HV) can provide clinically useful information. A pooled analysis of the HRRHV after 60 s of hyperventilation was conducted in 282 participants including healthy controls; patients with heart failure (HF); coronary artery disease (CAD); a combination of both; or patients suspected of CAD but with a normal angiogram. Hyperventilation significantly increased heart rate in all groups, although healthy controls aged 55 years and older (15 ± 9 bpm) had a larger HRRHV than each of the disease groups . No significant differences were found between disease groups. The HRRHV may serve as an easily measurable additional marker of cardiovascular health. Future studies should test its diagnostic potential as a simple, inexpensive pre-screening test to improve patient selection for other diagnostic exams.An increase of heart rate to physical or mental stress reflects the ability of the autonomous nervous system and the heart to respond adequately. Hyperventilation is a user-controlled breathing maneuver that has a significant impact on coronary function and hemodynamics. Thus, we aimed to investigate if the heart rate response to hyperventilation (HRR As a result, research focused on predictive metrics of cardiovascular disease is paramount4. Presently, several diagnostic tests are used—including stress tests and coronary angiograms—to verify or exclude the presence of cardiovascular disease. However, these approaches have many limitations, including higher costs, intricate diagnostic equipment, exposure to radiation, invasive procedures, or injections of pharmacological agents. These factors restrict their clinical utility. Tests like 12-lead ECG and physical exams are more easily accessible, but often provide less information than imaging modalities5. The addition of a simple pre-screening test, performed without supplemental imaging techniques, could supplement the information gained through existing screening tests and reduce the number of costly advanced diagnostic tests.Cardiovascular disease affects nearly one third of people over the age of 657. A higher resting HR has been shown to be correlated with higher risk of cardiovascular disease and death in the general population and several patient groups, including heart failure with preserved ejection fraction (HFpEF)8 and coronary heart disease10. Another similar assessment associated with cardiovascular disease is HR variability, measured through stationary or ambulatory recordings13. Such parameters however may not consistently be abnormal at rest. Therefore, inducible HR changes as a response to physiological stress could provide useful incremental information. The response of the heart rate to stress, commonly exercise or pharmacological injection, has been shown to hold prognostic and diagnostic power. An inadequate heart rate response to increased activity, chronotropic incompetence, is especially prevalent in patients with heart failure (HF)14. The heart rate response to exercise has been shown to distinguish HF patients from age-matched controls and those with hypertension15, while a large outcome based analysis of the general population demonstrated that the magnitude of the heart rate response increase following exercise was a predictor of sudden cardiac death16. The heart rate response to adenosine has also been associated with advanced myocardial imaging results as one of the strongest negative predictors of reduced coronary flow reserve in women with non-obstructive coronary artery disease17. Additionally, a diminished heart rate response to adenosine infusion was an incremental prognostic marker for cardiovascular outcomes beyond traditional clinical and imaging risk factors, especially for women18. A heart rate response can also be induced through voluntary hyperventilation without the need for exercise of an injected agent. In nineteen controls we previously reported that while adenosine increased HR by 18 ± 14 bpm, an increase of 25 ± 14 bpm was also observed with hyperventilation19, although it is so far unknown if this is related to cardiovascular health.Heart rate (HR), an accessible, quantifiable measure, has long been investigated as a predictor of cardiovascular disease and mortality21. CMR, while considered the gold standard modality for many cardiac function and tissue parameters, is not suitable as an initial diagnostic or screening test because of the associated cost. On the other hand, the response of the heart rate to hyperventilation (HRRHV) would not require any equipment other than a device to measure heart rate. To investigate whether the HRRHV may have potential as a preliminary indicator of cardiovascular health, we undertook a retrospective pooled analysis to investigate if differences in heart rate responses differ between controls and patient groups with CAD and HF.Recently, cardiovascular magnetic resonance (CMR) studies by our groups and collaborators have used hyperventilation as a tool to investigate myocardial oxygenation and heart diseaseThe baseline characteristics of healthy subjects and patients are summarized in Table HV of 25 ± 14 bpm, while the ≥55 years control sub-group yielded an HRRHV of 15 ± 9, and this was significantly greater than any HRRHV observed in the patient groups % and a negative predictive value of 91 (80–96)% with an HRRHV of 15.5 bpm for distinguishing from cardiovascular patients (Table As no difference in HRRts Table .Table 3PHV) was significantly diminished in cardiovascular patients , when compared to controls older than 55years (HRRHV = 15 ± 9). No differences in HRRHV were observed between cardiac disease groups.Our pooled analysis of 9 studies revealed that 60 seconds of hyperventilation consistently induced a marked increase of heart rate in healthy controls and in patients with cardiovascular disease. However, the heart rate response to hyperventilation  is attenuated in patients with cardiovascular disease. HRRHV should be further investigated for its potential utility as a simple, accessible, and inexpensive pre-screening test with the potential to help improve patient selection for more expensive diagnostic modalities. A prospective study with a tightly protocolized breathing maneuver and a larger sample size should be conducted to evaluate a more accurate cut-off between healthy and disease populations while also assessing any potential adverse effects. The goal of future assessments would be to use more universal HR measuring devices that are publicly available including newer wearable devices that report additional variables such as heart rate variability.The present study suggests that a hyperventilation-induced increase