Symptomatic post COVID patients have impaired alveolar capillary membrane function and high VE/VCO2.

BACKGROUND: Post COVID-19 syndrome is characterized by several cardiorespiratory symptoms but the origin of patients' reported symptomatology is still unclear. METHODS: Consecutive post COVID-19 patients were included. Patients underwent full clinical evaluation, symptoms dedicated questionnaires, blood tests, echocardiography, thoracic computer tomography (CT), spirometry including alveolar capillary membrane diffusion (DM) and capillary volume (Vcap) assessment by combined carbon dioxide and nitric oxide lung diffusion (DLCO/DLNO) and cardiopulmonary exercise test. We measured surfactant derive protein B (immature form) as blood marker of alveolar cell function. RESULTS: We evaluated 204 consecutive post COVID-19 patients (56.5 ± 14.5 years, 89 females) 171 ± 85 days after the end of acute COVID-19 infection. We measured: forced expiratory volume (FEV1) 99 ± 17%pred, FVC 99 ± 17%pred, DLCO 82 ± 19%, DM 47.6 ± 14.8 mL/min/mmHg, Vcap 59 ± 17 mL, residual parenchymal damage at CT 7.2 ± 3.2% of lung tissue, peakVO2 84 ± 18%pred, VE/VCO2 slope 112 [102-123]%pred. Major reported symptoms were: dyspnea 45% of cases, tiredness 60% and fatigability 77%. Low FEV1, Vcap and high VE/VCO2 slope were associated with persistence of dyspnea. Tiredness was associated with high VE/VCO2 slope and low PeakVO2 and FEV1 while fatigability with high VE/VCO2 slope. SPB was fivefold higher in post COVID-19 than in normal subjects, but not associated to any of the referred symptoms. SPB was negatively associated to Vcap. CONCLUSIONS: In patients with post COVID-19, cardiorespiratory symptoms are linked to VE/VCO2 slope. In these patients the alveolar cells are dysregulated as shown by the very high SPB. The Vcap is low likely due to post COVID-19 pulmonary endothelial/vasculature damage but DLCO is only minimally impaired being DM preserved.

Effects of sacubitril/valsartan on exercise capacity: a prognostic improvement that starts during uptitration.

PURPOSE: Sacubitril/valsartan is a mainstay of the treatment of heart failure with reduced ejection fraction (HFrEF); however, its effects on exercise performance yielded conflicting results. Aim of our study was to evaluate the impact of sacubitril/valsartan on exercise parameters and echocardiographic and biomarker changes at different drug doses. METHODS: We prospectively enrolled consecutive HFrEF outpatients eligible to start sacubitril/valsartan. Patients underwent clinical assessment, cardiopulmonary exercise test (CPET), blood sampling, echocardiography, and completed the Kansas City Cardiomyopathy Questionnaire (KCCQ-12). Sacubitril/valsartan was introduced at 24/26 mg b.i.d. dose and progressively uptitrated in a standard monthly-based fashion to 97/103 mg b.i.d. or maximum tolerated dose. Study procedures were repeated at each titration visit and 6 months after reaching the maximum tolerated dose. RESULTS: Ninety-six patients completed the study, 73 (75%) reached maximum sacubitril/valsartan dose. We observed a significant improvement in functional capacity across all study steps: oxygen intake increased, at peak exercise (from 15.6 ± 4.5 to 16.5 ± 4.9 mL/min/kg; p trend = 0.001), while minute ventilation/carbon dioxide production relationship reduced in patients with an abnormal value at baseline. Sacubitril/valsartan induced positive left ventricle reverse remodeling (EF from 31 ± 5 to 37 ± 8%; p trend < 0.001), while NT-proBNP reduced from 1179 [610-2757] to 780 [372-1344] pg/ml (p trend < 0.0001). NYHA functional class and the subjective perception of limitation in daily life at KCCQ-12 significantly improved. The Metabolic Exercise Cardiac Kidney Index (MECKI) score progressively improved from 4.35 [2.42-7.71] to 2.35% [1.24-4.96], p = 0.003. CONCLUSIONS: A holistic and progressive HF improvement was observed with sacubitril/valsartan in parallel with quality of life. Likewise, a prognostic enhancement was observed.

Dysregulation of Iron Metabolism-Linked Genes at Myocardial Tissue and Cell Levels in Dilated Cardiomyopathy.

