Author + information
- Received August 27, 2018
- Revision received December 13, 2018
- Accepted January 23, 2019
- Published online May 15, 2019.
- Monika Przewlocka-Kosmala, MD, PhDa,b,c,
- Thomas H. Marwick, MBBS, PhD, MPHb,c,
- Hilda Yang, PhDb,
- Leah Wright, BSc, PhDc,
- Kazuaki Negishi, MD, PhDb and
- Wojciech Kosmala, MD, PhDa,b,c,∗ ()
- aCardiology Department, Wroclaw Medical University, Wroclaw, Poland
- bMenzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia
- cBaker Heart and Diabetes Institute, Melbourne, Victoria, Australia
- ↵∗Address for correspondence:
Prof. Wojciech Kosmala, Cardiology Department, Wroclaw Medical University, Borowska 213, 50-556 Wroclaw, Poland.
Objectives This study investigated the prognostic utility of left ventricular (LV) untwisting (UT) in the elderly patients at risk of heart failure (HF).
Background LV UT mechanics represent a unique combination of LV filling linking ventricular relaxation and suction. The value of this parameter in the prediction of outcomes in patients at risk of HF is unclear.
Methods A group of 465 asymptomatic subjects ≥65 years of age with ≥1 HF risk factor (hypertension, diabetes, obesity), recruited from the community, underwent clinical evaluation and echocardiography including measurement of LV apical and basal peak UT velocities. Cox regression analysis was used to identify predictors of new-onset HF and cardiovascular death after a mean follow-up of 18.2 ± 7.5 months.
Results A composite of both of the study endpoints occurred in 54 patients (11.6%). Adverse outcome was significantly associated with apical (hazard ratio [HR]: 0.98; 95% confidence interval [CI]: 0.96 to 0.99; p = 0.006) UT but not with basal (p = 0.18) UT. The prognostic value of apical UT was independent of and incremental to clinical data, as expressed by the ARIC (Atherosclerosis Risk In Communities) study risk score, left atrial volume index (LAVI), and LV global longitudinal strain (GLS). The addition of apical UT to the model including ARIC risk score, LAVI, and GLS was associated with a 41% improvement in reclassification (p = 0.006).
Conclusions Echocardiographic assessment of apical UT provides incremental value in predicting adverse outcome in asymptomatic patients with HF risk factors. The inclusion of apical UT to the diagnostic algorithm may improve the prognostication process in this population.
The progressive course of heart failure (HF) from asymptomatic to clinically overt disease may be prevented or delayed by applying an early treatment strategy (1,2). Accordingly, the identification of individuals with preclinical HF could be an important step in HF prevention.
Echocardiography is a potential candidate for this screening process. Previous investigations in the preclinical stages of HF demonstrated that left ventricular (LV) hypertrophy, left atrial enlargement, higher LV filling pressure (estimated as the E/e′ ratio [where E is the peak early diastolic mitral inflow velocity and e′ is the early diastolic mitral annular velocity]) and lower global longitudinal strain (GLS) were the most effective echocardiographic predictors of incident HF (3–6). In addition to these parameters, a decline in LV untwisting is believed to be a determinant of exertional dyspnea (7,8). Invasive studies revealed that LV untwisting is a precursor to isovolumic pressure decay that generates an intraventricular pressure gradient causing LV suction, which facilitates LV inflow (9,10). Recent data suggest that LV untwisting may contribute to cardiovascular risk prediction (11). This study sought to determine the prognostic utility of LV untwisting in elderly patients at an asymptomatic stage of HF.
Patients were recruited from the community by means of local media advertising. The inclusion criteria included ≥65 years of age and the presence of 1 or more HF risk factors, such as, hypertension (based on systolic blood pressure >140 mm Hg and self-reported hypertension including antihypertensive medication); type 2 diabetes mellitus (based on self-reported diagnosis including medical management); obesity (body mass index ≥30 kg/m2); previous potentially cardiotoxic chemotherapy; and a family history of HF and a history of heart disease (but not existing HF) (12). Exclusion criteria encompassed symptoms or a known history of HF; known ischemic heart disease, including a history of myocardial infarction, coronary artery bypass grafting, and coronary stenting; more than moderate valvular heart disease; LV ejection fraction <40%; atrial fibrillation; and an inability to acquire interpretable echocardiographic images.