in heart rate . Hemodynamic responses to HR was not the defined end-point in any of the original studies. We pooled data from studies at these sites that applied the specific 60 s hyperventilation technique in their study in rest conditions, based on the protocol first used by Guensch et al.45. Nine studies were included with a total of 282 participants, each of which measured the heart rate response to 60 s of hyperventilation in healthy controls, patients with known or suspected CAD, or HF patients. Each of the included studies used the same 60 s hyperventilation technique in addition to other breathing maneuvers as part of a cardiac magnetic resonance (MR) imaging protocol.The primary aim of this retrospective pooled analysis was to investigate differences in the heart rate responses to a short period of hyperventilation between controls and patients with cardiovascular disease. Data was collected from studies that were conducted between 2010 and 2018 at the Bern University Hospital in Switzerland, the Stephenson Cardiac Imaging Centre, the Montreal Heart Institute, and the McGill University Health Centre in CanadaHV was calculated as the relative difference to the resting HR. HR was recorded with an MRI-compatible ECG tracer, typically using three to four leads and directly recorded onto the images which could then be verified post-exam. Demographic information, along with ventricular function parameters were obtained on the day of the procedure.Following a period of normal breathing, resting HR was recorded, after which hyperventilation commenced at a pace of at least 30 breaths per minute for 60 seconds. Immediately after, the post-hyperventilation heart rate was recorded, and HRRIn all studies, healthy controls were screened for disorders and medications that are known to affect the cardiovascular and respiratory systems. Participants from the studies were combined and re-classified into five groups: healthy controls, patients who presented with CAD symptoms but had no significant coronary stenosis as evaluated via angiography (CAD−/HF− group), angiographically validated CAD patients (CAD + group), HF patients (HF + group), and patients with both HF and a history of CAD (CAD+/HF + group). Patients in the CAD + group had at least one untreated coronary stenosis ≥50% of the diameter as evaluated by angiography at the time of the hyperventilation procedure. Patients with heart failure (HF+) included patients both with reduced (<50%) and preserved (≥50) ejection fraction, had no known history of CAD and were presenting with heart failure symptoms, with either New York Heart Association classification of ≥2 or a positive B-type natriuretic peptide (BNP) or N-terminal pro B-type natriuretic peptide (NTproBNP). CAD+/HF + patients met the HF criteria and had a history of CAD, while patients in the CAD-/HF- group were patients without heart failure or a previous history of CAD who had been referred for an invasive angiography at the time of the hyperventilation procedure for the suspicion of CAD, with no relevant obstructive stenosis found on the resulting exam. Patients with implantable cardioverter defibrillators or pacemakers were excluded. More specific inclusion and exclusion criteria can be found in the relevant publications and in the NCT registry.Each study was approved by the local research boards at the aforementioned sites, the Cantonal Ethics Committee of Bern, Bern, Switzerland, the Conjoint Health Research Ethics Board, Alberta, Canada, and the Montreal Heart Institute Research Ethics Board and McGill University Health Centre Research Ethics Board, Quebec, Canada. Written informed consent was obtained from all subjects. The data included in this specific analysis were either published with data available upon request, conducted on participants who gave consent to secondary use of their data, or were granted approval for secondary use of data by local research ethics boards. All methods were carried out in accordance with relevant guidelines and regulations.48) and GraphPad Prism .Statistical analysis and presentation were performed primarily with MATLAB , diastolic and systolic blood pressure, gender, ejection fraction, cardiac index, resting HR) were compared across groups, using ANOVA for continuous variables and a non-parametric ANOVA for categorical variables, with Bonferroni or Dunn’s multiple comparison post-hoc analysis for a direct comparison to the healthy control sub-group (≥55 years) if appropriate. An ANOVA and post-hoc analysis were then performed for comparing HRRHV between all four disease groups and the sub-group of healthy controls (≥55 years). By using this older healthy control sub-group with similar demographics to the patient groups , with an equal number of patients and controls pseudo-randomized for inclusion into each bin. With this sub-analysis population, n = 54 were available for each group.Receiver operating characteristic (ROC) curves were used to assess preliminary cut-offs between healthy and patient groups. Subsequent analysis was performed to assess the diagnostic accuracy of the cut-offs. Prior to this assessment, all cardiovascular patient were combined into a single patient group. As age is a significant factor in HRRHV was also assessed in the 20 healthy controls who completed the breathing maneuver multiple times. Test-retest reproducibility was assessed with both the Lin concordance coefficient and the absolute single measure intraclass correlation coefficient (ICC) using a two-way mixed model. Unless otherwise indicated, all stats are reported as mean ± standard deviation.Finally, reproducibility of HRRSupplemental InformationDataset 1


