Subclinical Myocardial Dysfunction in Patients Recovered from COVID-19 Disease: Correlation with Exercise Capacity.

AIMS: Myocardial abnormalities are common during COVID-19 infection and recovery. We examined left (LV) and right (RV) ventricular longitudinal strain in patients who had recovered from COVID-19 and assessed the correlation with exercise capacity. METHODS AND RESULTS: One hundred and eighty-four consecutive patients with history of COVID-19 disease who had been referred to rest or stress echocardiography because of symptoms, mainly dyspnea and chest pain, were included in the study. These patients were compared to 106 patients with similar age, symptoms, and risk factor profile with no history of COVID-19 disease. Clinical and echocardiographic parameters, including strain imaging, were assessed. The patient's age was 48 ± 12 years. Twenty-two patients had undergone severe disease. There were no differences in the LV ejection fraction and diastolic function between the groups. However, LV and RV global and free wall strain were significantly lower (in absolute numbers) in patients who had recovered form COVID-19 infection (-20.41 ± 2.32 vs -19.39 ± 3.36, p = 0.001, -23.69 ± 3.44 vs -22.09 ± 4.20, p = 0.001 and -27.24 ± 4.7 vs -25.43 ± 4.93, p = 0.021, respectively). Global Longitudinal Strain (GLS) < -20% was present in only 37% of post COVID-19 patients. Sixty-four patients performed exercise echocardiography. Patients with GLS < -20% had higher exercise capacity with higher peak metabolic equivalent and exercise time compared to patients with GLS ≥ -20% (12.6 ± 2 vs 10 ± 2.5 METss and 8:00 ± 2:08 vs 6:24 ± 2:03 min, p < 0.001 and p = 0.003, respectively). CONCLUSION: In patients, who had recovered from COVID-19 infection, both LV and RV strain are significantly lower compared to control patients. The exercise capacity of these patients correlates with LV strain values. Rest and stress echocardiography in patients with symptoms after COVID-19 infection may identify patients that need further follow up to avoid long term complications of the disease. These preliminary results warrant further research, to test the natural history of these findings and the need and timing of treatment.

Transthyretin cardiac amyloidosis in patients after TAVR: clinical and echocardiographic findings and long term survival.

AIMS: The aim of this study was to examine the prevalence of amyloid transthyretin (ATTR) cardiac amyloidosis in patients 1-2 years after trans-catheter aortic valve replacement (TAVR) and to assess their clinical and echocardiographic outcome and long-term survival. METHODS AND RESULTS: We enrolled 88 patients, mean age 81 years, 534 (390-711) days after TAVR. Patients underwent a Tc99m-PYP scintigraphy for the diagnosis of ATTR cardiac amyloidosis. Eleven (12.5%) participants were diagnosed with ATTR cardiac amyloidosis. Eighty eight per cent of patients without amyloidosis were in New York Heart Association Classes 1-2 after TAVR, compared with 64% patients with ATTR cardiac amyloidosis (P = 0.022). There were no differences in left ventricular (LV) ejection fraction (P = 0.69) between patients with and without ATTR cardiac amyloidosis at enrolment. The LV mass index and pulmonary artery pressure were significantly higher in patients with ATTR cardiac amyloidosis (P = 0.046 and P = 0.002, respectively). Global longitudinal strain and myocardial work efficiency were significantly lower in patients with ATTR cardiac amyloidosis (P = 0.031 and P = 0.048, respectively). We assessed changes in echocardiographic data, from the time of TAVR to enrolment, and as expected, there was a significant decrease in aortic valve gradient in both groups. There was a significant reduction in LV mass and LV mass index and improvement in basal segment LV strain in the ATTR cardiac amyloidosis negative group (P = 0.045, P = 0.046 and 0.023, respectively). However, in the ATTR cardiac amyloidosis group the change in LV mass and LV mass index and LV basal strain values was not significant (P = 0.24, P = 0.13 and P = 0.35, respectively). The were no significant changes in other echocardiographic parameters in both groups. The patients were followed for 1150 (1086-1221) days after enrolment. Twenty seven patients had at least one cardiac hospitalization during of follow up, of them seven were with ATTR cardiac amyloidosis and 20 patients without amyloidosis (P = 0.017). Eighteen patients (20%) died during follow up; 12 (14%) patients died due to cardiac causes. There was no difference in all-cause and cardiac mortality between patients with and without ATTR cardiac amyloidosis (P = 0.6 and P = 0.53, respectively). CONCLUSIONS: The long-term survival after TAVR is not significantly affected by the presence of ATTR cardiac amyloidosis. However, the clinical course of these patients and the LV hemodynamic improvement is less favourable. This hypothesis-generating study suggests screening for ATTR cardiac amyloidosis in patients who underwent TAVR and have limited clinical or echocardiographic improvement, because they may potentially improve with new therapies for ATTR cardiac amyolidosis.

