Mitophagy modulation for the treatment of cardiovascular diseases.

BACKGROUND: Defects of mitophagy, the selective form of autophagy for mitochondria, are commonly observed in several cardiovascular diseases and represent the main cause of mitochondrial dysfunction. For this reason, mitophagy has emerged as a novel and potential therapeutic target. METHODS: In this review, we discuss current evidence about the biological significance of mitophagy in relevant preclinical models of cardiac and vascular diseases, such as heart failure, ischemia/reperfusion injury, metabolic cardiomyopathy and atherosclerosis. RESULTS: Multiple studies have shown that cardiac and vascular mitophagy is an adaptive mechanism in response to stress, contributing to cardiovascular homeostasis. Mitophagy defects lead to cell death, ultimately impairing cardiac and vascular function, whereas restoration of mitophagy by specific compounds delays disease progression. CONCLUSIONS: Despite previous efforts, the molecular mechanisms underlying mitophagy activation in response to stress are not fully characterized. A comprehensive understanding of different forms of mitophagy active in the cardiovascular system is extremely important for the development of new drugs targeting this process. Human studies evaluating mitophagy abnormalities in patients at high cardiovascular risk also represent a future challenge.

Massive pericardial effusion in an infant with Aymé-Gripp syndrome: A case report and review of the literature.

Aymé-Gripp syndrome (AYGRPS) is a multisystemic disorder caused by a subset of pathogenic variants in the MAF gene. Major clinical features include bilateral early cataracts, sensorineural hearing loss (SNHL), and a characteristic facial appearance along with variable neurodevelopmental delay. Pericarditis resulting in pericardial effusion of varying degree has been observed in a subset of affected individuals and could represent a severe feature in neonatal or infantile age. Here, we describe a syndromic infant with massive pericardial effusion and craniofacial features that oriented toward the suspicion of AYGRPS, which was subsequently confirmed by the molecular analysis of MAF. Pericardial effusion was first observed prenatally and documented to be recurrent, progressive, and severe in the first months of life, thus requiring pericardiocentesis and surgical procedures. In this report, we provide further delineation of the minor clinical characteristics, particularly focusing on cardiac features of AYGRPS. A dedicated cardiac surveillance of these findings may help reduce the morbidity and mortality of this rare condition.

Similarities and differences between myocarditis following COVID-19 mRNA vaccine and multiple inflammatory syndrome with cardiac involvement in children.

Despite the multiple benefits of vaccination, cardiac adverse Events Following COVID-19 Immunization (c-AEFI) have been reported. These events as well as the severe cardiac involvement reported in Multisystem inflammatory syndrome in children (MIS-C) appear more frequent in young adult males. Herein, we firstly report on the inflammatory profiles of patients experiencing c-AEFI in comparison with age, pubertal age and gender matched MIS-C with cardiac involvement. Proteins related to systemic inflammation were found higher in MIS-C compared to c-AEFI, whereas a higher level in proteins related to myocardial injury was found in c-AEFI. In addition, higher levels of DHEAS, DHEA, and cortisone were found in c-AEFI which persisted at follow-up. No anti-heart muscle and anti-endothelial cell antibodies have been detected. Overall current comparative data showed a distinct inflammatory and androgens profile in c-AEFI patients which results to be well restricted on heart and to persist months after the acute event.

Variability of cardiac troponin levels in normal subjects and in patients with cardiovascular diseases: analytical considerations and clinical relevance.