LV geometry pattern was most related to SAC among clinical parameters (p = 0.019). LVGLS was most related to LV geometry and diastolic blood pressure. In contrast, e’ velocity was most related to PIIINP. Conclusion: Our findings may indicate that in young patients with never-treated HT, aldosterone significantly contributes to changes in LV geometry and functional impairment through its pro-hypertrophic and myocardial fibrosis effects beyond blood pressure.Background: Although aldosterone has been demonstrated to induce left ventricular (LV) hypertrophy not only in primary aldosteronism but also in primary hypertension (HT), it can be affected by multiple factors, including age, and the effect of aldosterone on LV function is controversial. This study was to investigate the relationship of aldosterone to changes in LV geometry and function in young adults with never-treated HT. Methods: Seventy-five consecutive patients  with never-treated HT and 45 normal controls were enrolled. Echocardiographic values and LV global longitudinal strain (LVGLS) were obtained. Serum aldosterone concentration (SAC) and serum procollagen type III amino-terminal peptide (PIIINP) level were obtained in HT patients. Results: HT patients had higher LV mass index, higher relative wall thickness (RWT), and worse LV function than normal controls. LVGLS and e’ velocity were worse in HT patients with normal geometry than in normal controls. SAC was well correlated with LV mass index, RWT, e’ velocity, LVGLS, and PIIINP (all  Elevation in blood pressure (BP) increases the afterload and left ventricular (LV) wall stress, resulting in subendocardial damage and myocardial fibrosis, which then lead to LV remodeling with increased LV mass in systemic arterial hypertension (HT). Previous studies have shown that increased LV mass, known as LV hypertrophy (LVH), increases cardiovascular disease risk and is an independent predictor of cardiovascular events ,2,3. ManAldosterone excess in primary aldosteronism has been associated with higher risks of HT, kidney damage, and LVH. Recently, it has been shown that circulating aldosterone levels, even within the physiological range, are also related to an increased risk of cardiovascular mortality, fatal stroke, and sudden cardiac death . AldosteHowever, the renin–angiotensin–aldosterone system (RAAS) and aldosterone as the end product can be affected by multiple factors, including antihypertensive agents, comorbidities, and aging ,9,10. AlTherefore, this study aims to evaluate the relationship of aldosterone to LV geometry, function, and myocardial fibrosis in these patients.Seventy-five consecutive young patients (age ≤ 40 years) diagnosed with primary arterial HT and with no history of use of anti-HT medications were enrolled. The exclusion criteria were a history of coronary artery disease, diabetes, LV ejection fraction (LVEF) <50%, any valvular or congenital heart disease, atrial fibrillation, and renal dysfunction (plasma creatinine >1.5 mg/dL). Forty-five age- and sex-matched normal healthy subjects were enrolled as controls. These subjects were selected from patients who underwent echocardiography for noncardiac causes and from volunteers, through frequency matching. All subjects had no medical history or specific medication. Based on the 7th Report of the Joint National Committee on Prevention, Detection Evaluation, and Treatment of High Blood Pressure, the HT criteria were systolic BP (SBP) ≥140 mmHg and/or diastolic BP (DBP) ≥90 mmHg . BP recoAll measurements, including BP, echocardiographic study, and blood tests were performed before starting antihypertensive medications. All subjects provided informed consent, and study approval was obtained from the Institutional Review Board of the Korea University College of Medicine.A commercially available echocardiography system  with a 3.5 MHz phased-array transducer was used for conventional 2-dimensional (2D) echocardiography imaging. Echocardiography was performed in accordance with the standards of the American Society of Echocardiography (ASE) .Mitral inflow velocity was obtained using pulsed-wave Doppler echocardiography with the sample volume between mitral leaflet tips during early diastole (E), and its deceleration time (DT) was measured. Early diastolic septal mitral annular velocities were obtained from the pulse wave velocity of spectral tissue Doppler imaging and averaged (e’). The E/e’ was also calculated. LV mass index (LVMI) was calculated from end-diastolic M-mode or 2D-guided measurements of the ventricular septum, LV end-diastolic diameter (LVEDD), LV end-systolic diameter (LVESD), and posterior wall thickness (PWT), according to the method of Devereux et al. .LV relative wall thickness (RWT) and systolic wall stress were calculated as follows:RWT = 2 × (diastolic PWT ÷ LVEDD)Systolic wall stress = 0.334 × SBP × LVESD ÷ (systolic PWT × (1+systolic PWT/LVESD))2 in male patients and 95 g/m2 in female patients, respectively, according to the 2015 ASE guideline, and the cutoff point for abnormal RWT was 0.44 [LVH was defined as an LVMI exceeding 115 g/mwas 0.44 . Patternwas 0.44 , as follSecond-harmonic B-mode images with a frame rate of 77 ± 6 frames/s  were obtained for offline analysis. According to the ASE guidelines ,16, apicVenous blood was collected in the morning after a 12 h fast with the patients in the sitting position after an approximately 30 min rest. Plasma was immediately separated and frozen at −80 °C until the assay was performed. The SAC was measured in EDTA plasma . The plasma renin activity (PRA) was determined with the radioimmunoassay method and Immunotech kit . ARR was calculated as SAC divided by PRA.The serum procollagen type III amino-terminal peptide (PIIINP) level was measured in 45 of the 75 patients who agreed to undergo blood sampling for this test. Blood samples were centrifuged immediately after sampling, and the separated serum was stored at –40 °C for subsequent analysis. Serum PIIINP levels were measured using a specific immunoradiometric assay .To estimate the 24 h urinary sodium excretion from spot urine samples, we used Tanaka’s prediction model . The estt-test for continuous variables. Pearson correlation analysis was used to analyze the correlations between SAC, PRA, ARR, and echocardiographic variables of LV structure and function. The differences in LV geometries in HT patients were tested using the analysis of variance test. To assess the relationship of SAC to several clinical parameters and the LV geometry pattern , we performed univariate and multivariate analyses based on stepwise multiple linear regression. SPSS version 20.0 for Windows  was used for statistical analysis. A value of p < 0.05 was considered to indicate statistical significance.Values were presented as mean ± standard deviation or as numbers and percentages. Comparisons between normal controls and HT patients were made using the Student’s p = 0.032). Body mass index was higher in HT patients than in normal controls (p = 0.005). The average office SBP and DBP in HT patients were 151.9 ± 15.9 mmHg and 97.2 ± 12.2 mmHg, respectively  HT patients were women. The total cholesterol level was higher in HT patients than in normal controls . The left atrial diameter was larger and other LV diastolic parameters including DT, E/A, and e’ velocity were worse in HT patients than in normal controls . LVGLS was significantly lower in HT patients than in normal controls, whereas LVEF was similar between the 2 groups . The e’ velocity was significantly reduced in patients with concentric LVH  had any LV geometric changes. HT