Comparative Analysis of the Kinetic Behavior of Systemic Inflammatory Markers in Patients with Depressed versus Preserved Left Ventricular Function Undergoing Transcatheter Aortic Valve Implantation.

BACKGROUND: Prior studies have proven the safety and efficacy of transcatheter aortic valve implantation (TAVI) in patients with reduced left ventricular (LV) function. This study's aim was to investigate periprocedural inflammatory responses after TAVI. METHODS: Patients with severe symptomatic aortic stenosis and reduced LV function who underwent transfemoral TAVI were enrolled. A paired-matched analysis (1:2 ratio) was performed using patients with preserved LV function. Whole white blood cells (WBC) and subpopulation dynamics as well as the neutrophil to lymphocyte ratio (NLR) were evaluated at different times. RESULTS: A total of 156 patients were enrolled, including 52 patients with LVEF < 40% 35.00 [30.00, 39.25] and 104 with LVEF > 50% 55.00 [53.75, 60.0], p < 0.001. Baseline NLR in the reduced LV function group was significantly higher compared to the preserved LV function group, 2.85 [2.07, 4.78] vs. 3.90 [2.67, 5.26], p < 0.04. After a six-month follow-up, the inflammatory profile was found to be similar in the two groups, NLR 2.94 [2.01, 388] vs. 3.30 [2.06, 5.35], p = 0.288. No significant mortality differences between the two groups were observed in the long-term outcome. CONCLUSIONS: TAVI for severe symptomatic aortic stenosis, with reduced LV function, was associated with an improvement in the inflammatory profile that may account for some of the observable benefits of the procedure in this subset of patients.

Urea level is an independent predictor of mortality in patients with severe aortic valve stenosis.

INTRODUCTION: Severe aortic stenosis (AS) is the most common valvular heart disease in the western world. Various factors are related to severe AS prognosis, including chronic kidney disease. The aim of this study was to evaluate the prognostic value of urea level in patients with severe AS. METHODS: We prospectively enrolled 142 patients (79.1±9.4 years, 88 women) with severe AS (mean valve area 0.67± 0.17 cm2). Clinical assessment, blood tests and echocardiography were performed at enrollment and follow up. The patient population was divided into low and high urea level groups, according to the median urea level at enrollment (72 patients, mean urea 35.5±6.2 mg/dL and 70 patients, mean urea 61.1±17.8 mg/dL, respectively). Hundred and twelve patients (79%) underwent aortic valve intervention. The primary endpoint was all-cause and cardiovascular mortality. OUTCOMES: During follow-up of 37±19.5 months, 56 (37.1%) patients died, 39 due to cardiovascular causes. In univariate analysis, age, urea level, creatinine, New York Heart Association (NYHA) class and aortic valve intervention were associated with all-cause mortality. However, in multivariate analysis only aortic valve intervention and blood urea were independent predictors of all-cause mortality (HR 0.494; 95% CI 0.226-0.918, P = 0.026 and HR 1.015; 95% CI 1.003-1.029, P = 0.046 respectively). Urea level, NYHA class and age were also significant predictors of cardiovascular mortality. Whereas, in multivariate analysis, only urea level predicted cardiovascular mortality in these patients (HR 1.017; CI 1.003-1.031 P = 0.019). CONCLUSIONS: Blood urea, a generally readily available and routinely determined marker of renal function, is an independent prognostic factor in patients with severe AS.

The Association Between Longitudinal Strain at Rest and Stress and Outcome in Asymptomatic Patients With Moderate and Severe Aortic Stenosis.