In heart failure, the biological and clinical connection between abnormal iron homeostasis, myocardial function, and prognosis is known; however, the expression profiles of iron-linked genes both at myocardial tissue and single-cell level are not well defined. Through publicly available bulk and single-nucleus RNA sequencing (RNA-seq) datasets of left ventricle samples from adult non-failed (NF) and dilated cardiomyopathy (DCM) subjects, we aim to evaluate the altered iron metabolism in a diseased condition, at the whole cardiac tissue and single-cell level. From the bulk RNA-seq data, we found 223 iron-linked genes expressed at the myocardial tissue level and 44 differentially expressed between DCM and NF subjects. At the single-cell level, at least 18 iron-linked expressed genes were significantly regulated in DCM when compared to NF subjects. Specifically, the iron metabolism in DCM cardiomyocytes is altered at several levels, including: (1) imbalance of Fe3+ internalization (SCARA5 down-regulation) and reduction of internal conversion from Fe3+ to Fe2+ (STEAP3 down-regulation), (2) increase of iron consumption to produce hemoglobin (HBA1/2 up-regulation), (3) higher heme synthesis and externalization (ALAS2 and ABCG2 up-regulation), (4) lower cleavage of heme to Fe2+, biliverdin and carbon monoxide (HMOX2 down-regulation), and (5) positive regulation of hepcidin (BMP6 up-regulation).

What's behind your eosinophilic myocarditis? A case of Churg-Strauss syndrome diagnosed during acute heart failure.

Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare multisystem disorder; cardiac involvement may include eosinophilic myocarditis. A 67-year-old woman presented with 1-week history of dyspnoea and orthopnoea. She had a history of adult-onset asthma and peripheral eosinophilia. The investigations showed T-wave inversion on lateral leads, peripheral eosinophilia, elevated troponin and BNP values, and severe biventricular systolic dysfunction with diffuse hypokinesia and apical akinesia. Computed tomography excluded coronary disease and showed bilateral basal ground-glass opacities, air-space consolidation, and bilateral reticular-nodular pattern. Cardiac magnetic resonance findings were compatible with active myocardial inflammation. An endomyocardial biopsy (EMB) confirmed the diagnosis of eosinophilic myocarditis, and a therapy with oral corticosteroids and heart failure medications was started.

Revisiting a Prognosticating Algorithm from Cardiopulmonary Exercise Testing in Chronic Heart Failure (from the MECKI Score Population).

Cardiopulmonary exercise testing is a prognostic tool in heart failure with reduced left ventricular ejection fraction (HFrEF). Prognosticating algorithms have been proposed, but none has been validated. In 2017, a predictive algorithm, based on peak oxygen consumption (VO2), ventilatory response to exercise (ventilation [VE] carbon dioxide production [VCO2], the VE/VCO2 slope), exertional oscillatory ventilation (EOV), and peak respiratory exchange ratio, was recommended, according treatment with ß blockers: patients with HFrEF registered in the metabolic exercise test data combined with cardiac and kidney indexes (MECKIs) database were used to validated this algorithm. According to the inclusion/exclusion criteria, 4,683 MECKI patients with HFrEF were enrolled. At 3 years follow-up, the end point was cardiovascular death and urgent heart transplantation (cardiovascular events [CV]). CV events occurred in 25% in patients without ß blockers, whereas those with ß-blockers had 11% (p <0.0001). In patients without ß blockers, 36%, 24%, and 7% CV events were observed in those with peak VO2 ≤10, with peak VO2 >10 <18, and with peak VO2 ≥18 ml/kg/min (p = 0.0001), respectively; in MECKI patients with peak VO2 ≤10 and patients with intermediate exercise capacity, a peak respiratory exchange ratio (≥1.15) and VE/VCO2 slope (≥35) were diriment, respectively (p = 0.0001). EOV, when occurred, increased risk. In MECKI patients on ß blockers, 29%, 17%, and 8% CV events were noticed in those with a peak VO2 ≤8, with peak VO2 = 8 to 12, and patients with peak VO2 ≥12 ml/kg/min, respectively (p = 0.0000); when EOV was monitored an increment of risk was witnessed. In conclusion, the outcome of this algorithm was confirmed with the MECKI cohort.