patients with concentric LVH had higher RWT and LVMI than other HT patients  and e’ velocity tended to be lower in HT patients with normal geometry than in normal controls . With the cutoff value with −15.2% of LVGLS , the sensitivity and specificity for the detection of LVH were 70.0% and 86.7%, respectively.Moreover, LVGLS was lower . In contrast, PRA was not different among the 4 groups (p = 0.48).SAC was significantly higher in patients with any LV geometric changes than in patients with normal geometry, and it was the highest in patients with concentric LVH (p < 0.001) and RWT , and negatively related to LVGLS  and e’ velocity  (p = 0.013).SAC was positively correlated with LVMI  . SAC wasp = 0.026, p = 0.043).PIIINP was higher in HT patients with concentric LVH than in those with other LV geometry Young HT patients had higher LVMI, higher RWT, and worse LV function than normal controls. LVGLS and e’ velocity were worse in HT patients even with normal geometry than in normal controls. (2) SAC was well correlated with LVMI, RWT, LVGLS, and e’ velocity. (3) SAC was related to PIIINP, which was higher in concentric LVH than in other LV geometries. (4) LVGLS was most related to LV geometry and DBP, whereas e’ velocity was most related to PIIINP and LV geometry. (5) LV geometric change to concentric LVH was most related to SAC beyond age and BP.The development of LVH is influenced by various neurohumoral factors, and the RAAS is strongly involved. Many studies have suggested that an elevated aldosterone level can contribute to LVH beyond the effects of the BP-related hemodynamic load on such a hypertrophy.Excess plasma aldosterone in patients with primary aldosteronism is frequently associated with an increase in LV mass beyond levels needed to compensate for the BP-related hemodynamic load in this condition ,20. In aAge-related changes in the RAAS in normal humans are well recognized. PRA and SAC decrease with aging, and they are the highest in newborns and the lowest in elderly persons.In addition, the RAAS has an important role in the BP increase induced by increased peripheral vascular resistance and early structural damage in younger people with a hypertensive phenotype. However, the superimposition of a disease process or the prescription of a drug to induce a change in electrolyte balance, inhibiting renin release, or angiotensin II production could precipitate hyporeninemic hypoaldosteronism .Although some investigations have described the relationship between LV geometry and aldosterone in HT patients who are already receiving treatment ,29, therIn this study, we attempted to exclude confounding factors affecting the RAAS, such as aging, antihypertensive medication, and renal dysfunction. Finally, a narrow spectrum of young patients was enrolled.Inappropriate activation of the RAAS and a lack of ability to lower aldosterone levels in response to the high salt intake in modern diets are considered maladaptations of this regulatory system.Several reports have revealed that aldosterone promotes LV remodeling and interstitial fibrosis via direct effects on the cardiac extracellular matrix , changesMyocardial fibrosis and the associated alterations of the extracellular matrix are the major determinants of a hypertensive heart , and intSAC was related to an increase in LV mass, concentric remodeling, and myocardial fibrosis. In addition, SAC was related to both systolic and diastolic impairment. In multivariate analysis, change in LV geometry pattern to concentric LVH was most related to SAC. Therefore, it can be assumed that SAC is more related to LV structural remodeling than functional remodeling, and functional remodeling may be due to multiple factors, including age, BP, and myocardial fibrosis. Moreover, the functional impairment might not yet be highly progressed because of the young age of the patients.Two-dimensional speckle-tracking imaging is a simple and noninvasive echocardiographic technique that can detect subtle changes in myocardial function in HT patients with preserved LVEF ,39,40,41The major limitation of our study was the relatively small number of HT patients, even if the accurate selection of never-treated young HT patients could justify this small number. We consecutively enrolled young HT patients who were referred to a tertiary hospital. Moreover, to minimize other confounding factors, we excluded patients who had significant comorbidities, such as diabetes mellitus, renal insufficiency, and already decreased LVEF. Only 18 of the 75 HT patients were women, consistent with the reported low prevalence of HT in young women, and we did not find any sex-related differences. Second, PIIINP was not obtained in all study subjects, and even in HT patients with normal geometry, PIIINP may be higher than that of normal controls. Third, other biological and neurohumoral factors that could affect the results were not evaluated. Lastly, a long-term follow-up with use of mineralocorticoid receptor antagonists is required to evaluate the change in LV geometry and function.HT is an established risk factor for cardiovascular diseases, especially premature atherosclerosis and heart failure. Therefore, early and accurate identification of patients with myocardial dysfunction but without symptoms is considered the main starting point for the development of effective primary prevention plans. However, young HT patients tend to ignore the importance of BP management. Most young HT patients undergo a screening test to evaluate the possibility of secondary HT, including aldosterone and renin tests. This study indicates that SAC can be a good biomarker for subclinical LV remodeling and dysfunction, although the values are within the normal range. Detecting signs of myocardial damage by using 2D speckle-tracking imaging can be useful in evaluating patients in the early stage. In addition, more advanced progression to concentric LVH and fibrosis induced by HT and SAC results in reduced e’ velocity as an LV diastolic impairment. Therefore, more aggressive management is considered for preventing further damage in HT patients with elevated SAC and LV geometric change, even in young patients.High serum aldosterone level was related to an increase in LV mass and concentric remodeling, as well as to a decrease in both LV systolic and diastolic function. Serum aldosterone was also associated with myocardial fibrosis. Our findings may indicate that in young patients with never-treated primary HT, aldosterone significantly contributes to changes in LV geometry and functional impairment through its pro-hypertrophic and myocardial fibrosis effects.