In accordance with all the most recent international guidelines, the variation of circulating levels of cardiac troponins I and T, measured with high-sensitivity methods (hs-cTnI and hs-cTnT), should be used for the detection of acute myocardial injury. Recent experimental and clinical evidences have demonstrated that the evaluation of hs-cTnI and hs-cTnT variations is particularly relevant: a) for the differential diagnosis of Acute Coronary Syndromes (ACS) in patients admitted to the Emergency Department (ED); b) for the evaluation of cardiovascular risk in patients undergoing major cardiac or non-cardiac surgery, and in asymptomatic subjects of the general population aged >55 years and with co-morbidities; c) for the evaluation of cardiotoxicity caused by administration of some chemotherapy drugs in patients with malignant tumors. The aim of this document is to discuss the fundamental statistical and biological considerations on the intraindividual variability of hs-cTnI and hs-cTnT over time in the same individual. Firstly, it will be discussed in detail as the variations of circulating levels strictly depend not only on the analytical error of the method used but also on the intra-individual variability of the biomarker. Afterwards, the pathophysiological interpretation and the clinical relevance of the determination of the variability of the hs-cTnI and hs-cTnT values ​​ in patients with specific clinical conditions are discussed. Finally, the evaluation over time of the variation in circulating levels of hs-cTnI and hs-cTnT is proposed for a more accurate estimation of cardiovascular risk in asymptomatic subjects from the general population.

Inflammageing and Cardiovascular System: Focus on Cardiokines and Cardiac-Specific Biomarkers.

The term "inflammageing" was introduced in 2000, with the aim of describing the chronic inflammatory state typical of elderly individuals, which is characterized by a combination of elevated levels of inflammatory biomarkers, a high burden of comorbidities, an elevated risk of disability, frailty, and premature death. Inflammageing is a hallmark of various cardiovascular diseases, including atherosclerosis, hypertension, and rapid progression to heart failure. The great experimental and clinical evidence accumulated in recent years has clearly demonstrated that early detection and counteraction of inflammageing is a promising strategy not only to prevent cardiovascular disease, but also to slow down the progressive decline of health that occurs with ageing. It is conceivable that beneficial effects of counteracting inflammageing should be most effective if implemented in the early stages, when the compensatory capacity of the organism is not completely exhausted. Early interventions and treatments require early diagnosis using reliable and cost-effective biomarkers. Indeed, recent clinical studies have demonstrated that cardiac-specific biomarkers (i.e., cardiac natriuretic peptides and cardiac troponins) are able to identify, even in the general population, the individuals at highest risk of progression to heart failure. However, further clinical studies are needed to better understand the usefulness and cost/benefit ratio of cardiac-specific biomarkers as potential targets in preventive and therapeutic strategies for early detection and counteraction of inflammageing mechanisms and in this way slowing the progressive decline of health that occurs with ageing.

Performance evaluation of the new Chemiluminescence Immunoassay CL-1200i Thyroid Panel.

Aim of this work was to verify the analytical performance of thyroid panel tests measured by chemiluminescence immunoassay (CLIA) CL-1200i and to validate its efficacy as laboratory test for thyroid disorder.Serum samples were obtained by standard centrifugation, thawed and assayed in a blinded fashion, and in a single batch. This study compares the values of thyroid panel tests measured by Mindray CL-1200i chemiluminescent system to the Abbott platforms for TSH, FT3, FT4, and Beckman Coulter for Tg, TgAb, and TPOAb on patient serum samples. A total of 180 randomly selected patients including both hospitalized and ambulatory patients from the Policlinico Tor Vergata (PTV) of the University of Rome Tor Vergata were used. In all analyses performed, the thyroid panel tests of the Mindray platform showed discriminative ability to quantitatively assess the analyte involved in thyroid disease and disorder. This study verified that Mindray CL-1200i chemiluminescent system thyroid panel tests is a valid method for obtaining a quantitative analysis of thyroid disorders. It showed high diagnostic efficiency and could represent a valid tool with a potential reduction in time and workload for the diagnosis.

Concurrent Aerobic Plus Resistance Training Elicits Different Effects on Short-Term Blood Pressure Variability of Hypertensive Patients in Relation to Their Nocturnal Blood Pressure Pattern.

