Age- and sex-based normal reference ranges of the cardiac time intervals: the Copenhagen City Heart Study.

BACKGROUND: Color tissue Doppler imaging (TDI) M-mode can be used to measure the cardiac time intervals including the isovolumic contraction time (IVCT), the left ventricular ejection time (LVET), the isovolumic relaxation time (IVRT), and the combination of all the cardiac time intervals in the myocardial performance index (MPI) defined as [(IVCT + IVRT)/LVET]. The aim of this study was to establish normal age- and sex-based reference ranges for the cardiac time intervals. METHODS AND RESULTS: A total of 1969 participants free of cardiovascular diseases and risk factors from the general population with limited age range underwent an echocardiographic examination including TDI. The median age was 46 years (25th-75th percentile: 33-58 years), and 61.5% were females. In the entire study population, the IVCT was observed to be 40 ± 10 ms [95% prediction interval (PI) 20-59 ms], the LVET 292 ± 23 ms (95% PI 248-336 ms), the IVRT 96 ± 19 ms (95% PI 59-134 ms) and MPI 0.47 ± 0.09 (95% PI 0.29-0.65). All the cardiac time intervals differed significantly between females and males. With increasing age, the IVCT increased in females, but not in males. The LVET did not change with age in both sexes, while the IVRT increased in both sexes with increasing age. Furthermore, we developed regression equations relating the heart rate to the cardiac time intervals and age- and sex-based normal reference ranges corrected for heart rate. CONCLUSION: In this study, we established normal age- and sex-based reference ranges for the cardiac time intervals. These normal reference ranges differed significantly with sex.

Changes in cardiac time intervals over a decade and the risk of incident heart failure: The Copenhagen City Heart Study.

BACKGROUND: The cardiac time intervals include the isovolumic contraction time (IVCT), the left ventricular ejection time (LVET), the isovolumic relaxation time (IVRT) and the combination of all the cardiac time intervals in the myocardial performance index (MPI) (defined as [(IVCT+IVRT)/LVET)]. Whether the cardiac time intervals change over time and which clinical factors that accelerate these changes is not well-established. Additionally, whether these changes are associated with subsequent heart failure (HF), remains unknown. METHODS: We investigated participants from the general population (n = 1064) who had an echocardiographic examination including color tissue Doppler imaging performed in both the 4th and 5th Copenhagen City Heart Study. The examinations were performed 10.5 years apart. RESULTS: The IVCT, LVET, IVRT and MPI increased significantly over time. None of the investigated clinical factors were associated with increase in IVCT. Systolic blood pressure (standardized ß= - 0.09) and male sex (standardized ß= - 0.08) were associated with an accelerated decrease in LVET. Age (standardized ß=0.26), male sex (standardized ß=0.06), diastolic blood pressure (standardized ß=0.08), and smoking (standardized ß=0.08) were associated with an increase in IVRT, while HbA1c (standardized ß= - 0.06) was associated with a decrease in IVRT. Increasing IVRT over a decade was associated with an increased risk of subsequent HF in participants aged <65 years (per 10 ms increase: HR 1.33; 95%CI (1.02-1.72), p = 0.034). CONCLUSION: The cardiac time increased significantly over time. Several clinical factors accelerated these changes. An increase in IVRT was associated with an increased risk of subsequent HF in participants aged <65 years.

Myocardial Work in Patients Hospitalized With COVID-19: Relation to Biomarkers, COVID-19 Severity, and All-Cause Mortality.