The investigations were performed in accordance with the Declaration of Helsinki, and a research protocol was approved by the Tasmanian Human Research Ethics Committee and registered with the Australian and New Zealand Clinical Trials Registry (Study of heart failure outcomes in stage A heart failure patients screened using advanced echocardiography techniques; ACTRN12614000080628). All participants were informed of the purpose of the study and provided written informed consent.
Data were acquired prospectively from all subjects. The baseline evaluation consisted of a physical examination with anthropometric and blood pressure measurements, a symptom questionnaire, a transthoracic echocardiographic study and a 6-min walk test (6MWT, in meters). Complete medical and family histories were also obtained. The ARIC (Atherosclerosis Risk In Communities; NCT00005131) study risk score was used to assess the absolute risk of HF. The ARIC Heart Failure Risk Calculator was adopted, which uses the 10 most common clinical variables including age, race, sex, systolic blood pressure, current use of blood pressure-lowering medication, smoking status, heart rate, body mass index, prevalent coronary artery disease, and diabetes (the calculator and additional details are available online by using the search phrase “ARIC Heart Failure Risk Calculator using Clinical Factors”). We made minor modifications (using open-source code) to permit quantification of risk at 4 years.
Functional capacity was evaluated by using 6MWT results, following a standardized protocol (13). A 25-m flat, obstacle-free corridor was used, with visible markers at each meter interval and stop coins located at either end. Participants walked unaccompanied and were instructed to walk as far as possible.
A standard scanner (model ACUSON SC2000, Siemens Healthcare, Mountain View, California) and transducers (model 4V1c, 1.25 to 4.5 MHz; and 4Z1c, 1.5 to 3.5 MHz) were used for echocardiographic imaging. LV dimensions, and wall thicknesses were measured according to standard recommendations, and LV mass index was calculated accordingly (14). LV hypertrophy was defined as LV mass index >115 g/m2 in men and >95 g/m2 in women. LV and left atrial volumes were assessed by using the biplane Simpson method. LV inflow parameters including peak early (E) and late diastolic flow velocity (A), and deceleration time of early diastolic flow was evaluated by pulsed-wave Doppler from the apical 4-chamber view with the sample volume placed between the tips of mitral leaflets. Tissue Doppler mitral annular early diastolic velocity (e′) was measured at septal and lateral aspects and were averaged for calculation of the E/e′ ratio to an approximate LV filling pressure.
LV longitudinal deformation was assessed from gray scale images in the apical 4-, 2-, and 3-chamber views by using velocity vector imaging (Syngo VVI, Siemens Medical Solutions, Hoffman Estates, Illinois) as the greatest negative value on the strain curve. GLS was measured online by averaging strain from the region of interest in all 3 apical views.
LV rotational deformation was evaluated offline from 2-dimensional loops in the 2 parasternal short-axis views at the basal and apical levels, using dedicated software (Image-Arena version 126.96.36.199 software, TomTec Imaging Systems, Unterschleissheim, Germany) installed on an external computer workstation, with typical temporal resolution of 60 to 70 fps. After the endocardial border was initially manually traced, the software was used to identify 4 segments at the apical and 6 segments at the basal level and to track the movement of acoustic markers. The basal level was identified by the presence of mitral leaflets while excluding the mitral annulus, and the apical level was identified by the presence of LV cavity in the absence of papillary muscles. The LV rotation/rotation velocity ratio was evaluated as the average angular displacement/displacement velocity of all the segments identified in each level. LV twist was determined by subtracting basal rotation from apical rotation at corresponding time points in the cardiac cycle, and the greatest positive value on the curve was measured. LV torsion was obtained as the peak LV twist divided by the LV end-diastolic longitudinal length, assessed in the apical 4-chamber view. LV untwisting rate (UT) was defined as the peak UT velocity occurring on an LV rotation velocity curve in early diastole (Figure 1) and was evaluated separately for the basal and apical short-axis planes. The times of cardiac events (aortic valve closure, mitral valve opening) were derived from spectral Doppler recordings.