Pick Your Threshold: A Comparison Among Different Methods of Anaerobic Threshold Evaluation in Heart Failure Prognostic Assessment.

BACKGROUND: In clinical practice, anaerobic threshold (AT) is used to guide training and rehabilitation programs, to define risk of major thoracic or abdominal surgery, and to assess prognosis in heart failure (HF). AT of oxygen uptake (V.O2; V.O2AT) has been reported as an absolute value (V.O2ATabs), as a percentage of predicted peak V.O2 (V.O2AT%peak_pred), or as a percentage of observed peak V.O2 (V.O2AT%peak_obs). A direct comparison of the prognostic power among these different ways to report AT is missing. RESEARCH QUESTION: What is the prognostic power of these different ways to report AT? STUDY DESIGN AND METHODS: In this observational cohort study, we screened data of 7,746 patients with HF with a history of reduced ejection fraction (< 40%) recruited between 1998 and 2020 and enrolled in the Metabolic Exercise Combined With Cardiac and Kidney Indexes register. All patients underwent a maximum cardiopulmonary exercise test, executed using a ramp protocol on an electronically braked cycle ergometer. RESULTS: This study considered 6,157 patients with HF with identified AT. Follow-up was median, 4.2 years (25th-75th percentiles, 1.9-5.0 years). Both V.O2ATabs (mean ± SD, 823 ± 305 mL/min) and V.O2AT%peak_pred (mean ± SD, 39.6 ± 13.9%), but not V.O2AT%peak_obs (mean ± SD, 69.2 ± 17.7%), well stratified the population regarding prognosis (composite end point: cardiovascular death, urgent heart transplant, or left ventricular assist device). Comparing area under the receiver operating characteristic curve (AUC) values, V.O2ATabs (0.680) and V.O2AT%peak_pred (0.688) performed similarly, whereas V.O2AT%peak_obs (0.538) was significantly weaker (P < .001). Moreover, the V.O2AT%peak_pred AUC value was the only one performing as well as the AUC based on peak V.O2 (0.710), with an even a higher AUC (0.637 vs 0.618, respectively) in the group with severe HF (peak V.O2 < 12 mL/min/kg). Finally, the combination of V.O2AT%peak_pred with peak V.O2 and V. per CO2 production shows the highest prognostic power. INTERPRETATION: In HF, V.O2AT%peak_pred is the best way to report V.O2 at AT in relationship to prognosis, with a prognostic power comparable to that of peak V.O2 and, remarkably, in patients with severe HF.

Unexpected Huge Prevalence of Intracardiac Extension of Wilms Tumor-A Single Center Experience from a Ugandan Hospital.

Wilms tumor (WT) is the most common primary renal malignancy in young children. WT vascular extension to the inferior vena cava (IVC) occurs in 4-10% of cases and can reach the right atrium (RA) in 1%. Data on WT clinical presentation and outcome in developing countries are limited. The aim of the present study is to describe the prevalence of intracardiac extension in a consecutive population of WT patients observed in a large non-profit Ugandan hospital. A total of 16 patients with a histological diagnosis of 29 WT were screened in a 6-month period. Patient n°2, a 3 y/o child, presented with a 3-week history of abdominal distension, difficulty in breathing, and swelling of the lower limbs. A cardiovascular system exam showed rhythmic heart sounds, a heart rate of 110 beats per minute, and a pansystolic murmur on the tricuspid area; the abdomen was grossly distended with a palpable mass in the right flank, hepatomegaly, and splenomegaly. An abdomen ultrasound showed an intra-abdominal tumor, involving the right kidney and the liver and extended to the IVC. An ultrasound guided biopsy showed a picture consistent with WT. Cardiac echo showed a huge, mobile, cardiac mass attached to the right side of the interatrial septum, involving the tricuspid valve annulus, causing a "functional" tricuspid stenosis. The patient died of cardiogenic shock 7 days after admission. Patient n°3, a 3 y/o child, presented with analogue symptoms and the same diagnosis. The cardiac echo showed a round mass in the RA. Thirteen more patients were screened with cardiac echo, showing a normal heart picture. In our limited series, we found WT cardiac extension in three patients over 16 (19%). Cardiac echo performed routinely can lead to a better staging, prognostic, and therapeutic assessment. In our setting, the intra-cardiac extension could be more frequent than previously reported and might have prognostic implications.