Background COVID-19 infection has been hypothesized to affect left ventricular function; however, the underlying mechanisms and the association to clinical outcome are not understood. The global work index (GWI) is a novel echocardiographic measure of systolic function that may offer insights on cardiac dysfunction in COVID-19. We hypothesized that GWI was associated with disease severity and all-cause death in patients with COVID-19. Methods and Results In a multicenter study of patients admitted with COVID-19 (n=305), 249 underwent pressure-strain loop analyses to quantify GWI at a median time of 4 days after admission. We examined the association of GWI to cardiac biomarkers (troponin and NT-proBNP [N-terminal pro-B-type natriuretic peptide]), disease severity (oxygen requirement and CRP [C-reactive protein]), and all-cause death. Patients with elevated troponin (n=71) exhibited significantly reduced GWI (1508 versus 1707 mm Hg%; P=0.018). A curvilinear association to NT-proBNP was observed, with increasing NT-proBNP once GWI decreased below 1446 mm Hg%. Moreover, GWI was significantly associated with a higher oxygen requirement (relative increase of 6% per 100-mm Hg% decrease). No association was observed with CRP. Of the 249 patients, 37 died during follow-up (median, 58 days). In multivariable Cox regression, GWI was associated with all-cause death (hazard ratio, 1.08 [95% CI, 1.01-1.15], per 100-mm Hg% decrease), but did not increase C-statistics when added to clinical parameters. Conclusions In patients admitted with COVID-19, our findings indicate that NT-proBNP and troponin may be associated with lower GWI, whereas CRP is not. GWI was independently associated with all-cause death, but did not provide prognostic information beyond readily available clinical parameters. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT04377035.

Lung ultrasound findings following COVID-19 hospitalization: A prospective longitudinal cohort study.

BACKGROUND: Lung ultrasound (LUS) is a useful tool for diagnosis and monitoring in patients with active COVID-19-infection. However, less is known about the changes in LUS findings after a hospitalization for COVID-19. METHODS: In a prospective, longitudinal study in patients with COVID-19 enrolled from non-ICU hospital units, adult patients underwent 8-zone LUS and blood sampling both during the hospitalization and 2-3 months after discharge. LUS images were analyzed blinded to clinical variables and outcomes. RESULTS: A total of 71 patients with interpretable LUS at baseline and follow up (mean age 64 years, 61% male, 24% with acute respiratory distress syndrome (ARDS)) were included. The follow-up LUS was performed a median of 72 days after the initial LUS performed during hospitalization. At baseline, 87% had pathologic LUS findings in ≥1 zone (e.g. ≥3 B-lines, confluent B-lines or subpleural or lobar consolidation), whereas 30% had pathologic findings at follow-up (p < 0.001). The total number of B-lines and LUS score decreased significantly from hospitalization to follow-up (median 17 vs. 4, p < 0.001 and 4 vs. 0, p < 0.001, respectively). On the follow-up LUS, 28% of all patients had ≥3 B-lines in ≥1 zone, whereas in those with ARDS during the baseline hospitalization (n = 17), 47% had ≥3 B-lines in ≥1 zone. CONCLUSION: LUS findings improved significantly from hospitalization to follow-up 2-3 months after discharge in COVID-19 survivors. However, persistent B-lines were frequent at follow-up, especially among those who initially had ARDS. LUS seems to be a promising method to monitor COVID-19 lung changes over time. GOV ID: NCT04377035.

Lung ultrasound findings in hospitalized COVID-19 patients in relation to venous thromboembolic events: the ECHOVID-19 study.