BACKGROUND: Calcific aortic stenosis (AS) is a progressive disease, and once moderate AS is present, the likelihood of symptom onset within 5 years is significant. The aim of this study was to determine the incremental value of global longitudinal strain (GLS) and basal longitudinal strain (BLS) at rest and during exercise on outcomes among asymptomatic patients' with moderate and severe AS. METHODS: Seventy-five patients with isolated, asymptomatic AS and preserved left ventricular function were retrospectively enrolled and underwent symptom-limited exercise echocardiography. Clinical and echocardiographic data, including GLS and BLS at rest and during exercise, were assessed. Occurrence of AS-related cardiovascular events was recorded. RESULTS: The mean age was 71 ± 10 years, and 63% were men. The mean aortic valve gradient was 30 ± 11 mm Hg, and the mean aortic valve area was 0.98 ± 0.21 cm2. Resting GLS and BLS were -16.5 ± 4% and -16.9 ± 3.6%, respectively. Exercise stress test results were positive in 27 patients (36%). Mean exercise GLS was -17.8 ± 3.5%, and mean exercise BLS was -17.9 ± 4%. During mean follow-up of 34.5 ± 3.5 months, cardiovascular events were observed in 45 patients. In multivariate analysis, aortic valve mean gradient (HR, 1.073; 95% CI, 1.032-1.115; P < .001) and peak exercise BLS (HR, 1.177; 95% CI, 1.07-1.295; P = .001) were associated with cardiac events during follow-up. CONCLUSIONS: Reduced exercise BLS is associated with future cardiovascular events in patients' with asymptomatic AS, independently of clinical factors and conventional echocardiographic parameters. Detection of postexercise myocardial dysfunction in patients with asymptomatic AS with preserved left ventricular function can aid in risk assessment of these patients.

Circulating regulatory T cells in patients with aortic valve stenosis: Association with disease progression and aortic valve intervention.

BACKGROUND: Severe aortic valve stenosis (AS) accounts for considerable morbidity and death, especially in older patients. There is increasing evidence to suggest a role for immune modulating cells in aortic valve (AV) degeneration. Regulatory T cells (Tregs) tune down inflammation. We aimed to study the levels of circulating Tregs in patients with AS and to assess their association with disease progression. METHOD AND RESULTS: The number of Tregs (CD4+CD25+Foxp3+) was determined by flow cytometry in 229 patients with AS and a control group of 69 patients. Tregs were significantly higher in patients with AS compared to the control group (1.64± .61% vs 1.13±0.97%, p=0.04). In the logistic regression analysis, adjusted for baseline characteristics, only the hemoglobin level and Treg percent correlated with the presence of AS (OR 0.642 95% CI 0.512-0.805, p<0.001 and OR 1.411, 95% CI 1.080-1.844, p=0.011, respectively). One hundred patients underwent 2 echocardiographic studies during follow-up. The median decrease in AV area (AVA) was 0.1cm(2)/year. A borderline association was observed between Tregs and AVA progression (r=0.19, p=0.054). In a subgroup of 68 patients with severe AS, the association between Tregs and AVA progression was significant (r=0.374, p=0.0017). In addition, a drop in Treg levels was observed 3-6months after AV-intervention (1.86±1.6% vs 1.04±1.8%, p=0.0005). CONCLUSIONS: Circulating Tregs are elevated in patients with AS. The levels of Tregs are higher in patients with severe AS and accelerated progression of valve narrowing. These results may help to identify AS patients with accelerated disease progression and possibly in need for earlier intervention.

Circulating Endothelial Progenitor Cells and Clinical Outcome in Patients with Aortic Stenosis.

BACKGROUND: Aortic stenosis (AS) is the most common valvular disease. Endothelial progenitor cells (EPCs) have a role in the repair of endothelial surfaces after injury. Reduced numbers of EPCs are associated with endothelial dysfunction and adverse clinical events, suggesting that endothelial injury in the absence of sufficient repair by circulating EPCs promotes the progression of vascular and possibly valvular disorders. The aim of this study was to assess EPC number in patients with AS and to study the predictive value of their circulating levels on prognosis. METHODS: The number of EPCs was determined by flow cytometry in 241 patients with AS and a control group of 73 pts. Thirty-eight, 52 and 151 patients had mild, moderate and severe AS, respectively. We evaluated the association between baseline levels of EPCs and death from cardiovascular causes during follow up. RESULTS: EPC level was significantly higher in patients with AS compared to the control group (p = 0.017). Two hundred and three patients with moderate and severe AS were followed for a median of 20 months. One hundred and twenty patients underwent an intervention. Thirty four patients died during follow up, 20 patients died due to cardiac causes. Advanced age, the presence of coronary artery disease, AS severity index (combination of high NYHA class, smaller aortic valve area and elevated pulmonary artery pressure) and a low EPC number were predictors of cardiac death in the univariate analysis. Multivariate logistic regression model identified low EPCs number and AS severity index as associated with cardiac death during follow up (p = 0.026 and p = 0.037, respectively). CONCLUSIONS: EPC number is increased in patients with AS. However, in patients with moderate or severe AS a relatively low number of EPCs is associated with cardiac death at follow up. These results may help to identify AS patients at increased cardiovascular risk.

Circulating CD14(+) monocytes in patients with aortic stenosis.