Interactions between the left ventricular (LV) and the arterial system,  are key determinants of cardiovascular function. However, most of studies covered multiple cardiovascular risk factors, which also contributed to the morphological and functional changes of LV. The aim of this study was to examine the relationship between arterial stiffness and LV structure and function in healthy women with a low burden of risk factors.n = 147, mean age was 54.07 ± 11.90 years) were studied. Arterial stiffness was evaluated by carotid-femoral pulse wave velocity (cf-PWV). LV structure and function were assessed by two-dimensional speckle tracking echocardiography.Healthy women from the Twins UK cohort (p <  0.05), but bore no relation to global longitudinal strain. After adjustment for age, body mass index, blood pressure and heart rate, cf-PWV was significantly correlated with RWT, global circumferential strain, apical rotation and LV twist .cf-PWV was significantly associated with most measures of LV geometry and function, including relative wall thickness (RWT), E/e’ ratio, global circumferential and radial strain, apical rotation and LV twist (each In healthy women with a low burden of risk factors, elevated arterial stiffness was intimately interwoven with increased LV twisting even before LV dysfunction becomes clinically evident. Arterial stiffening and ventricular remodeling are considered features of cardiovascular ageing . HoweverAlthough, several echocardiographic studies have shown the relationship between arterial stiffness and LV diastolic dysfunction in healthy populations , 3, howeThe study population was comprised of a sub-sample of 200 consecutively recruited women from the Twins UK cohort with characteristics similar to the general U.K. population  who partBrachial blood pressure was measured in duplicate, by using a validated oscillometric monitor  after subjects had rested in a supine position for at least 10 min. cf-PWV was measured using sequential carotid-femoral ECG-referenced applanation tonometry using the SphygmoCor system . The path distance between the carotid and femoral sites was estimated from the distance between the sternal notch and femoral artery at the point of applanation. At least two sequential measurements satisfying the inbuilt quality control criteria of the SphygmoCor system were obtained and the mean value was used for analysis.A transthoracic echocardiographic examination was performed in the left lateral decubitus position using a Vivid-7 ultrasound scanner with an M3S cardiac probe . Two-dimensional views were obtained via the apical  and parasternal  approaches. Three consecutive cardiac cycles of each view were acquired during end-expiration breath holding and stored digitally on a hard disk for offline analysis. All images were obtained at a frame rate of 50 to 80 frames per second. Time of aortic valve closure was assessed by aortic valve motion in the apical long-axis view.Echocardiographic measurements were obtained offline on a PC work-station by using a commercially available analysis software package . LV end-diastolic dimension (LVED), end-systolic dimension (LVES), end-diastolic septal thickness (IVSd) and end-diastolic LV posterior wall thickness (LVPWd) were measured from a parasternal long-axis view in accordance with recommendations of the American Society of Echocardiography . LV massTransmitral flow velocity was obtained from the apical 4-chamber view using pulsed Doppler. The peak early diastolic velocity (E), peak atrial systolic velocity (A), and E/A ratio were measured. Peak motion velocity in early diastolic (e’) and atrial contraction (a’) were measured by tissue Doppler imaging (TDI) at all basal segments from apical 4- and 2-chamber views. Measurements were averaged over all segments.Two-dimensional speckle tracking imaging was performed on three apical views and parasternal short-axis views of the LV. The endocardial border of the LV was defined by placing several points along it and the width of interest was then adjusted to accommodate myocardial thickness. The image analysis software identified natural acoustic markers that moved with the tissue. Automatic frame-by-frame tracking of these markers during the cardiac cycle yielded a strain value and a strain rate. Each LV view was divided into 6 equal segments, providing strain and strain rate curves for these segments.Global longitudinal strain (GLS) measurements were obtained on 3 apical views. The global circumferential and radial strain  measurements were acquired on the short-axis view at papillary muscle level. The systolic peak of strain values between aortic valve opening and closing was determined. Rotation parameters were measured in short-axis views at mitral valve level  and apical level . Basal-to-apical LV twist was defined as the net difference between apical and basal rotations at the aortic valve closing. Intra- and inter-observer variability of LV strain, rotation and twist were measured in 15 subjects.p-value < 0.05 was considered statistically significant and all tests were 2-tailed.Statistical analyses were performed using SPSS . Continuous variables were presented as means ± standard deviation (SD). The sample was divided into 3 groups according to tertiles of the distribution of cf-PWV. Differences between groups were evaluated by one-way analysis of variance (ANOVA). Bivariate correlations between cf-PWV and LV structural and functional measurements were assessed by Pearson’s correlation coefficient. Multivariate linear regression analysis was then applied to examine the independence of association between cf-PWV and LV measurements after adjustment for age, BMI, blood pressure (systolic blood pressure and pulse pressure) and heart rate. Intra- and inter-observer variability of LV strain and twist were assessed using intra-class correlation coefficients (ICC) with 95% confidence intervals and coefficient of variation ). A Demographic and clinical characteristics of the subjects are summarized in Table p <  0.05, Table Pearson’s correlation analysis showed that cf-PWV was correlated with most measures of LV geometry and function, including RWT, LVED, LVES, E/A, e’/a’, E/e’, GCS, GRS, ApexRot, and LV Twist, but bore no significant relation to LVMI, LVEF, GLS and BaseRot. Figure There was a good reproducibility and consistency in the measurement of the LV strain and twist. Detailed inter-observer and intra-observer variability are shown in Table Arterial stiffening is the hallmark of vascular ageing and, when measured by cf-PWV, is predictive of outcome independent of blood pressure components. cf-PWV is a major determinant of the pulsatile load on the ventricle up to the time of peak, myocardial wall stress and thus may have an effect on ventricular remodeling and ventricular function that is not captured by classical blood pressure components , 10.Consistent with previous results –15, thisCurrently, the noninvasive estimation of LV diastolic function is based on conventional echocardiographic and tissue Doppler measurements. LV diastolic dysfunction is mainly characterized by decreased E/A ratio, e’/a’ ratio, and enhanced E/e’ ratio. Arterial stiffness has