Right ventricular deformation was evaluated offline from the right ventricle-focused apical 4-chamber view, using the same software as for LV rotational mechanics.
The primary composite endpoint was defined as new-onset HF or cardiovascular death. Potential HF symptoms were evaluated by regular follow-up phone calls, symptom surveillance questionnaires, and clinical visits. Information for all-cause hospitalization was monitored and collected. HF was diagnosed if HF signs and symptoms were deemed consistent with those of the Framingham criteria for HF (15) by a consensus of 3 independent cardiologists.
Data are mean ± SD for normally distributed variables, median (interquartile range) for skewed variables, and counts and (percentages) for categorical variables. Between-group comparisons for continuous variables were performed using an unpaired 2-sided Student t-test, or, when more than 2 groups were included, by 1-way ANOVA using Scheffe’s post hoc test and by chi-square test for categorical variables. Skewed variables were log-transformed before being analyzed. The primary outcome of time to event was examined using univariate and multivariate Cox proportional hazards models. To reach the final multivariate model, a stepwise approach was used, with a p value <0.05 as entry criterion, and p value ≥0.15 as removal criterion. Predictors with p values in univariate associations <0.20 were considered in the multivariate models. Relative risks were expressed as hazard ratios with 95% confidence intervals (CI). The incremental value of echocardiographic predictors was assessed in a nested Cox model by sequential addition of left atrial volume index (LAVI), GLS, and apical UT to an initial model including the ARIC risk score, a parameter based on clinical features. The change in overall log-likelihood ratio chi-square test result was used to assess the increase in predictive power after the addition of subsequent parameter. The C-statistic was used to evaluate model performance. The net reclassification improvement, calculated on the basis of category-free approach, was used to assess the effect of reclassification obtained at each step. Event-free survival curves were estimated using the Kaplan-Meier method, and a difference was assessed with the log-rank test. The reproducibility of UT measurements was evaluated by the Bland-Altman method (mean difference and 95% CI) and intraclass correlation coefficient. All calculations were carried out with commercially available software (Statistica, StatSoft Inc., Tulsa, Oklahoma for Windows [Microsoft, Redmond, Washington]). Statistical significance was set at a p value of <0.05.
A total of 584 participants were enrolled in the study. Of 531 participants with known outcome, imaging data for LV rotational mechanics were available in 465 subjects. The reasons for inability to analyze the remaining patients was insufficient quality of short-axis images. The subset of subjects not included did not differ from those included in this study analysis (Supplemental Table S1).
After a mean follow-up of 18.2 ± 7.5 months, the primary endpoint occurred in 54 patients (11.6%), all of whom were new HF presentations.
The demographic, clinical, and echocardiographic characteristics of individuals with and without the composite endpoint are presented in Tables 1 and 2⇓⇓. Subjects with events were older, had a larger prevalence of diabetes and obesity, a higher body mass index, an ARIC risk score, an LV end-diastolic dimension and mass index, a LAVI and E/e′ ratio, and lower 6MWT distances, and GLS and apical UT.
Associations with outcome
In unadjusted Cox proportional hazard models, patient age, body mass index, 6MWT distance, ARIC risk score, presence of diabetes, LV end-diastolic dimension, LV mass index, LAVI, E/e′ ratio, GLS and apical UT were significantly associated with the primary composite endpoint (Table 3).
In multivariate stepwise Cox regression analysis, the independent predictors of adverse outcome were ARIC score, LAVI, and GLS and apical UT (see Model 4 in Figure 2).
Using an externally validated cutpoint for apical UT of 36°/s (mean minus ±2 SD in the cohort of healthy subjects) (7), we demonstrated that the subset with apical UT below the above-cited threshold was characterized by a higher risk of the composite study endpoint (Figure 3).