PURPOSE: Several studies have reported thromboembolic events to be common in severe COVID-19 cases. We sought to investigate the relationship between lung ultrasound (LUS) findings in hospitalized COVID-19 patients and the development of venous thromboembolic events (VTE). METHODS: A total of 203 adults were included from a COVID-19 ward in this prospective multi-center study (mean age 68.6 years, 56.7% men). All patients underwent 8-zone LUS, and all ultrasound images were analyzed off-line blinded. Several LUS findings were investigated (total number of B-lines, B-line score, and LUS-scores). RESULTS: Median time from admission to LUS examination was 4 days (IQR: 2, 8). The median number of B-lines was 12 (IQR: 8, 18), and 44 (21.7%) had a positive B-line score. During hospitalization, 17 patients developed VTE (4 deep-vein thrombosis, 15 pulmonary embolism), 12 following and 5 prior to LUS. In fully adjusted multivariable Cox models (excluding participants with VTE prior to LUS), all LUS parameters were significantly associated with VTE (total number of B-lines: HR = 1.14, 95% CI (1.03, 1.26) per 1 B-line increase), positive B-line score: HR = 9.79, 95% CI (1.87, 51.35), and LUS-score: HR = 1.51, 95% CI (1.10, 2.07), per 1-point increase). The B-line score and LUS-score remained significantly associated with VTE in sensitivity analyses. CONCLUSION: In hospitalized COVID-19 patients, pathological LUS findings were common, and the total number of B-lines, B-line score, and LUS-score were all associated with VTE. These findings indicate that the LUS examination may be useful in risk stratification and the clinical management of COVID-19. These findings should be considered hypothesis generating. GOV ID: NCT04377035.

Usefulness of left atrial strain for predicting incident atrial fibrillation and ischaemic stroke in the general population.

AIMS: Left atrial enlargement predicts incident atrial fibrillation (AF). However, the prognostic value of peak atrial longitudinal strain (PALS) for predicting incident AF in participants from the general population is currently unknown. Our aim was to investigate if PALS can be used to predict AF and ischaemic stroke in the general population. METHODS AND RESULTS: A total of 400 participants from the general population underwent a health examination, including two-dimensional speckle tracking echocardiography of the left atrium. The primary endpoint was incident AF at follow-up. All participants with known AF and prior stroke at baseline were excluded (n = 54). The secondary endpoint consisted of the composite of AF and ischaemic stroke. During a median follow-up of 16 years, 36 participants (9%) were diagnosed with incident AF and 30 (7%) experienced an ischaemic stroke, resulting in 66 (16%) experiencing the composite outcome. PALS was a univariable predictor of AF [per 5% decrease: hazard ratio (HR) 1.42; 95% confidence interval (CI) (1.19-1.69), P < 0.001]. However, the prognostic value of PALS was modified by age (P = 0.002 for interaction). After multivariable adjustment PALS predicted AF in participants aged <65 years [per 5% decrease: HR 1.46; 95% CI (1.06-2.02), P = 0.021]. In contrast, PALS did not predict AF in participants aged ≥65 years after multivariable adjustment [per 5% decrease: HR 1.05; 95% CI (0.81-1.35), P = 0.72]. PALS also predicted the secondary endpoint in participants aged <65 years and the association remained significant after multivariable adjustment. CONCLUSION: In a low-risk general population, PALS provides novel prognostic information on the long-term risk of AF and ischaemic stroke in participants aged <65 years.

Lung Ultrasound Findings Associated With COVID-19 ARDS, ICU Admission, and All-Cause Mortality.

BACKGROUND: As lung ultrasound (LUS) has emerged as a diagnostic tool in patients with COVID-19, we sought to investigate the association between LUS findings and the composite in-hospital outcome of ARDS incidence, ICU admission, and all-cause mortality. METHODS: In this prospective, multi-center, observational study, adults with laboratory-confirmed SARS-CoV-2 infection were enrolled from non-ICU in-patient units. Subjects underwent an LUS evaluating a total of 8 zones. Images were analyzed off-line, blinded to clinical variables and outcomes. A LUS score was developed to integrate LUS findings: ≥ 3 B-lines corresponded to a score of 1, confluent B-lines to a score of 2, and subpleural or lobar consolidation to a score of 3. The total LUS score ranged from 0-24 per subject. RESULTS: Among 215 enrolled subjects, 168 with LUS data and no current signs of ARDS or ICU admission (mean age 59 y, 56% male) were included. One hundred thirty-six (81%) subjects had pathologic LUS findings in ≥ 1 zone (≥ 3 B-lines, confluent B-lines, or consolidations). Markers of disease severity at baseline were higher in subjects with the composite outcome (n = 31, 18%), including higher median C-reactive protein (90 mg/L vs 55, P < .001) and procalcitonin levels (0.35 µg/L vs 0.13, P = .033) and higher supplemental oxygen requirements (median 4 L/min vs 2, P = .001). However, LUS findings and score did not differ significantly between subjects with the composite outcome and those without, and were not associated with outcomes in unadjusted and adjusted logistic regression analyses. CONCLUSIONS: Pathologic findings on LUS were common a median of 3 d after admission in this cohort of non-ICU hospitalized subjects with COVID-19 and did not differ among subjects who experienced the composite outcome of incident ARDS, ICU admission, and all-cause mortality compared to subjects who did not. These findings should be confirmed in future investigations. The study is registered at Clinicaltrials.gov (NCT04377035).