been found to be associated with diastolic dysfunction in various populations , 16, 17.. found carotid artery stiffness parameter (β) not to correlate with LV systolic function in hypertensive patients.Results of previous studies on the relationship of arterial stiffness to LV systolic function have varied substantially according to the methods used and populations studied. Arterial stiffness has been associated with sub-clinical LV systolic dysfunction and impaired LV longitudinal function in patients with hypertension , type 1 LV strain and twist, due to their complicated helical myocardial fiber architecture, play important roles in ventricular systolic and diastolic performance. To understand the progression of LV systolic dysfunction at different stages of heart disease, it is important to analyze the various components involved in LV deformation. Recently, the angle-independent two-dimensional speckle tracking echocardiography has been successfully used for the measurement of myocardial deformational and rotational parameters. This technique tracks the motion of speckles within the myocardium, allowing complete and accurate assessment of myocardial deformation in all three spatial dimensions. In the present study, we measured LV longitudinal, radial, and circumferential strain and LV twist in healthy women by using speckle tracking echocardiography and found that cf-PWV bore no significant relation to LV longitudinal strain and basal rotation. However, there was a significant positive correlation between cf-PWV and circumferential strain, apical rotation and LV twist after adjustment for confounding factors. Consistent with our findings, previous studies also revealed an increase in LV twisting with increasing aortic stiffness in patients with diabetes, hypertension, and diastolic heart failure , 21. TheThe discrepancies between our findings and previous studies about the relationship between arterial stiffness and LV GLS may be explained by a relatively low cf-PWV (mean cf-PWV was 8.85 ± 1.75 m/s) in our subjects and certain confounding factors, such as an effect of cardiovascular risk factors on the systolic function.Our results showed that increased arterial stiffness might contribute to increased LV twist in healthy women with a low burden of risk factors. Given that LV twist is an important determinant of LV function and the change in twist always far precedes irreversible tissue damage , 28, it The study had some limitations. First, the subjects were limited to female twins, although their lifestyle was similar to the general population of women in the U.K. The applicability of our findings to men or other ethnicities, remains to be confirmed in future studies. Second, our study is cross-sectional, therefore observational nature and causal relationship cannot definitively be established. This is particularly relevant as some of the observed correlations are likely to be bidirectional. In addition, effects of other confounding factors, such as smoking habits, alcohol consumption and physical activity could not be eliminated. Further longitudinal studies are warranted. Third, the results of this study need to be further confirmed by large sample size studies. Moreover, several unproven assumptions are involved in assessment of the relationship between the arterial stiffness and LV dysfunction. Finally, we only used parasternal short-axis view at the level of the papillary muscle to evaluate GRS and GCS, and the exact locations of the basal and apical planes varied from individual to individual, which might cause intrinsic error in the calculation of LV twist.This study demonstrates that in healthy women with a low burden of risk factors, increased aortic stiffening is associated with an increase in LV twist but is not significantly related to LV diastolic function and global longitudinal strain of LV myocardium. These findings suggest a close interaction between arterial remodeling and LV twisting even before LV dysfunction becomes clinically evident.


Patients with lower FMD had significantly decreased circulating EPCs, elevated TMAO, hsCRP, and IL-1β concentrations. Plasma TMAO levels were negatively correlated with circulating EPC numbers and the FMD, and positively correlated with hsCRP, IL-1β concentrations. In in vitro studies, incubation of TMAO in cultured EPCs promoted cellular inflammation, elevated oxidative stress, and suppressed EPC functions. Enhanced plasma TMAO levels were associated with reduced circulating EPCs numbers, endothelial dysfunction, and more adverse cardiovascular events. These findings provided evidence of TMAO’s toxicity on EPCs, and delivered new insight into the mechanism of TMAO-mediated atherosclerosis, which could be derived from TMAO-downregulated EPC functions.Trimethylamine N-oxide (TMAO) is a metabolite originated from bacterial metabolism of choline-rich foods. Evidence suggests an association between TMAO and atherosclerosis, but the relationship between TMAO and endothelial progenitor cells (EPCs) remains unclear. This study aimed to identify the relationship between TMAO concentrations, circulating EPCs, and endothelial function in patients with stable angina. Eighty-one stable angina subjects who underwent coronary angiography were enrolled. The circulating EPCs and flow-mediated vasodilation (FMD) were measured to evaluate endothelial function. Plasma TMAO and inflammatory markers, such as hsCRP and IL-1β, were determined. Furthermore, the effect of TMAO on EPCs was assessed  Trimethylamine N-oxide (TMAO) is a proinflammatory metabolite that originates from bacterial metabolism of choline-rich foods, such as red meats and eggs, in the large intestine and is rapidly oxidized by flavin-containing monooxygenase-3 in the liver4. TMAO has been found to contribute to vascular inflammation5, platelet hyperreactivity6, and atherosclerosis7. An elevated plasma TMAO level is an independent predictor of adverse cardiovascular events in the general population8 and CAD patients9. Dietary supplement with choline promote upregulation of macrophage receptors and enhance atherosclerosis in the apoE−/− mice. Deletion of gut microbiota by antibiotics cancels the proatherosclerotic effect and reduces plasma TMAO concentration at the same time10. In human umbilical vein endothelial cells (HUVECs), TMAO also has been suggested to be associated with endothelial dysfunction5, an early event in the development of atherosclerosis11. However, most studies indicating a relationship between TMAO and endothelial dysfunction are performed in rodents12 or cells5. Though Ke Y et al. had recently conducted a study to show the association between circulating TMAO and vascular aging in 186 subjects, suggesting TMAO may deteriorate the endothelial function by increasing oxidative stress in HUVECs, they did not provide clinical information about the endothelial functions of enrolled patients13. Clinical data interpreting the effect of TMAO on endothelial function are still very limited.Due to improvements of bioinformatics technology, the role of intestinal microbiota in common diseases has been explored widely in recent years. Accumulating evidence indicates that the