A case of myopericarditis recurrence after third dose of BNT162b2 vaccine against SARS-CoV-2 in a young subject: link or causality?

The rate of post-vaccine myocarditis is being studied from the beginning of the massive vaccination campaign against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Although a direct cause-effect relationship has been described, in most cases, the vaccine pathophysiological role is doubtful. Moreover, it is not quite as clear as having had a previous myocarditis could be a risk factor for a post-vaccine disease relapse. A 27-year-old man presented to the emergency department for palpitations and pericardial chest pain radiated to the upper left limb, on the 4th day after the third dose of BNT162b2 vaccine. He experienced a previous myocarditis 3 years before, with full recovery and no other comorbidities. Electrocardiogram showed normal atrioventricular conduction, incomplete right bundle branch block, and diffuse ST-segment elevation. A cardiac echo showed lateral wall hypokinesis with preserved ejection fraction. Troponin-T was elevated (160 ng/L), chest X-ray was normal, and the SARS-CoV-2 molecular buffer was negative. High-dose anti-inflammatory therapy with ibuprofen and colchicine was started; in the 3rd day high-sensitivity Troponin I reached a peak of 23000 ng/L. No heart failure or arrhythmias were observed. A cardiac magnetic resonance was performed showing normal biventricular systolic function and abnormal tissue characterization suggestive for acute non-ischaemic myocardial injury (increased native T1 and T2 values, increased signal intensity at T2-weighted images and late gadolinium enhancement, all findings with matched subepicardial distribution) at the level of mid to apical septal, anterior, and anterolateral walls. A left ventricular electroanatomic voltage mapping was negative (both unipolar and bipolar), while the endomyocardial biopsy showed a picture consistent with active myocarditis. The patient was discharged in good clinical condition, on bisoprolol 1.25 mg, ramipril 2.5 mg, ibuprofen 600 mg three times a day, colchicine 0.5 mg twice a day. We presented the case of a young man with history of previous myocarditis, admitted with a non-complicated acute myopericarditis relapse occurred 4 days after SARS-CoV-2 vaccination (3rd dose). Despite the observed very low incidence of cardiac complications following BNT162b2 administration, and the lack of a clear proof of a direct cause-effect relationship, we think that in our patient this link can be more than likely. In the probable need for additional SARS-CoV-2 vaccine doses in the next future, studies addressing the risk-benefit balance of this subset of patient are warranted. We described a multidisciplinary management of a case of myocarditis recurrence after the third dose of SARS-CoV-2 BNT162b2 vaccine.

The double anaerobic threshold in heart failure: MECKI score database overview.

AIMS: In heart failure (HF), anaerobic threshold (AT) may be indeterminable but its value held a relevant prognostic role. AT is evaluated joining three methods: V-slope, ventilatory equivalent, and end-tidal methods. The possible non-concordance between the V-slope (met AT) and the other two methods (vent AT) has been highlighted in healthy individuals and named double threshold (DT). METHODS AND RESULTS: We reanalysed 1075 cardiopulmonary exercise tests of HF patients recruited in the Metabolic Exercise test data combined with Cardiac and Kidney Indexes (MECKI) score database. We identified DT in 43% of cases. Met AT precedes vent AT being met-ventΔVO2 221 (interquartile range: 129-319) mL/min. Peak VO2 , 1307 ± 485 vs. 1343 ± 446 mL/min (63 ± 17 vs. 63 ± 17 percentage of predicted), was similar between DT+ and DT- patients. Differently, DT+ showed a lower ventilatory vs. carbon dioxide production (VE/VCO2 ) slope (29.6 ± 6.1 vs. 31.0 ± 6.3), a lower peak exercise end-tidal oxygen tension (PetO2 ) 115.3 (111.5-118.9) vs. 116.4 (112.4-120.2) mmHg, and a higher carbon dioxide tension (PetCO2 ) 34.2 (30.9-37.1) vs. 32.4 (28.7-35.5) mmHg. Vent AT showed a significant higher VO2 , 957 ± 318 vs. 719 ± 252 mL/min, VCO2 , 939 ± 319 vs. 627 ± 226 mL/min, ventilation, 31.0 ± 8.3 vs. 22.5 ± 6.3 L/min, respiratory exchange ratio, 0.98 ± 0.08 vs. 0.87 ± 0.07, PetO2 , 108 (104-112) vs. 105 (101-109) mmHg, PetCO2 , 37 (34-40) vs. 36 (33-39) mmHg, and VE/VO2 ratio, 33.5 ± 6.7 vs. 32.6 ± 6.9, but lower VE/VCO2 ratio, 33 (30-37) vs. 36 (32-41), compared with met AT. At 2 year survival by Kaplan-Meier analysis, even adjusted for confounders, DT resulted not associated with survival. CONCLUSIONS: Double threshold is frequently observed in HF patients. DT+ is associated to a decreased ventilatory response during exercise.