Background and Objectives: The purpose of this study was to investigate the effects of a 12-week concurrent training (CT) (i.e., aerobic plus resistance exercise) on short-term blood pressure variability (BPV) and BP values in hypertensive patients with non-dippper BP nocturnal pattern and underlying coronary artery disease. Material and Methods: The study included 72 consecutive patients who were divided into two groups according to the nocturnal BP pattern: dipping pattern (33 pts) and non-dipping (39 pts). Before starting CT and at 12 weeks, patients underwent the six minute walk test, ergometric test, assessment of 1-repetiton maximum (1 RM), and 24/h BP monitoring (24-h ABPM). Results: After CT, exercise capacity increased in both groups in a similar fashion. Twenty-four/h systolic BPV and daytime systolic BPV decreased significantly in the dipping group while they were unchanged in the non-dipping group (between groups changes: -1.0 ± 0.4 mmHg and -1.3 ± 0.9 mmHg; p = 0.02 and p = 0.006, respectively). Twenty-four/h systolic BP and daytime systolic BP decreased significantly in the dipping group while they were unchanged in the non-dipping group (between groups changes: -7.1 ± 2.6 mmHg and -7.8 ± 2.4 mmHg; p = 0.004 and p = 0.002, respectively). Nighttime systolic BP and BPV was unchanged in both groups. Twenty-four/h diastolic BP presented small but not significant changes in both groups. Conclusions: The effects of CT on BPV and BP were blunted in hypertensive subjects with a non-dipping BP pattern.

Evaluation of the Diesse Cube 30 touch erythrocyte sedimentation method in comparison with Alifax test 1 and the manual Westergren gold standard method.

The erythrocyte sedimentation rate (ESR) is a traditional nonspecific laboratory test used for the assessment of inflammation. Even if its usefulness is nowadays being largely debated, it is still considered a valuable laboratory test in selected clinical conditions, such as rheumatoid diseases, orthopedic infections and Hodgkin's lymphoma, and it can be used for the infectious, inflammatory, malignancies, and autoimmune diseases follow-up. The introduction of new methodologies on semi-automated and automated analyzers started about four decades ago and opened a new era of ESR analysis characterized by shorter assay time, use of (EDTA) undiluted blood, that increases sample stability and allows using a single sample for also other hematologic tests, and greater safety for laboratory personnel. In this context, the aim of this study was to evaluate the performances of new device Diesse Cube 30 touch, comparing it with Alifax Test 1 and with the gold standard Westergren method. The new Diesse Cube 30 touch for determination of the ESR shows a good correlation with the manual Westergren gold standard method in a shorter time, and in a standardized way, since all the phases of the test are automatized. The Diesse Cube 30 touch respect the manual gold standard method, displayed a small bias to confirm that the new automated test system tended to have a small bias for ESR values (mean positive bias +0.2 mm/h). The findings of the present study show that the Diesse Cube 30 touch Westergren-based method can be a valid alternative in laboratory analysis for the determination of ESR.

The unpredictable resorption of bioresorbable scaffolds-A tale of two ABSORBs.

Bioresorbable stents represent a revolutionary treatment for coronary artery disease. Such a device offers the prospect for complete naturalization of artery lumen after strut resorption and restoration of vasomotion while curtailing the duration of dual anti-platelet therapy. The prototype bioresorbable scaffold (BRS-ABSORB GT1) demonstrated good feasibility and safety in the initial studies compared to metallic drug eluting stent but later fell out of favor due to multiple report of stent thrombosis and target lesion failure. Unpredictable resorption of struts turned out to be one of the "Achilles heel" of the BRS and stent strut were still visible in vessel on optical coherence tomography (OCT) at 3 years. We report a case of differential resorption of two ABSORB BRS implanted simultaneously in the same patient by the same operator. Follow up coronary angiogram revealed only minimal plaques on right coronary artery (RCA) and left anterior descending artery (LAD). The BRS were identified on cine-angiogram by their radio-opaque markers at both ends. The OCT run in LAD artery revealed "ghost remnants" of BRS struts in LAD, whereas the RCA BRS had completely healed with minimal "ghost" struts. The ghost remnants of BRS resembled the original "Check box" appearance on OCT during the index implantation.