Echocardiographic abnormalities and predictors of mortality in hospitalized COVID-19 patients: the ECHOVID-19 study.

AIMS: The present study had two aims: (i) compare echocardiographic parameters in COVID-19 patients with matched controls and (2) assess the prognostic value of measures of left (LV) and right ventricular (RV) function in relation to COVID-19 related death. METHODS AND RESULTS: In this prospective multicentre cohort study, 214 consecutive hospitalized COVID-19 patients underwent an echocardiographic examination (by pre-determined research protocol). All participants were successfully matched 1:1 with controls from the general population on age, sex, and hypertension. Mean age of the study sample was 69 years, and 55% were male participants. LV and RV systolic function was significantly reduced in COVID-19 cases as assessed by global longitudinal strain (GLS) (16.4% ± 4.3 vs. 18.5% ± 3.0, P < 0.001), tricuspid annular plane systolic excursion (TAPSE) (2.0 ± 0.4 vs. 2.6 ± 0.5, P < 0.001), and RV strain (19.8 ± 5.9 vs. 24.2 ± 6.5, P = 0.004). All parameters remained significantly reduced after adjusting for important cardiac risk factors. During follow-up (median: 40 days), 25 COVID-19 cases died. In multivariable Cox regression reduced TAPSE [hazard ratio (HR) = 1.18, 95% confidence interval (CI) [1.07-1.31], P = 0.002, per 1 mm decrease], RV strain (HR = 1.64, 95%CI[1.02;2.66], P = 0.043, per 1% decrease) and GLS (HR = 1.20, 95%CI[1.07-1.35], P = 0.002, per 1% decrease) were significantly associated with COVID-19-related death. TAPSE and GLS remained significantly associated with the outcome after restricting the analysis to patients without prevalent heart disease. CONCLUSIONS: RV and LV function are significantly impaired in hospitalized COVID-19 patients compared with matched controls. Furthermore, reduced TAPSE and GLS are independently associated with COVID-19-related death.

Myocardial performance index is associated with cardiac computed tomography findings in patients with suspected coronary artery disease.

BACKGROUND: Studies suggest cardiac time intervals to be associated with cardiac ischemia. A novel method to assess cardiac time intervals by tissue Doppler echocardiography has been proposed. Cardiac time intervals can assess the myocardial performance index (MPI), which quantifies the proportion of time spent contributing effective myocardial work. We hypothesized that MPI associates with coronary artery lesions detected by cardiac computed tomography (CT) in patients suspected of coronary artery disease (CAD). METHODS: We investigated patients referred for cardiac CT under suspicion of CAD who had an echocardiogram performed. Curved m-mode tissue Doppler imaging was used to measure cardiac time intervals and MPI. The outcome was coronary artery lesions, defined as a calcium score > 400 and/or coronary artery stenosis (>70% luminal narrowing). Logistic regression was applied with multivariable models including: (a) SCORE chart risk factors and (b) SCORE chart risk factors, body mass index, dyslipidemia, familial history of CAD, diabetes mellitus, LVEF, and left ventricular mass index. RESULTS: Of 404 patients, 41 (10%) had a coronary artery lesion. Overall, 42% were male, mean age was 58 years, and LVEF was 58%. Patients with coronary artery lesions exhibited higher MPI than those without (0.52 vs. 0.44, P < .001). MPI associated with coronary artery lesions in unadjusted analyses (OR = 1.69 [1.30-2.19], per 0.1 increase), and this association persisted when adjusted for SCORE chart risk factors (OR = 1.55 [1.16-2.07], P = .003, per 0.1 increase), and additional risk factors (OR = 1.64 [1.11-2.41], P = .013, per 0.1 increase). CONCLUSION: Curved m-mode-derived MPI is associated with coronary artery lesions detected by cardiac CT in suspected CAD patients.

