. This pilot study uncovered GLS as a valuable parameter for improving rhythmic risk stratification.

Diabetic cardiomyopathy: the need for adjusting experimental models to meet clinical reality.

Diabetic cardiomyopathy (CM), occurring in the absence of hypertension, coronary artery disease, and valvular or congenital heart disease, is now recognized as a distinct, multifactorial disease leading to ventricular hypertrophy and abnormal myocardial contractility that correlates with an array of complex molecular and cellular changes. Animal models provide the unique opportunity to investigate mechanistic aspects of diabetic CM, but important caveats exist when extrapolating findings obtained from preclinical models of diabetes to humans. Indeed, animal models do not recapitulate the complexity of environmental factors, most notably the duration of the exposure to insulin resistance that may play a crucial role in the development of diabetic CM. Moreover, most preclinical studies are performed in animals with uncontrolled or poorly controlled diabetes, whereas patients tend to undergo therapeutic intervention. Finally, whilst type 2 diabetes mellitus prevalence trajectory mainly increases at 40- < 75 years (with a currently alarming increase at younger ages, however), it is a legitimate concern how closely rodent models employing young animals recapitulate the disease developing in old people. The aim of this review is to identify the current limitations of rodent models and to discuss how future mechanistic and preclinical studies should integrate key confounding factors to better mimic the diabetic CM phenotype.

Electrical cardioversion of atrial arrhythmias with cardiac amyloidosis in the era of direct oral anticogulants.

AIMS: Atrial fibrillation (AF)/atrial flutter is common during cardiac amyloidosis (CA). Electrical cardioversion (EC) is a strategy to restore sinus rhythm (SR). However, left atrial thrombus (LAT) represents a contraindication for EC. CA patients with AF/atrial flutter have a high prevalence of LAT. We aimed to evaluate EC characteristics, LAT prevalence and risk factors, and AF/atrial flutter outcome in CA patients undergoing EC, predominantly treated with direct oral anticoagulants (DOACs). METHODS AND RESULTS: All patients with CA and AF/atrial flutter referred for the first time to our national referral centre of amyloidosis for EC from June 2017 to February 2021 were included in this study. In total, 66 patients (median age 74.5 [70;80.75] years, 67% male) were included with anticoagulation consisted of DOAC in 74% of cases. All patients underwent cardiac imaging before EC to rule out LAT. EC was cancelled due to LAT in 14% of cases. Complete thrombus resolution was observed in only 17% of cases. The two independent parameters associated with LAT were creatinine [hazard ratio (HR) = 1.01; confidence interval (CI) = 1.00-1.03, P = 0.036] and the use of antiplatelet agents (HR = 13.47; CI = 1.85-98.02). EC acute success rate was 88%, and we observed no complication after EC. With 64% of patients under amiodarone, AF/atrial flutter recurrence rate following EC was 51% after a mean follow-up of 30 ± 27 months. CONCLUSIONS: Left atrial thrombus was observed in 14% of CA patients listed for EC and mainly treated with DOAC. The acute EC success rate was high with no complication. The long-term EC success rate was acceptable (49%).

Impact of cardiac resynchronization therapy optimization inside a heart failure programme: a real-world experience.

AIMS: This study sought to describe and evaluate the impact of a routine in-hospital cardiac resynchronization therapy (CRT) programme, including comprehensive heart failure (HF) evaluation and systematic echo-guided CRT optimization. METHODS AND RESULTS: CRT implanted patients were referred for optimization programme at 3 to 12 months from implantation. The program included clinical and biological status, standardized screening for potential cause of CRT non-response and systematic echo-guided atrioventricular and interventricular delays (AVd and VVd) optimization. Initial CRT-response and improvement at 6 months post-optimization were assessed with a clinical composite score (CCS). Major HF events were tracked during 1 year after optimization. A total of 227 patients were referred for CRT optimization and enrolled (71 ± 11 years old, 77% male, LVEF 30.6 ± 7.9%), of whom 111 (48.9%) were classified as initial non-responders. Left ventricular lead dislodgement was noted in 4 patients (1.8%), and loss or ≤90% biventricular capture in 22 (9.7%), mostly due to arrhythmias. Of the 196 patients (86%) who could undergo echo-guided CRT optimization, 71 (36.2%) required VVd modification and 50/144 (34.7%) AVd modification. At 6 months post-optimization, 34.3% of the initial non-responders were improved according to the CCS, but neither AVd nor VVd echo-guided modification was significantly associated with CCS-improvement. After one-year follow-up, initial non-responders maintained a higher rate of major HF events than initial responders, with no significant difference between AVd/VVd modified or not. CONCLUSIONS: Our study supports the necessity of a close, comprehensive and multidisciplinary follow-up of CRT patients, without arguing for routine use of echo-guided CRT optimization.