Prevalence, Characteristics, and Outcomes of COVID-19-Associated Acute Myocarditis.

BACKGROUND: Acute myocarditis (AM) is thought to be a rare cardiovascular complication of COVID-19, although minimal data are available beyond case reports. We aim to report the prevalence, baseline characteristics, in-hospital management, and outcomes for patients with COVID-19-associated AM on the basis of a retrospective cohort from 23 hospitals in the United States and Europe. METHODS: A total of 112 patients with suspected AM from 56 963 hospitalized patients with COVID-19 were evaluated between February 1, 2020, and April 30, 2021. Inclusion criteria were hospitalization for COVID-19 and a diagnosis of AM on the basis of endomyocardial biopsy or increased troponin level plus typical signs of AM on cardiac magnetic resonance imaging. We identified 97 patients with possible AM, and among them, 54 patients with definite/probable AM supported by endomyocardial biopsy in 17 (31.5%) patients or magnetic resonance imaging in 50 (92.6%). We analyzed patient characteristics, treatments, and outcomes among all COVID-19-associated AM. RESULTS: AM prevalence among hospitalized patients with COVID-19 was 2.4 per 1000 hospitalizations considering definite/probable and 4.1 per 1000 considering also possible AM. The median age of definite/probable cases was 38 years, and 38.9% were female. On admission, chest pain and dyspnea were the most frequent symptoms (55.5% and 53.7%, respectively). Thirty-one cases (57.4%) occurred in the absence of COVID-19-associated pneumonia. Twenty-one (38.9%) had a fulminant presentation requiring inotropic support or temporary mechanical circulatory support. The composite of in-hospital mortality or temporary mechanical circulatory support occurred in 20.4%. At 120 days, estimated mortality was 6.6%, 15.1% in patients with associated pneumonia versus 0% in patients without pneumonia (P=0.044). During hospitalization, left ventricular ejection fraction, assessed by echocardiography, improved from a median of 40% on admission to 55% at discharge (n=47; P<0.0001) similarly in patients with or without pneumonia. Corticosteroids were frequently administered (55.5%). CONCLUSIONS: AM occurrence is estimated between 2.4 and 4.1 out of 1000 patients hospitalized for COVID-19. The majority of AM occurs in the absence of pneumonia and is often complicated by hemodynamic instability. AM is a rare complication in patients hospitalized for COVID-19, with an outcome that differs on the basis of the presence of concomitant pneumonia.

Brisk walking can be a maximal effort in heart failure patients: a comparison of cardiopulmonary exercise and 6 min walking test cardiorespiratory data.

AIMS: Cardiopulmonary exercise test (CPET) and 6 min walking test (6MWT) are frequently used in heart failure (HF). CPET is a maximal exercise, whereas 6MWT is a self-selected constant load test usually considered a submaximal, and therefore safer, exercise, but this has not been tested previously. The aim of this study was to compare the cardiorespiratory parameters collected during CPET and 6MWT in a large group of healthy subjects and patients with HF of different severity. METHODS AND RESULTS: Subjects performed a standard maximal CPET and a 6MWT wearing a portable device allowing breath-by-breath measurement of cardiorespiratory parameters. HF patients were grouped according to their CPET peak oxygen uptake (peakV̇O2 ). One hundred and fifty-five subjects were enrolled, of whom 40 were healthy (59 ± 8 years; male 67%) and 115 were HF patients (69 ± 10 years; male 80%; left ventricular ejection fraction 34.6 ± 12.0%). CPET peakV̇O2 was 13.5 ± 3.5 mL/kg/min in HF patients and 28.1 ± 7.4 mL/kg/min in healthy subjects (P < 0.001). 6MWT-V̇O2 was 98 ± 20% of the CPET peakV̇O2 values in HF patients, while 72 ± 20% in healthy subjects (P < 0.001). 6MWT-V̇O2 was >110% of CPET peakV̇O2 in 42% of more severe HF patients (peakV̇O2  < 12 mL/kg/min). Similar results have been found for ventilation and heart rate. Of note, the slope of the relationship between V̇O2 at 6MWT, reported as a percentage of CPET peakV̇O2 vs. 6MWT V̇O2 reported as the absolute value, progressively increased as exercise limitation did. CONCLUSIONS: In conclusion, the last minute of 6MWT must be perceived as a maximal or even supramaximal exercise activity in patients with more severe HF. Our findings should influence the safety procedures needed for the 6MWT in HF.