The cardiac isovolumetric contraction time is an independent predictor of incident heart failure in the general population.

BACKGROUND: Color Tissue Doppler imaging (TDI) M-mode through the mitral leaflet is a novel method to obtain the cardiac time intervals including the isovolumic contraction time (IVCT), isovolumic relaxation time (IVRT) and ejection time (ET). The myocardial performance index (MPI) is defined as [(IVCT+IVRT)/ET]. Our aim was to investigate if the cardiac time intervals can be used to predict heart failure (HF) in the general population. METHODS AND RESULTS: A total of 1915 participants (mean age 58 ± 16 years, 42% male) from the general population (The Copenhagen City Heart Study) underwent a health examination including TDI-echocardiography. The primary endpoint was incident HF. Participants with a history of HF were excluded (n = 23). During a median follow-up time of 16 years, 172 (9%) participants were diagnosed with incident HF. The risk of HF increased with 24% per 10 ms increase in IVCT (per 10 ms increase: HR 1.24; 95%CI (1.14-1.36), p < 0.001). The association remained significant after adjusting for age, sex, hypertension, diabetes, previous ischemic heart disease, diastolic blood pressure, heart rate, body mass index, eGFR, proBNP, LVEF <50%, s', LAVI, and E/e' (per 10 ms increase: HR 1.13; 95% CI (1.00-1.27), p = 0.045). A significant association was found between MPI and HF both in unadjusted and adjusted models (per 0.1 increase: HR 6.93; 95% CI (1.63-29.31), p = 0.009). No associations between the IVRT or ET and HF remained significant after multivariable adjustment. CONCLUSION: In the general population the IVCT provides novel and independent prognostic information on the long-term risk of incident HF.

The cardiac isovolumetric contraction time is an independent predictor of incident atrial fibrillation and adverse outcomes following first atrial fibrillation event in the general population.

AIMS: Colour tissue Doppler imaging (TDI) M-mode through the mitral leaflet is an easy and precise method to obtain cardiac time intervals including the isovolumic contraction time (IVCT), isovolumic relaxation time (IVRT), and ejection time (ET). The myocardial performance index (MPI) was defined as [(IVCT + IVRT)/ET]. Our aim was to investigate if cardiac time intervals can be used to predict atrial fibrillation (AF) in the general population. METHODS AND RESULTS: A total of 1915 participants from the general population underwent a health examination including TDI echocardiography. The primary endpoint was AF, and the secondary endpoint was complicated AF as assessed by the occurrence of either stroke or heart failure (HF) after the diagnosis of AF. Participants with known AF were excluded (n = 54). During a median follow-up of 11 years, 166 participants (9%) were diagnosed with AF and of these 44 participants (27%) developed HF or stroke. Assessing the association between IVCT and incident AF, the risk increased with 27% per 10 ms increase in IVCT [per 10 ms increase: hazard ratio (HR) 1.27, 95% confidence interval (CI) (1.17-1.38); P < 0.001]. The association remained significant after multivariable adjustment [per 10 ms increase: HR 1.22, 95% CI (1.09-1.35); P < 0.001]. No associations between the IVRT, ET, MPI, and AF remained significant after multivariable adjustment. The IVCT also predicted complicated AF and the association remained significant even after multivariable adjustment [per 10 ms increase: HR 1.39, 95% CI (1.06-1.81); P = 0.015]. CONCLUSION: In the general population, the IVCT provides novel and independent prognostic information on the long-term risk of AF. Additionally, the IVCT can identify persons in risk of complicated AF.