Incremental prognostic value of echocardiographic variables
In the sequential Cox analysis, each subsequent parameter added to a previous model improved the predictive power for the study endpoint, namely the addition of LAVI improved the model including ARIC risk score; the addition of GLS improved the model based on ARIC risk score and LAVI; and the addition of apical UT improved the model based on ARIC risk score, LAVI, and GLS (Figure 2).
Net reclassification improvement showed improvement in reclassification of 57% (p < 0.001) after addition of LAVI to ARIC risk score, 30% (p = 0.04) after addition of GLS to the model including ARIC risk score and LAVI, and 41% (p = 0.006) after addition of apical UT to the model including ARIC risk score, LAVI, and GLS.
The degree of concordance of measurements untwisting velocities was assessed in 15 randomly selected examinations and analyzed twice by 2 observers (M.P.K. and W.K.) blinded to the patients’ clinical data on 2 separate days. The intra- and interobserver variabilities as expressed by intraclass correlation coefficient was 0.84 and 0.76 for apical UT and 0.81 and 0.80 for basal UT, respectively. Mean differences were apical UT −1°/s (95% CI: −7 to 6) and 1°/s (95% CI: −7 to 9) and basal UT 1°/s (95% CI: −4 to 6) and −5°/s (95% CI: −14 to 4) for intra- and interobserver comparisons, respectively.
This study demonstrates that echocardiographic assessment of apical UT provides incremental value in predicting HF onset in asymptomatic patients with HF risk factors. The inclusion of apical UT to the diagnostic algorithm in this population may improve the prognostication process based on clinical factors and the widely recognized echocardiographic markers—left atrial volume and LV longitudinal deformation.
HF prediction in the community
The prevalence of HF in at-risk groups is expected to reach 23% by 2030 and will be associated with a large economic burden (16). An effective means of community screening for at-risk individuals is potentially important for primary prevention of HF. However, determination of an adequate screening algorithm is challenging. Previous reports indicate that clinical, echocardiographic, and imaging data offer predictive value (12,17–25). However, conventional prognosticators such as LV ejection fraction and natriuretic peptide levels seem to be insufficiently sensitive to detect early myocardial impairment in the community (26–30). Therefore, the identification of novel risk factors to supplement the HF risk profile is still needed. Given the heterogeneous nature of HF progression, the attempts to extend the spectrum of potential risk predictors to cover new pathophysiological aspects may improve the accuracy of prognostication.
Role of echocardiography in screening and contribution from LV untwisting
The previously demonstrated contributions of echocardiography to the process of screening for increased HF risk in asymptomatic populations were related to LV systolic, diastolic, and structural domains (3–6,24). Abnormalities in LV deformation and filling and LV hypertrophy were the most commonly evidenced predictive markers. LV untwist is a part of LV rotational physiology, which impacts on early diastolic filling. The physiologic background of untwist is mechanical recoil resulting from the release of elastic energy deposited during contraction both in the intracellular and the extracellular compartments of myocardium and is associated with the helical architecture of cardiac fibers (9,31,32). Disturbances in LV untwisting have been demonstrated under various clinical conditions including HF with preserved ejection fraction, hypertrophic cardiomyopathy, aortic stenosis, and LV hypertrophy (11,33–37). However, the significance of impaired untwist in the preclinical setting has not been determined to date.
The current work shows the prognostic value of LV apical UT in a cohort of asymptomatic subjects with HF risk factors that is independent of and incremental to clinical data, as expressed by the ARIC risk score, and echocardiographic indices reflecting LV functional status, longitudinal deformation, and left atrial volume. This indicates the distinctiveness of clinical information provided by LV UT and may have an impact on patient management. These findings are in line with the authors’ previous work showing the predictive value of LV UT in HF with preserved ejection fraction (11,37). Accordingly, it appears that reduced UT contributes to different stages of the pathophysiologic continuum and may serve as a prognostic marker not only in early, but also in more advanced disease. The link between UT and the risk of incident HF is conceptually supported by the notion of exercise-induced exacerbation of abnormal resting UT due to the tachycardia-associated shortening of diastole, with subsequent compromised LV filling and limitations on exertion (38). The abnormal response of UT to exercise should be viewed in the context of reduced overall cardiac functional reserve, including both systolic and diastolic components, which detrimentally affects patient prognosis.