Acute Kidney Injury in Critically-Ill COVID-19 Patients.

Purpose: Acute kidney injury (AKI) is common in patients with COVID-19, however, its mechanism is still controversial, particularly in ICU settings. Urinary proteinuria profile could be a non-invasive tool of interest to scrutinize the pathophysiological process underlying AKI in COVID-19 patients. Material and Methods: We conducted a retrospective study between March 2020 and April 2020. All patients with laboratory-confirmed COVID-19 and without end-stage kidney disease requiring renal replacement therapy before ICU admission were included. Our objectives were to assess the incidence and risk factors for AKI and to describe its clinical and biological characteristics, particularly its urinary protein profile. Results: Seventy patients were included; 87% needed mechanical ventilation and 61% needed vasopressor during their ICU stay; 64.3% of patients developed AKI and half of them needed dialysis. Total and tubular proteinuria on day 1 were higher in patients with AKI, whereas glomerular proteinuria was similar in both groups. The main risk factor for AKI was shock at admission (OR = 5.47 (1.74−17.2), p < 0.01). Mortality on day 28 was higher in AKI (23/45, 51.1%) than in no-AKI patients (1/25, 4%), p < 0.001. Risk factors for 28-days mortality were AKI with need for renal replacement therapy, non-renal SOFA score and history of congestive heart failure. Conclusions: AKI is common in COVID-19 patients hospitalized in ICU; it seems to be related to tubular lesions rather than glomerular injury and is related to shock at ICU admission.

Identification of factors impairing exercise capacity after severe COVID-19 pulmonary infection: a 3-month follow-up of prospective COVulnerability cohort.

BACKGROUND: Patient hospitalized for coronavirus disease 2019 (COVID-19) pulmonary infection can have sequelae such as impaired exercise capacity. We aimed to determine the frequency of long-term exercise capacity limitation in survivors of severe COVID-19 pulmonary infection and the factors associated with this limitation. METHODS: Patients with severe COVID-19 pulmonary infection were enrolled 3 months after hospital discharge in COVulnerability, a prospective cohort. They underwent cardiopulmonary exercise testing, pulmonary function test, echocardiography, and skeletal muscle mass evaluation. RESULTS: Among 105 patients included, 35% had a reduced exercise capacity (VO2peak < 80% of predicted). Compared to patients with a normal exercise capacity, patients with reduced exercise capacity were more often men (89.2% vs. 67.6%, p = 0.015), with diabetes (45.9% vs. 17.6%, p = 0.002) and renal dysfunction (21.6% vs. 17.6%, p = 0.006), but did not differ in terms of initial acute disease severity. An altered exercise capacity was associated with an impaired respiratory function as assessed by a decrease in forced vital capacity (p < 0.0001), FEV1 (p < 0.0001), total lung capacity (p < 0.0001) and DLCO (p = 0.015). Moreover, we uncovered a decrease of muscular mass index and grip test in the reduced exercise capacity group (p = 0.001 and p = 0.047 respectively), whilst 38.9% of patients with low exercise capacity had a sarcopenia, compared to 10.9% in those with normal exercise capacity (p = 0.001). Myocardial function was normal with similar systolic and diastolic parameters between groups whilst reduced exercise capacity was associated with a slightly shorter pulmonary acceleration time, despite no pulmonary hypertension. CONCLUSION: Three months after a severe COVID-19 pulmonary infection, more than one third of patients had an impairment of exercise capacity which was associated with a reduced pulmonary function, a reduced skeletal muscle mass and function but without any significant impairment in cardiac function.

Cardiovascular phenotypes predict clinical outcomes in sickle cell disease: An echocardiography-based cluster analysis.