BACKGROUND: Calcific aortic stenosis (AS) is an active process sharing similarities with atherosclerosis and chronic inflammation. The pathophysiology of AS is notable for three cardinal components: inflammation, fibrosis and calcification. Monocytes play a role in each of these processes. The role of circulating monocytes in AS is not clear. The aim of the present study was to study an association between circulating apoptotic and non apoptotic CD14(+) monocytes and AS features. METHODS: We assessed the number of CD14(+) monocytes and apoptotic monocytes in 54 patients with significant AS (aortic valve area 0.74 ± 0.27 cm(2)) and compared them to 33 patients with similar risk factors and no valvular disease. The level of CD14(+) monocytes and apoptotic monocytes was assessed by flow cytometry. RESULTS: There was no difference in the risk factor profile and known coronary or peripheral vascular diseases between patients with AS and controls. Patients with AS exhibited increased numbers of CD14(+) monocytes as compared to controls (9.9% ± 4.9% vs. 7.7% ± 3.9%, P = 0.03). CD14(+) monocyte number was related to age and the presence and severity of AS. In patients with AS, both CD14(+) monocytes and apoptotic monocytes were inversely related to aortic valve area. CONCLUSIONS: Patients with significant AS have increased number of circulating CD14(+) monocytes and there is an inverse correlation between monocyte count and aortic valve area. These findings may suggest that inflammation is operative not only in early valve injury phase, but also at later developed stages such as calcification when AS is severe.

Stroke volume adjusted to afterload for assessment of cardiac performance in patients with severe aortic stenosis and preserved left ventricular ejection fraction.

OBJECTIVES: The aim of this study was to evaluate the relationship between valvular resistance and stroke volume (SV) and to assess SV adequacy to afterload in patients with severe aortic stenosis (AS) and normal left ventricular ejection fraction (LVEF). METHODS: We assessed clinical characteristics and echocardiographic parameters in 44 patients with isolated severe AS and preserved LVEF. LV end-diastolic pressure (LVEDP) and LV mean diastolic pressure (LVMDP) were measured by cardiac catheterization. SV values were plotted in relation to valvular resistance. Patients were divided into 2 groups, with an SV that was higher (group 1) or lower (group 2) than the SV calculated by a regression equation using valvular resistance as the dependent variable. RESULTS: At the same degree of valvular stenosis, the patients in group 1 exhibited better contractility as assessed by global longitudinal strain (p < 0.05), higher peak (p < 0.01) and mean gradient (p < 0.05), indexed SV (p < 0.001) and transvalvular flow (p = 0.01) than the patients in group 2, who had a higher heart rate (HR, p < 0.05), shorter ejection time (ET, p < 0.05) and more elevated LVEDP (p < 0.05) and LVMDP (p < 0.05). CONCLUSION: The presence of inappropriately decreased SV relative to afterload in patients with severe AS and normal LVEF was associated with lower contractility, higher HR, shorter ET and elevated LV diastolic pressure, which suggest failed hemodynamic adaptation to afterload.

Low circulating monocyte count is associated with severe aortic valve stenosis.

BACKGROUND: The pathophysiology of aortic stenosis (AS) involves inflammatory features including infiltration of the aortic valve (AV) by activated macrophages and T cells, deposition of lipids, and heterotopic calcification. OBJECTIVES: To evaluate the correlation between white blood cell (WBC) differential count and the occurrence and progression of AS. METHODS: We identified in our institutional registry 150 patients with AS who underwent two repeated echo studies at least 6 months apart. We evaluated the association between the average of repeated WBC differential counts sampled during the previous 3 years and subsequent echocardiographic AS indices. RESULTS: There was no significant difference in total WBC, lymphocyte or eosinophil count among mild, moderate or severe AS groups. There was a progressive decrease in monocyte count with increasing AS severity (P = 0.046), more prominent when comparing the mild and severe groups. There was a negative correlation between AV peak velocity or peak or mean gradient and monocyte count in the entire group (r = -0.31, -0.24, and -0.25 respectively, all P < 0.01). Similar partial correlations controlling for age, gender, hypertension, smoking, dyslipidemia and ejection fraction remained significant. The median changes over time in peak velocity and peak gradients in AS patients were 0.44 (0-1.3) m/sec/ year and 12 (0-39) mmHg/year, respectively. There was no correlation between any of the WBC differential counts and the change in peak velocity or peak gradient per year. CONCLUSIONS: Severe AS is associated with decreased total monocyte count. These findings may provide further clues to the mechanism underlying the pathogenesis of aortic stenosis.