Vitamin D Deficiency in Professional Football Players during Competitive Season of Italian First Division (Serie A).

BACKGROUND: Data in the literature have demonstrated the crucial role that vitamin D plays in the human organism, and recent studies also emphasize this essential role of vitamin D in athletes. Indeed, vitamin D acts on the skeletal muscles and plays a fundamental role in numerous physiological processes involved in immune function. Many factors such as sun exposure, skin tone, body mass index and chronic illness affect vitamin D levels. The aim of the study is to evaluate vitamin D levels in professional football players in Italy and investigate the variations in vitamin D values in footballers who train at different latitudes. METHODS: The study performed is a retrospective observational study analyzing 25-OH vitamin D values in professional football players of the Italian First Division (Serie A). Two teams during the competitive season were selected: team A (latitude of 41° N in southern Italy) and team B (latitude of 45° N in northern Italy). Three time periods were identified and were classified as follows: the first quarter (May, June, July, and August), the second quarter (September, October, November, and December) and the third quarter (January, February, March, and April). The purpose of this was to study the average values of vitamin D during the year corresponding to different levels of sunlight exposure. Each athlete was subjected to at least one sampling during the three quarters of the competitive season. RESULTS: Both vitamin D insufficiency (10.1%) and overt deficiency (1.93%) were found in Italian Serie A players. Insufficient vitamin D values are between 20 ng/mL and 29 ng/mL and overt deficiency values <20 ng/mL. At the same time, the data demonstrated a significant variation in vitamin D values depending on the period of the competitive season and the latitude of the cities of the two teams. In detail, there was no significant difference in the first quarter, while there was a significant increase in vitamin D values in team B in the second and third quarter, at p < 0.01 and p < 0.05, respectively. CONCLUSIONS: Latitude and seasons have a significant impact on vitamin D levels. Therefore, it is essential to measure vitamin D in professional football players, especially during the spring and winter months, so as to monitor changes in levels in relation to the season and latitude and evaluate any supplements. Further studies should be performed to evaluate the relationship between vitamin D deficiency and football players' athletic performance.

Changes in left atrial function following two regimens of combined exercise training in patients with ischemic cardiomyopathy: a pilot study.

Purpose: Left atrial dysfunction has shown to play a prognostic role in patients with ischemic cardiomyopathy (ICM) and is becoming a therapeutic target for pharmacological and non-pharmacological interventions. The effects of exercise training on the atrial function in patients with ICM have been poorly investigated. In the present study, we assessed the effects of a 12-week combined training (CT) program on the left atrial function in patients with ICM. Methods: We enlisted a total of 45 clinically stable patients and randomly assigned them to one of the following three groups: 15 to a supervised CT with low-frequency sessions (twice per week) (CTLF); 15 to a supervised CT with high-frequency sessions (thrice per week) (CTHF); and 15 to a control group following contemporary preventive exercise guidelines at home. At baseline and 12 weeks, all patients underwent a symptom-limited exercise test and echocardiography. The training included aerobic continuous exercise and resistance exercise. The analysis of variance (ANOVA) was used to compare within- and inter-group changes. Results: At 12 weeks, the CTLF and CTHF groups showed a similar increase in the duration of the ergometric test compared with the control (ANOVA p < 0.001). The peak atrial longitudinal strain significantly increased in the CTHF group, while it was unchanged in the CTLF and control groups (ANOVA p = 0.003). The peak atrial contraction strain presented a significant improvement in the CTHF group compared with the CTLF and control groups. The left ventricular global longitudinal strain significantly increased in both the CTHF and the CTLF groups compared with the control group (ANOVA p = 0.017). The systolic blood pressure decreased in the CTHF and CTLF groups, while it was unchanged in the control group. There were no side effects causing the discontinuation of the training. Conclusions: We demonstrated that a CT program effectively improved atrial function in patients with ICM in a dose-effect manner. This result can help with programming exercise training in this population.