This study sought to link cardiac phenotypes in homozygous Sickle Cell Disease (SCD) patients with clinical profiles and outcomes using cluster analysis. We analyzed data of 379 patients included in the French Etendard Cohort. A cluster analyses was performed based on echocardiographic variables, and the association between clusters, clinical profiles and outcomes was assessed. Three clusters were identified. Cluster 1 (n = 123) patients had the lowest cardiac output, mild left cardiac cavities remodeling, mild diastolic dysfunction, and higher tricuspid regurgitation velocity (TRV). They were predominantly female and displayed the most altered functional limitation. Cluster 2 (n = 102) patients had the highest cardiac output and the most remodeled cardiac cavities. Diastolic function and TRV were similar to cluster 1. These patients had a higher blood pressure and a severe hemolytic anemia. Cluster 3 (n = 154) patients had mild left cardiac cavities remodeling, normal diastolic function and lowest TRV values. They were younger with the highest hemoglobin value. Right heart catheterization was performed in 94 patients. Cluster 1 (n = 33) included the majority of pre-capillary PH whilst cluster 2 (n = 34) included post-capillary PH. No PH was found in cluster 3 (n = 27). After a follow-up of 11.4 ± 2 years, death occurred in 41 patients (11%). Cluster 2 patients had the worst prognosis with a 19% mortality rate versus 12% in cluster 1 and 5% in cluster 3 (p log-rank = 0.003). Cluster analysis of echocardiography variables identified three hemodynamic and clinical phenotypes among SCD patients, each predicting a different prognosis.

Dysregulated Phenylalanine Catabolism Plays a Key Role in the Trajectory of Cardiac Aging.

BACKGROUND: Aging myocardium undergoes progressive cardiac hypertrophy and interstitial fibrosis with diastolic and systolic dysfunction. Recent metabolomics studies shed light on amino acids in aging. The present study aimed to dissect how aging leads to elevated plasma levels of the essential amino acid phenylalanine and how it may promote age-related cardiac dysfunction. METHODS: We studied cardiac structure and function, together with phenylalanine catabolism in wild-type (WT) and p21-/- mice (male; 2-24 months), with the latter known to be protected from cellular senescence. To explore phenylalanine's effects on cellular senescence and ectopic phenylalanine catabolism, we treated cardiomyocytes (primary adult rat or human AC-16) with phenylalanine. To establish a role for phenylalanine in driving cardiac aging, WT male mice were treated twice a day with phenylalanine (200 mg/kg) for a month. We also treated aged WT mice with tetrahydrobiopterin (10 mg/kg), the essential cofactor for the phenylalanine-degrading enzyme PAH (phenylalanine hydroxylase), or restricted dietary phenylalanine intake. The impact of senescence on hepatic phenylalanine catabolism was explored in vitro in AML12 hepatocytes treated with Nutlin3a (a p53 activator), with or without p21-targeting small interfering RNA or tetrahydrobiopterin, with quantification of PAH and tyrosine levels. RESULTS: Natural aging is associated with a progressive increase in plasma phenylalanine levels concomitant with cardiac dysfunction, whereas p21 deletion delayed these changes. Phenylalanine treatment induced premature cardiac deterioration in young WT mice, strikingly akin to that occurring with aging, while triggering cellular senescence, redox, and epigenetic changes. Pharmacological restoration of phenylalanine catabolism with tetrahydrobiopterin administration or dietary phenylalanine restriction abrogated the rise in plasma phenylalanine and reversed cardiac senescent alterations in aged WT mice. Observations from aged mice and human samples implicated age-related decline in hepatic phenylalanine catabolism as a key driver of elevated plasma phenylalanine levels and showed increased myocardial PAH-mediated phenylalanine catabolism, a novel signature of cardiac aging. CONCLUSIONS: Our findings establish a pathogenic role for increased phenylalanine levels in cardiac aging, linking plasma phenylalanine levels to cardiac senescence via dysregulated phenylalanine catabolism along a hepatic-cardiac axis. They highlight phenylalanine/PAH modulation as a potential therapeutic strategy for age-associated cardiac impairment.

Clinical spectrum of ischaemic arterial diseases associated with COVID-19: a series of four illustrative cases.

BACKGROUND: Severe coronavirus-induced disease 2019 (COVID-19) leads to acute respiratory distress syndrome with an increased risk of venous thrombo-embolic events. To a much lesser extent, arterial thrombo-embolic events have also been reported in this setting. CASE SUMMARY: Here, we describe four different cases of COVID-19 infection with ischaemic arterial events, such as a myocardial infarction with high thrombus load, ischaemic stroke on spontaneous thrombosis of the aortic valve, floating thrombus with mesenteric, splenic and renal infarction, and acute limb ischaemia. DISCUSSION: Cardiovascular risk factors such as hypertension, obesity, and diabetes are comorbidities most frequently found in patients with a severe COVID-19 infection and are associated with a higher death rate. Our goal is to provide an overview of the clinical spectrum of ischaemic arterial events that may either reveal or complicate COVID-19. Several suspected pathophysiological mechanisms could explain the association between cardiovascular events and COVID-19 (role of systemic inflammatory response syndrome, endothelial dysfunction, activation of coagulation cascade leading to a hypercoagulability state, virus-induced secondary antiphospholipid syndrome). We need additional studies of larger size, to estimate the incidence of these arterial events and to assess the efficacy of anticoagulation therapy.