Immature Circulating SP-B, Bound to HDL, Represents an Early Sign of Smoke-Induced Pathophysiological Alterations.

Cigarette smoking is a major independent risk factor for cardiovascular diseases (CVD). The underlying mechanisms, however, are not clearly understood. Lungs are the primary route of exposure to smoke, with pulmonary cells and surfactant being the first structures directly exposed, resulting in the leakage of the immature proteoform of surfactant protein B (proSP-B). Herein, we evaluated whether proSP-B joined the cargo of high-density lipoprotein (HDL) proteins in healthy young subjects (n = 106) without any CVD risk factor other than smoking, and if HDL-associated proSP-B (HDL-SPB) correlated with pulmonary function parameters, systemic inflammation, and oxidative stress. At univariable analysis, HDL-SPB resulted significantly higher in smokers (2.2-fold, p < 0.001) than in non-smokers. No significant differences have been detected between smokers and non-smokers for inflammation, oxidation variables, and alveolar-capillary diffusion markers. In a multivariable model, HDL-SPB was independently associated with smoking. In conclusion, HDL-SPB is not only a precocious and sensitive index of the acute effects of smoke, but it might be also a potential causal factor in the onset of the vascular damage induced by modified HDL. These findings contribute to the emerging concept that the quality of the HDL proteome, rather than the quantity of particles, plays a central role in CVD risk protection.

Mortality risk assessment in Spain and Italy, insights of the HOPE COVID-19 registry.

Recently the coronavirus disease (COVID-19) outbreak has been declared a pandemic. Despite its aggressive extension and significant morbidity and mortality, risk factors are poorly characterized outside China. We designed a registry, HOPE COVID-19 (NCT04334291), assessing data of 1021 patients discharged (dead or alive) after COVID-19, from 23 hospitals in 4 countries, between 8 February and 1 April. The primary end-point was all-cause mortality aiming to produce a mortality risk score calculator. The median age was 68 years (IQR 52-79), and 59.5% were male. Most frequent comorbidities were hypertension (46.8%) and dyslipidemia (35.8%). A relevant heart or lung disease were depicted in 20%. And renal, neurological, or oncological disease, respectively, were detected in nearly 10%. Most common symptoms were fever, cough, and dyspnea at admission. 311 patients died and 710 were discharged alive. In the death-multivariate analysis, raised as most relevant: age, hypertension, obesity, renal insufficiency, any immunosuppressive disease, 02 saturation < 92% and an elevated C reactive protein (AUC = 0.87; Hosmer-Lemeshow test, p > 0.999; bootstrap-optimist: 0.0018). We provide a simple clinical score to estimate probability of death, dividing patients in four grades (I-IV) of increasing probability. Hydroxychloroquine (79.2%) and antivirals (67.6%) were the specific drugs most commonly used. After a propensity score adjustment, the results suggested a slight improvement in mortality rates (adjusted-ORhydroxychloroquine 0.88; 95% CI 0.81-0.91, p = 0.005; adjusted-ORantiviral 0.94; 95% CI 0.87-1.01; p = 0.115). COVID-19 produces important mortality, mostly in patients with comorbidities with respiratory symptoms. Hydroxychloroquine could be associated with survival benefit, but this data need to be confirmed with further trials. Trial Registration: NCT04334291/EUPAS34399.

Sacubitril/valsartan use in a real-world population of patients with heart failure and reduced ejection fraction.