First, a relatively high rate of adverse outcomes may suggest the presence of some minimally symptomatic patients with HF (Stage C1) who escaped detection at baseline. These subjects might have quickly progressed to a diagnosis of HF as their symptoms became clearer. Second, the absence of ischemic heart disease was verified only on the basis of a negative history. Third, the presence of diabetes was established mainly from patient self-reports, which might have resulted in the underestimation of the actual frequency of this disease in the study cohort. Fourth, blood natriuretic peptide levels were not assessed; however, their performance in screening asymptomatic community-based populations for HF has been questioned (27). Fifth, the limited temporal resolution of speckle tracking imaging might have affected the accuracy of UT measurements. The differences in frame rate used during the data acquisition might have contributed to the disparities in absolute values of LV rotational parameters between in this study and those in some previous reports. Sixth, the input of basal UT may be underestimated because of a lesser reliability of measurements resulting from increased through-plane motion (7,38). The highest instantaneous differences between the apical and basal movements (i.e., net LV untwist) could not be assessed due to the lack of simultaneous measurements obtained from a single multiplane acquisition (3D dataset), a prerequisite for such an analysis with the software used in this study. Nonetheless, the finding of a significant association between outcomes for the apical but not for the basal UT is consistent with the concept of dominant contribution of the apex to rotatory mechanics (7,39,40). Seventh, the test-retest variability of UT measured from repeated acquisitions was not evaluated. This may be important in view of the fact that the adequacy of LV rotation assessment is dependent on the placement of imaging planes. Eighth and finally, the clinical applicability of UT may be constrained by the paucity of normative ranges and data on intervendor consistency of measurements.
Abnormalities of LV untwisting are independently associated with unfavorable outcomes in elderly asymptomatic patients with HF risk factors. The inclusion of a novel pathophysiologic component in the prognostic strategy may contribute to the more effective identification of individuals who may benefit from increased surveillance and timely treatment to prevent the development of clinically overt disease. Our findings provide further support for the use of echocardiography as a part of the prognostic assessment in subjects with increased clinical risk for HF.
COMPETENCY IN MEDICAL KNOWLEDGE: LV untwisting abnormalities have prognostic significance in asymptomatic patients with heart failure risk factors, independent of clinical data and widely recognized echocardiographic markers such as left atrial volume and LV global longitudinal strain.
TRANSLATIONAL OUTLOOK: Results from the present study support the use of echocardiography in heart failure screening. The inclusion of LV untwisting assessment into the prognostic strategy in subjects with preclinical disease may contribute to more effectively identify individuals who may benefit from increased surveillance and timely treatment for preventing the development of clinically overt heart failure.
Supported by Tasmanian Community Fund, Hobart, Tasmania, Australia, and Siemens Healthcare Australia, Melbourne, Victoria, Australia. Dr. Marwick has received research support from GE Medical Systems. Dr. Yang is supported by Health Professional Scholarship 100307 from the National Heart Foundation of Australia, Canberra. Dr. Negishi is supported by an award from the Select Foundation, Hobart, Tasmania, Australia. None of these agencies had any role in design, analysis, or interpretation of this study. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. James Thomas, MD, served as Guest Editor for this paper.
- Abbreviations and Acronyms
- 6-min walk test
- peak late diastolic mitral inflow velocity
- peak early diastolic mitral inflow velocity
- peak early diastolic mitral annular velocity
- global longitudinal strain
- heart failure
- left ventricle
- untwisting rate
- Received August 27, 2018.
- Revision received December 13, 2018.
- Accepted January 23, 2019.
- 2019 American College of Cardiology Foundation
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