imbalance of intestinal microbiota is associated with coronary artery disease (CAD) and cardiovascular risk factors, including diabetes, dyslipidemia, obesity, and chronic kidney disease14. The number of circulating EPCs also has been reported to correlate inversely with the risk factors for CAD15 and to be associated with peripheral16 and coronary endothelial function17. However, the relationship between circulating EPCs and TMAO concentration as well as the effects of TMAO on EPCs remain unclear. Therefore, we hypothesized that an enhanced TMAO level might provoke inflammation and induce changes in the numbers and function of EPCs, finally contributing to endothelial dysfunction. In this single-center translational study, we investigated the association between TMAO, circulating EPCs, and endothelial function in patients with stable angina. Also, to confirm the causal relationship between TMAO and endothelial dysfunction, we treated human EPCs with different concentrations of TMAO.Many clinical and basic studies have provided evidence that endothelial progenitor cells (EPCs) play a crucial role in restoring endothelial injury and maintaining endothelial function. When vascular injury occurs, bone marrow-derived EPCs can mobilize to the peripheral circulation and differentiate into endothelial cells at sites of damaged endotheliumTotally 81 patients with stable angina and admitted for coronary angiography were enrolled for analysis. The median age of the study population was 68 years old, 69% of the subjects were male, and 62% of the subjects had significant CAD. Table p = 0.105). Similarly, patients with lower circulating EPC levels were not associated with an increased occurrence of MACEs (log rank p = 0.923). Conversely, patients with either a higher TMAO concentration (log rank p = 0.004) or a higher SYNTAX score (log rank p = 0.003) were both significantly associated with an increased incidence of MACEs.During the median follow-up duration of 1.5 years , 16 cases (19.8%) of MACEs occurred after CAG, including 14 cases (17.3%) of target vessel revascularization and 2 cases (2.5%) of nonfatal MI. Kaplan–Meier survival analysis was performed to investigate the impact of endothelial function, TMAO, and SYNTAX score on adverse event-free survival, as illustrated in Fig. p = 0.034), hsCRP , and IL-1β ; but was negatively correlated with eGFR , circulating EPC , and FMD . The endothelium-dependent FMD values were positively correlated with circulating EPCs  and were negatively correlated with the concentrations of inflammatory cytokines  and TMAO .The correlation between TMAO, FMD, and various clinical factors are summarized in Table +KDR+ and CD34+KDR+CD133+ cells), and increased inflammatory biomarkers  were all significantly associated with lower FMD. According to multivariate regression analysis, circulating EPCs , IL-1β , and TMAO  remained significantly associated with the FMD levels, as shown in Table According to univariate linear regression analysis, hypertension, heart failure, decreased eGFR, circulating EPCs . TMAO treatment also stimulated ROS production and downregulated NO production in human EPCs -nod-like receptor family pyrin domain containing 3 (NLRP3) pathway, whereas inflammatory cytokines were released in a dose- and time-dependent manner5. Similarly, the activation of NLRP3 inflammasomes by TMAO had been reported to increase cell permeability in the mouse carotid artery endothelial cells20. Besides, TMAO has been found to promote monocyte adherence and impair the self-repair capacity of human endothelial cells21. In an animal study, TMAO was shown to accelerate vascular inflammation and impair endothelium-dependent relaxation of the aorta in aged rats, which was restored by 3,3-dimethyl-1-butanol (an inhibitor of trimethylamine formation)12. Our study suggests that the plasma TMAO level is associated with endothelium-dependent FMD in patients with symptoms of angina. Increased plasma TMAO levels and fewer circulating EPCs were independent predictors of reduced FMD. This is the first clinical study to clarify the relationship between TMAO and circulating EPCs in humans, thus providing novel insights into the role of TMAO in endothelial dysfunction.It is increasingly recognized that the intestinal microbiome has significant metabolic effects and maintains a delicate balance within the human host. TMAO is an intestinal microbiota-generated, proinflammatory metabolite, which has been demonstrated to be associated with atherosclerosis and various cardiovascular risk factors14. The inverse correlation between the plasma TMAO level and circulating EPCs found in the current study can be explained as follows. As a proinflammatory metabolite, the TMAO concentration is markedly increased in atherosclerotic diseases, including diabetes, chronic kidney disease, heart failure, and CAD2, which are also risk factors for fewer EPCs14. Shared risk factors may affect TMAO and EPCs simultaneously, leading to the reverse epidemiology, but cannot fully explain the results of the cell-based studies. Though there is currently no paper to investigate the mechanism about how TMAO influence the EPCs, just as what we observed in the study of HUVECs5, TMAO may increase intracellular ROS production and activate the NLRP3-TXNIP pathway, lead to the release of inflammatory cytokines (mainly IL-1β and IL-18)5, which have been demonstrated to be toxic to EPCs at high-dose exposure22. TMAO also inhibited the mRNA and protein expression of endothelial nitric oxide synthase and reduced NO production in HUVECs, which could be reversed by N-acetylcysteine treatment, a ROS inhibitor5. EPCs incubated with recombinant CRP exhibited decreased survival, differentiation, and angiogenic functions23. Furthermore, an enhanced TNF-α concentration contributes to fewer EPCs24. Incubation of EPCs with H2O2 had been reported to profoundly reduce the numbers of EPCs by inducing apoptosis25. In the presented study, cell viability was not significantly decreased under high concentrations of TMAO. Maybe 24 hours was not long enough to observe the cytotoxicity of TMAO on EPCs. Nevertheless, TMAO was found to enhance intracellular inflammation and ROS production, which directly causing functional impairment of circulating EPCs26.EPCs derived from bone marrow can mobilize to the peripheral circulation to regenerate the injured endothelium, playing an important role in maintaining endothelial function27, the increased numbers of EPCs in response to inflammatory stimulation may be functionally impaired28. The in vitro study showed reduced NO expression in TMAO-treated EPCs, suggesting that TMAO can directly impair the NO-mediated endothelial function even when the numbers of EPCs were not significantly decreased. So, it is not surprising that patients with fewer circulating EPCs were not associated with an increased occurrence of MACEs. However, the MACE incidence between patients with high and low FMD values did not achieve statistical significance in the present study. Compared to circulating EPCs or FMD, the severity of CAD and vascular inflammation seem to be more important prognostic factors for patients with angina pectoris.Our