AIMS: Practice guidelines recommend sacubitril/valsartan for heart failure with reduced ejection fraction. The aim of our study was to describe the use of sacubitril/valsartan in real-world clinical practice to help identify patients best able to tolerate titration to higher doses. METHODS: We retrospectively analyzed clinical data for 201 patients with heart failure with reduced ejection fraction prescribed sacubitril/valsartan at our heart failure clinic (Centro Cardiologico Monzino) between September 2016/December 2018. Patients had a mean age of 67.2 years, mean left ventricular ejection fraction of 30.1%, New York Heart Association class II (65%), class III (35%), and poor cardiopulmonary exercise capacity. Median 2-year risk of death/urgent cardiac transplantation was 8.9% [Metabolic Exercise Cardiac Kidney Index (MECKI) score]. RESULTS: After a median follow-up of 230 (interquartile interval: 105-366) days, 57 patients achieved higher-dose sacubitril/valsartan, 103 tolerated medium/low doses, nine died, and 20 interrupted treatment. The highest dose of sacubitril/valsartan was reached by younger patients with better hemoglobin (Hb) levels, renal function, and blood pressure (BP). Patients continuing on sacubitril/valsartan had significantly higher serum Hb and sodium, better BP, and lower MECKI scores than patients who discontinued treatment or died during follow-up. Our patients were older and frailer than those in the pivotal PARADIGM-HF trial. CONCLUSION: In our experience, more than one-third of the patients were able to tolerate the higher dose of sacubitril/valsartan, and these patients were younger, had higher Hb, and better BP and renal function. MECKI score stratification was useful to discriminate patients who continued treatment from those who did not. Future prospective studies should test if these clinical variables can guide the up-titration of sacubitril/valsartan.

Sacubitril/valsartan can improve exercise performance in systolic chronic heart failure patients: a case report.

OBJECTIVE: The cardiopulmonary exercise test (CPET) provides functional prognostic parameters for patients with chronic heart failure (CHF), such as peak volume of oxygen (VO2) and minute ventilation/carbon dioxide production (VE/VCO2) slope. Sacubitril/valsartan (LCZ696) has been recently approved for CHF patients as it reduces cardiovascular (CV) deaths and hospitalization for heart failure (HF). However, the potential beneficial effects of this therapy on exercise performance have been poorly investigated to date. CASE PRESENTATION: We present a 64 year old woman with systolic HF (New York Heart Association [NYHA] class III, ejection fraction 35%) due to moderate/severe aortic and tricuspid regurgitation and pulmonary hypertension. The patient had several co-morbidities and a history of CV surgery (mitral valve replacement due to bacterial endocarditis). In November 2016, a CPET was performed in stable clinical conditions, showing severe cardiogenic limitation with signs of pulmonary hypertension (peak VO2 46% of predicted, VE/VCO2 slope 36.5). According to current guidelines, an angiotensin-converting enzyme inhibitor was replaced with sacubitril/valsartan (24/26 mg for 2 weeks and then increased to 49/51 mg) without any other change in medical therapy. At 2 months, CPET showed improvement in exercise performance (peak VO2 61%, VE/VCO2 slope 26.9). Echocardiographic parameters also showed mild improvement, whereas renal function remained unchanged. Thus, the dose of sacubitril/valsartan was increased to 97/103 mg. CONCLUSIONS: We present a case of a systolic HF patient successfully treated with sacubitril/valsartan who showed a rapid improvement of exercise performance at CPET.

Comprehensive effects of left ventricular assist device speed changes on alveolar gas exchange, sleep ventilatory pattern, and exercise performance.