Myocardial performance index by tissue Doppler echocardiography predicts adverse events in patients with atrial fibrillation.

AIMS: The prognostic value of myocardial performance index (MPI) has not yet been assessed in patients with atrial fibrillation (AF). The aim of this study was to evaluate the prognostic value of MPI by tissue Doppler imaging (TDI) M-mode in AF patients. METHODS AND RESULTS: Echocardiograms from 210 patients with AF during examination were analysed offline. Patients with known heart failure (HF) were excluded. Time intervals were measured using an M-mode line through the mitral valve leaflets to provide a colour diagram of the mitral leaflet movement so all time intervals could be measured from one cardiac cycle. MPI was calculated as the sum of isovolumic relaxation time and isovolumic contraction time divided by the ejection time [(IVRT+IVCT)/ET]. During a median follow-up of 2.4 years, 84 patients (40%) reached the combined endpoint of major adverse cardiovascular events (MACE), being all-cause mortality, HF, myocardial infarction, or stroke. Increasing MPI was significantly associated with an increased risk of MACE, and the risk increased with 20% per 0.1 increase in MPI [hazard ratio (HR) 1.20, 95% confidence interval (CI) 1.10-1.32; P < 0.001]. Increasing MPI was also significantly associated with a lower left ventricular ejection fraction (LVEF) (P < 0.001). Nevertheless, MPI remained an independent predictor even after adjustment for age, sex, diabetes mellitus, left atrial volume, and LVEF (HR 1.12, 95% CI 1.01-1.25; P = 0.038). CONCLUSION: Increasing MPI was significantly associated with increased risk of MACE and remained an independent predictor after multivariable adjustment. This demonstrates that the MPI obtained by TDI M-mode might be useful in assessing cardiac function in AF patients with ongoing arrhythmia during examination.

Prognostic value of left atrial strain in predicting cardiovascular morbidity and mortality in the general population.

AIMS: Left atrial (LA) enlargement predicts cardiovascular risk. The prognostic value of left atrial peak reservoir strain (LA RS) by two-dimensional speckle tracking in the general population is currently unknown. This study sought to determine the prognostic value of LA RS in the general population. METHODS AND RESULTS: A total of 385 participants without atrial fibrillation, heart failure (HF), and ischaemic heart disease (IHD) had an echocardiogram including left ventricular and LA speckle-tracking analysis performed. LA RS was averaged from the three apical views. The endpoint was a composite of incident IHD, HF, or cardiovascular death. Median follow-up was 12.6 years (interquartile-range 11.5-12.8 years). Follow-up was 100%. Fifty-one participants (13.3%) reached the composite outcome. LA RS was a univariable predictor of outcome [hazard ratio (HR) 1.25, 95% confidence interval (95% CI) 1.09-1.43; P = 0.002]. However, LA RS did not remain an independent predictor of outcome after adjustment for clinical parameters. The prognostic value was modified by sex (P = 0.011). LA RS predicted the composite outcome in women but not in men when adjusting for clinical parameters (women: HR 1.46, 95% CI 1.05-2.02; P = 0.025) (men: HR 0.96, 95% CI 0.81-1.14; P = 0.65). Further adjustment for echocardiographic parameters did not significantly alter the results. LA RS added incremental prognostic information in addition to SCORE and the American Heart Association/American College of Cardiology Pooled Cohort Equation in women only. CONCLUSION: LA RS is a univariable predictor of cardiovascular morbidity and mortality in the general population. However, the prognostic value of LA RS is modified by sex. LA RS is an independent predictor of outcome in women but not in men.