Advanced echocardiographic phenotyping of critically ill patients with coronavirus-19 sepsis: a prospective cohort study.

BACKGROUND: Sepsis is characterized by various hemodynamic alterations which could happen concomitantly in the heart, pulmonary and systemic circulations. A comprehensive demonstration of their interactions in the clinical setting of COVID-19 sepsis is lacking. This study aimed at evaluating the feasibility, clinical implications, and physiological coherence of the various indices of hemodynamic function and acute myocardial injury (AMI) in COVID-19 sepsis. METHODS: Hemodynamic and echocardiographic data of septic critically ill COVID-19 patients were prospectively recorded. A dozen hemodynamic indices exploring contractility and loading conditions were assessed. Several cardiac biomarkers were measured, and AMI was considered if serum concentration of high-sensitive troponin T (hs-TNT) was above the 99th percentile, upper reference. RESULTS: Sixty-seven patients were assessed (55 males), with a median age of 61 [50-70] years. Overall, the feasibility of echocardiographic parameters was very good, ranging from 93 to 100%. Hierarchical clustering method identified four coherent clusters involving cardiac preload, left ventricle (LV) contractility, LV afterload, and right ventricle (RV) function. LV contractility indices were not associated with preload indices, but some of them were positively correlated with RV function parameters and negatively correlated with a single LV afterload parameter. In most cases (n = 36, 54%), echocardiography results prompted therapeutic changes. Mortality was not influenced by the echocardiographic variables in multivariable analysis. Cardiac biomarkers' concentrations were most often increased with high incidence of AMI reaching 72%. hs-TNT was associated with mortality and inversely correlated with most of LV and RV contractility indices. CONCLUSIONS: In this comprehensive hemodynamic evaluation in critically ill COVID-19 septic patients, we identified four homogeneous and coherent clusters with a good feasibility. AMI was common and associated with alteration of LV and RV functions. Echocardiographic assessment had a clinical impact on patient management in most cases.

Preventive measures for the critical postexercise period in sickle cell trait and disease.

The immediate postexercise/physical activity period is critical for sickle cell trait (SCT) carriers and disease (SCD) patients. Exercise-related blood acidosis is known to trigger the cascade of HbS deoxygenation and polymerization, leading to red blood cell sickling and subsequent complications. Unfortunately, two facts worsen exercise-related blood acidosis during the initial postexercise period: First, blood lactate and H+ concentrations continue to increase for several minutes after exercise completion, exacerbating blood acidosis. Second, blood lactate concentration remains elevated and pH altered for 20-45 min during inactivity after intense exercise, keeping acid/base balance disturbed for a long period after exercise. Therefore, the risk of complications (including vasoocclusive crises and even sudden death) persists and even worsens several minutes after intense exercise completion in SCT carriers or SCD patients. Light physical activity following intense exercise (namely, active recovery) may, by accelerating lactate removal and acid/base balance restoration, reduce the risk of complications. Scientific evidence suggests that light exercise at or below the first lactate threshold is an appropriate strategy.

Is hypoxemia explained by intracardiac or intrapulmonary shunt in COVID-19-related acute respiratory distress syndrome?

Hypoxemia is the main feature of COVID-19-related acute respiratory distress syndrome (C-ARDS), but its underlying mechanisms are debated, especially in patients with low respiratory system elastance (Ers). We assessed 60 critically ill patients hospitalized in our intensive care unit for C-ARDS. We used contrast transthoracic echocardiography to assess patent foramen ovale (PFO) shunt and transpulmonary bubble transit (TPBT). The median Ers was 32 cmH2O/L. PFO shunt was detected in six (10%) patients and TPBT in 12 (20%) patients. PFO shunt and TPBT were similar in patients with higher or lower Ers. In conclusion, PFO and TPBT do not seem to be the main drivers of hypoxemia in C-ARDS, especially in patients with lower Ers.