The Use of Stress Cardiovascular Imaging in Pediatric Population.

Although not frequent in the pediatric population, ischemia could occur in children due to several congenital and acquired disease. Stress imaging is key for the non-invasive evaluation of myocardial abnormalities and perfusion defect in this clinical setting. Moreover, beyond ischemia assessment, it can provide complementary diagnostic and prognostic information in valvular heart disease and cardiomyopathies. When performed using cardiovascular magnetic resonance, it could detect, in addition, myocardial fibrosis and infarction, increasing the diagnostic yield. Several imaging modalities are currently available for the evaluation of stress myocardial perfusion. Advances in technologies have also increased the feasibility, safety and availability of these modalities in the pediatric age group. However, despite the established role of stress imaging and its increasing use in daily clinical practice, there are currently no specific guidelines, and little data are available in the literature on this topic. The aim of this review is to summarize the most recent evidence on pediatric stress imaging and its clinical application with a focus on the advantages and limitations of each imaging modality currently available.

Anticoagulation for Left Ventricle Thrombus-Case Series and Literature Review for Use of Direct Oral Anticoagulants.

Left ventricular thrombus is a known complication following acute myocardial infarction that can lead to systemic thromboembolism. To obviate the risk of thromboembolism, the patient needs anticoagulation in addition to dual antiplatelet therapy. However, combining antiplatelets with anticoagulants substantially increases the bleeding risk. Traditionally, vitamin K antagonists (VKAs) have been the sheet anchor for anticoagulation in this scenario. The use of direct oral anticoagulants has significantly attenuated the bleeding risk associated with anticoagulation for atrial fibrillation and venous thromboembolism. Furthermore, in patients with atrial fibrillation undergoing percutaneous coronary intervention, the use of direct oral anticoagulants (DOACs) in conjunction with antiplatelets has been found to be noninferior in reducing ischemic events while significantly attenuating the bleeding compared with VKA. After initial case reports, multiple observational and nonrandomized studies have now safely and effectively utilized direct oral anticoagulants for anticoagulation in left ventricular thrombus. Here, we report a series of two cases presenting with left ventricular thrombus following acute myocardial infarction. In this case series, we try to address the issues concerning the choice and duration of anticoagulation in the case of postinfarct left ventricular thrombus. Pending the results of large randomized control trials, the judicious use of direct oral anticoagulant is warranted when taking into consideration the ischemic and bleeding profile in an individualized approach.

Effects of Concurrent, Within-Session, Aerobic and Resistance Exercise Training on Functional Capacity and Muscle Performance in Elderly Male Patients with Chronic Heart Failure.

BACKGROUND: The best format of exercise training (ET) in the setting of cardiac rehabilitation in patients with chronic heart failure (CHF) is still to be defined. Current guidelines recommend aerobic exercises, such as running and cycling, including some sessions per week of resistance exercise. AIM: The aim of this study was to address the effectiveness of a concurrent exercise training program utilizing a circuit of sequential endurance and resistance exercises on functional capacity and muscular strength in patients with CHF. METHODS: Ninety-five consecutive male patients (age 63.1 ± 6 years) with CHF (EF < 40%) in NYHA functional class II/III, were randomly assigned on 1:1 basis to a 12-week aerobic continuous training (AT) or concurrent CT), aerobic + resistance, training (CT), three times a week, with each session lasting 80 min. We used high quality, specifically designed ergometers, connected with each other and governed by a central console, and managed by a single physiotherapist. Before and after training all patients performed a symptoms-limited exercise test on a treadmill and a 6-min walking test (6MWT). Patients in the CT group also performed resistance exercises of upper and lower body. RESULTS: The 6MWT and exercise duration at ergometric test increased significantly in both AT and CT groups, with the increase being greater in CT group (p < 0.001; ES = 0.13; p < 0.01; ES = 0.07). Muscular strength increased significantly in the CT group, particularly in the lower body muscular districts (p < 0.001). Quality of life improved in both groups, with a significantly greater improvement in the CT group (p < 0.05). No side effects leading to discontinuation of training were observed. CONCLUSIONS: These findings indicate that concurrent, within-session training results in larger improvements in functional capacity, in addition to muscle performance, in patients with CHF, in comparison to single-mode aerobic training.