BACKGROUND: Increasing left ventricular assist device (LVAD) pump speed according to the patient's activity is a fascinating hypothesis. This study analyzed the short-term effects of LVAD speed increase on cardiopulmonary exercise test (CPET) performance, muscle oxygenation (near-infrared spectroscopy), diffusion capacity of the lung for carbon monoxide (Dlco) and nitric oxide (Dlno), and sleep quality. METHODS: We analyzed CPET, Dlco and Dlno, and sleep in 33 patients supported with the Jarvik 2000 (Jarvik Heart Inc., New York, NY). After a maximal CPET (n = 28), patients underwent 2 maximal CPETs with LVAD speed randomly set at 3 or increased from 3 to 5 during effort (n = 15). Then, at LVAD speed randomly set at 2 or 4, we performed (1) constant workload CPETs assessing O2 kinetics, cardiac output (CO), and muscle oxygenation (n = 15); (2) resting Dlco and Dlno (n = 18); and (3) nocturnal cardiorespiratory monitoring (n = 29). RESULTS: The progressive pump speed increase raised peak volume of oxygen consumption (12.5 ± 2.5 ml/min/kg vs 11.7 ± 2.8 ml/min/kg at speed 3; p = 0.001). During constant workload, from speed 2 to 4, CO increased (at rest: 3.18 ± 0.76 liters/min vs 3.69 ± 0.75 liters/min, p = 0.015; during exercise: 5.91 ± 1.31 liters/min vs 6.69 ± 0.99 liters/min, p = 0.014), and system efficiency (τ = 65.8 ± 15.1 seconds vs 49.9 ± 14.8 seconds, p = 0.002) and muscle oxygenation improved. At speed 4, Dlco decreased, and obstructive apneas increased despite a significant apnea/hypopnea index and a reduction of central apneas. CONCLUSIONS: Short-term LVAD speed increase improves exercise performance, CO, O2 kinetics, and muscle oxygenation. However, it deteriorates lung diffusion and increases obstructive apneas, likely due to an increase of intrathoracic fluids. Self-adjusting LVAD speed is a fascinating but possibly unsafe option, probably requiring a monitoring of intrathoracic fluids.

Transthoracic echocardiography in patients undergoing mitral valve repair: comparison of new transthoracic 3D techniques to 2D transoesophageal echocardiography in the localization of mitral valve prolapse.

Successful mitral valve (MV) repair for degenerative mitral regurgitation (DMR) is mainly related to surgical expertise and MV anatomy. Although 2D echocardiography, specifically transoesophageal (TOE), provides precise information regarding MV anatomy, recent advancements in matrix technology meant a decisive step forward to the point where segmental MV analysis can be accurately performed from a noninvasive 3D transthoracic (TTE) approach. The aims of this study were: (a) to evaluate the feasibility and time required for real-time 3D TTE in a large consecutive cohort of patients with severe DMR in the assessment of MV anatomy; (b) to compare the accuracy of 3D TTE and 2D TOE versus surgical inspection in the recognition and localization of all components of the MV leaflets; (c) to establish the added diagnostic value of 3D colourDoppler examination to pure 3D morphologic evaluation. 149 consecutive patients with severe DMR underwent complete 3D TTE before surgery and 2D TOE in the operating room. Echocardiographic data obtained by the different techniques were compared with surgical inspection. 3D TTE was feasible in a relatively short time (8 ± 4 min), with good (49%) and optimal (33%) imaging quality in the majority of cases. 3D TTE had significant better overall accuracy compared to 2D TOE (93 and 91%, p < 0.05, respectively). 2D TOE was significantly more specific than 3D TTE in the identification of A3 prolapse (99 vs. 96%). The colourDoppler mode did not improve significantly the accuracy of 3D TTE, albeit it determined a better sensitivity in the detection of A2 prolapse if compared to 2D TOE (95 vs. 85%). 3D TTE with or without colourDoppler is a feasible and useful method in the analysis of MV prolapse; it allows a preoperative and noninvasive description of the pathology as accurate as the 2D TOE.

Emergency transapical mitral valve-in-valve implantation for bioprosthesis failure: transapical implantation of an Edwards Sapien-XT in a dysfunctional mitral bioprosthesis in a critical patient.

Background: Valve-in-Valve (VIV) Transcatheter Aortic Valve Replacement (TAVR) is now the treatment of choice in high-surgical-risk patients with failing aortic bioprosthesis. Although less performed, VIV-Transcatheter Mitral Valve Replacement (TMVR) is a valid treatment option for selected high-risk patients with degenerated mitral bioprostheses. Several cases of elective ViV- TAVR and -TMVR have been reported but only few were performed in critical hemodynamic conditions. Case presentation: We report the case of a patient underwent balloon-expandable transapical mitral valve-in-valve implantation in an emergency setting due to a severe stenosis of a bioprosthesis in mitral position. The procedure was successfully performed, with no residual mitral regurgitation or paravalvular leaks, and uneventful. Conclusion: Transcatheter transapical mitral valve-in-valve implantation could represent a feasible and effective strategy even in critical setting.