Bempedoic Acid: An Emerging Therapy for Uncontrolled Low-Density Lipoprotein (LDL) Cholesterol.

Atherosclerotic cardiovascular disease (ASCVD) is a silent epidemic, which is progressing relentlessly across the globe. Developing countries such as India have a high prevalence of dyslipidemia and consequently a huge burden of coronary artery disease (CAD) and ASCVD. Low-density lipoprotein is regarded as the primary culprit in the genesis of ASCVD, and statins are the first line therapy for LDL-C lowering. Statin therapy has unequivocally demonstrated the benefit of lowering LDL-C in patients across the spectrum of CAD and ASCVD. Muscle symptoms and worsening of glycemic homeostasis could be challenges with statin therapy, especially with the use of high doses. A large fraction of patients are also unable to achieve their LDL goals with statins alone in clinical practice. Moreover, LDL-C goals have become aggressive over years, necessitating a combination of lipid lowering therapies. PCSK-9 inhibitors and Inclisiran have emerged as robust and safe lipid-lowering agents, but parenteral administration and high cost precludes their widespread use. Bempedoic acid is a novel lipid-lowering agent working upstream of statins by inhibiting the enzyme ATP citrate lyase (ACL). The drug produces an average LDL lowering of 22-28% in statin-naïve patients and 17-18% when given to preexisting statin users. Because skeletal muscles lack the ACL enzyme, there is minimal risk of muscle-related symptoms. In combination with ezetimibe, the drug synergistically reduced LDL-C by 39%. Moreover, the drug has no adverse effect on glycemic parameters and lowers hsCRP (inflammation) like statin. The series of four randomized CLEAR trials, involving >4000 patients, have shown consistent LDL lowering across the spectrum of ASCVD patients with or without background therapy. The large and only cardiovascular outcome trial of the drug (CLEAR Outcomes) has recently demonstrated a 13% reduction of MACE at 40 months. Rise in levels of uric acid (four times) and acute gout (three times) are more common compared to placebo with the drug, owing to competitive renal transportation by OAT 2. In a nutshell, Bempedoic acid represents a value addition to the inventory of dyslipidemia management.

Pregnancy in Patients with Moderate and Highly Complex Congenital Heart Disease.

Although not completely devoid of risk, pregnancy can be managed in virtually all patients affected by even the most complex forms of congenital heart disease. It is not however advisable in patients with any form of pulmonary arterial hypertension. Pregnancy is even manageable in patients with univentricular heart converted to Fontan circulation. A personalised risk stratification should be performed, and patients affected by advanced NYHA functional class appropriately warned of the potential risks. In this setting, metabolomics might represent a novel tool for use in conducting personalised risk stratification. All pregnancies, particularly those at higher risk, should be managed in a tertiary care centre capable of providing the necessary assistance to both the mother and infant. With a few rare exceptions, vaginal delivery is to be preferred over caesarean section due to the lower degree of maternal and foetal complications. The desire for motherhood, at times extreme in women with congenital heart disease, may often be accomplished, thus providing a ray of hope in the lives of these patients.

Myocardial Functional Imaging in Pediatric Nuclear Cardiology.

The role of nuclear medicine in pediatric cardiology has grown rapidly over the years, providing useful functional and prognostic information and playing a complementary role to morphological imaging in the evaluation of myocardial perfusion, cardiovascular inflammation and infections, and cardiac sympathetic innervation. The aim of this narrative review is to summarize and highlight the most important evidence on pediatric nuclear cardiology, describing clinical applications and the possibilities, advantages, and limitations of nuclear medicine techniques. Moreover, a special focus will be given to the minimization of radiation exposure in pediatric nuclear cardiology imaging, a critical topic in children.

Changes in the Cath Lab in the Treatment of Adult Patients with Congenital Heart Disease: A 12-Year Experience in a Single Referral Center with the Establishment of a Dedicated Working Group.

BACKGROUND: Adults with congenital heart disease (ACHD) are a growing population needing ongoing care. The aim of this study was to investigate if a dedicated ACHD team impacted the timing and indication of invasive cardiology procedures in these patients at our hospital. METHODS: Our retrospective single-center study enrolled adult patients with moderate or complex congenital heart disease and with at least one cardiac catheterization between January 2010 and December 2021. According to the period, procedures were labeled as group A (2010 to 2015) or group B (2016 to 2021) and further divided into diagnostic (DCC) and interventional cardiac catheterizations (ICC). RESULTS: 594 patients were eligible for the study. Both DCC (p < 0.05) and ICC increased between groups A and B (p < 0.05). In group B: Fontan patients accounted for the majority of DCC (p < 0.001), while DCC decreased in arterial switch repair (p < 0.001). In Fontan patients, conduit stenting was prevalent (p < 0.001), while fenestration closures dropped (p < 0.01). In patients with tetralogy of Fallot and native outflow tract, percutaneous pulmonary valve implantations (PPVI) increased, with a concurrent reduction in pulmonary valve replacements (p < 0.001 vs. surgical series). In right ventricular conduits, ICC increased (p < 0.01), mainly due to PPVI. Among Mustard/Senning patients, baffle stenting increased from Group A to Group B (p < 0.001). In patients with pulmonary atresia and biventricular repair, ICC often increased for pulmonary artery stenting. CONCLUSIONS: A dedicated working group could improve ACHD patients' indications for interventional procedures, leading to tailored treatment, better risk stratification and optimizing time until heart transplantation.

Acute Changes on Left Atrial Function during Incremental Exercise in Patients with Heart Failure with Mildly Reduced Ejection Fraction: A Case-Control Study.

BACKGROUND: the aim of this study was to assess acute changes in left atrial (LA) function during incremental aerobic exercise in patients with heart failure with mildly reduced ejection fraction (HFmrEF) in comparison to healthy subjects (HS). METHODS: twenty patients with established HFmrEF were compared with 10 HS, age-matched controls. All subjects performed a stepwise exercise test on a cycle ergometer. Echocardiography was performed at baseline, during submaximal effort, at peak of exercise, and after 5 min of recovery. RESULTS: HS obtained a higher value of METs at peak exercise than HFmrEF (7.4 vs. 5.6; between group p = 0.002). Heart rate and systolic blood pressure presented a greater increase in the HS group than in HFmrEF (between groups p = 0.006 and 0.003, respectively). In the HFmrEF group, peak atrial longitudinal strain (PALS) and conduit strain were both increased at submaximal exercise (p < 0.05 for both versus baseline) and remained constant at peak exercise. Peak atrial contraction strain (PACS) did not show significant changes during the exercise. In the HS group, PALS and PACS increased significantly at submaximal level (p < 0.05 for both versus baseline), but PALS returned near baseline values at peak exercise; conduit strain decreased progressively during the exercise in HS. Stroke volume (SV) increased in both groups at submaximal exercise; at peak exercise, SV remained constant in the HFmrEF, while it decreased in controls (between groups p = 0.002). CONCLUSIONS: patients with HFmrEF show a proper increase in LA reservoir function during incremental aerobic exercise that contributes to maintain SV throughout the physical effort.