findings support the hypothesis that an elevated TMAO level, via provoking intracellular inflammation and oxidative stress, may inhibit the functions of circulating EPCs, and finally lead to endothelial dysfunction. Though low-grade inflammation has been reported to induce EPC mobilization29. Finally, due to the retrospective nature of the present study, certain confounding factors affecting the TMAO concentration, such as the change of gut microbiota, permeability of the gut-blood barrier, and long-term dietary habits, could not be fully accessed.Several limitations of this study should be mentioned. First, this is a single-center study with small case numbers, which may be insufficient to reveal the clinical impacts of EPCs and FMD. Patients with lower FMD levels trended to have higher prevalence of hypertension, heart failure, and higher incidence of MACE during the follow-up period. But none of above findings achieved statistical significance. The clinical significance of endothelial function should be investigated in a large-scale study. Second, the study cohort was composed of patients with relatively low severity of CAD. Only 37% of the cases had angiographically significant CAD, which may underestimate the inflammation-related injuries of TMAO and atherosclerosis. In addition, mean age of the enrolled subjects were relatively elder in the presented study, which may limit the generalization of our results. For example, our study did not found a significant correlation between age and plasma TMAO concentration, which was observed in the large-scale studies in younger populationsIn conclusion, plasma TMAO increased intracellular oxidative stress and inflammatory cytokines, contributed to impaired functions as well as reduced NO production in human EPCs. An elevated TMAO concentration was associated with fewer circulating EPCs, a lower FMD value, and a higher incidence of MACEs in patients with angina pectoris. These findings provide evidence of the potential toxicity of TMAO on EPCs and deliver new insight into the mechanism of atherosclerosis regulation by intestinal microbiota.30. Coronary angiography (CAG) and left ventriculography (LVG) were performed for all enrolled subjects. A coronary lesion with narrowing of >50% in diameter was defined as significant stenosis. Patients with significant stenosis in at least one vessel were suggested to have significant CAD. Based on the CAG results, SYNTAX scores31 were calculated (http://www.Syntaxscore.com). The left ventricular ejection fraction (LVEF) was estimated by LVG, and the left ventricular end-diastolic pressure (LVEDP) was measured with a pigtail catheter placed in the mid-left ventricular cavity. This research was conducted according to the principles expressed in the Declaration of Helsinki. All participants provided their written informed consents, and the study was approved by the Research Ethics Committee of Taipei Veterans General Hospital.We retrospectively screen 203 patients who was more than 18 years of age, with stable angina, and admitted for cardiac catheterization at Taipei Veterans General Hospital from January 2013 to April 2015. After excluding patients with acute myocardial infarction (n = 27), absence of pre-procedure hsCRP and IL-1β data (n = 59), or incomplete study of FMD (n = 36), 81 patients were enrolled for analysis. Flowchart of patient enrollment was summarized in Fig. For each patient, 20 mL of blood was obtained to measure the TMAO and inflammatory markers after fasting and cessation of medications for at least 12 hours. After the blood samples were centrifuged, all plasma samples were stored at −20 °C until the measurement of TMAO and other inflammatory cytokines in the batched assays, which occurred approximately 1 week later. For each case, 200 μL of plasma was mixed with TMAO-d9 isotopologues. After filtration, plasma TMAO was quantified with the use of a stable isotope dilution assay and high-performance liquid chromatography with online electrospray ionization tandem mass spectrometry on an API 4000 Q-TRAP mass spectrometer . The concentrations of high-sensitivity C-reactive protein (hsCRP) were assessed using a commercial enzyme-linked immunosorbent assay ; and the concentrations of interkeukin-1β (IL-1β) were assessed using the human IL-1β/IL-1F2 Immunoassay .32. The peripheral blood of patients was incubated with human kinase insert domain receptor (KDR) antibody  for 30 min in the dark, and then by allophycocyanin-conjugated secondary antibody, phycoerythrin-conjugated human CD133 antibody , and FITC-conjugated human CD34 antibody . After incubation for 30 min, the cells were washed with phosphate-buffered saline before analysis. Each analysis included 100,000 events. We measured the numbers of circulating EPCs gated with monocytes, which were defined as CD34+KDR+ or CD34+KDR+CD133+. Reproducibility of the EPC measurements has been confirmed in our previously published studies33, in which we measured the circulating EPCs from two separate blood samples from 10 subjects.Quantification of the circulating EPCs by flow cytometry was performed as described previously15. A baseline image was acquired, and blood flow was estimated by time-averaging the pulsed Doppler velocity signals obtained from a mid-artery sample volume. The cuff was inflated to at least 50 mmHg above systolic pressure to occlude the brachial artery for 5 minutes. A mid-artery-pulsed Doppler signal was obtained immediately upon cuff release to assess the hyperemic velocity. Post-occlusion diameters were obtained at 60, 100, and 120 seconds after deflation. Endothelium-dependent FMD was calculated as the maximal post-occlusion diameter relative to the averaged pre-occlusion diameter. Subjects were classified according to the FMD results. Subjects with FMD values greater than the median were classified as the “high-FMD group;” otherwise, they were classified as the “low-FMD group.” The enrolled subjects were followed-up until December 2016 or until the occurrence of a major adverse cardiovascular event (MACE), including target vessel revascularization, nonfatal myocardial infarction (MI), and death. Target vessel revascularization was defined as balloon dilatation or stent deployment over a previously treated lesion. Nonfatal myocardial infarction was defined as elevation of cardiac troponin I (>1 ng/mL) with ischemic symptoms. All patients received regular follow-up appointments at our Out-Patient Department, and their medical records were carefully reviewed.FMD was assessed using a 7.5-MHz linear array transducer  to scan the brachial artery in the longitudinal section. The FMD measurement was performed as described previously4 cells on 24-well plates. After reaching 70% confluency, the cells were treated with different concentration  of TMAO for 24 hours. TMAO was purchased from Sigma-Aldrich, dissolved in distilled water, and then diluted in the culture medium for different concentrations to be used in the study. The cell viability of EPCs was determined by 3-−2,5,diphenyltetrazolium bromide (MTT) assay. Human EPCs were incubated with MTT  for 4 hours, lysed with dimethyl sulfoxide, and their absorbance were measured by a microplate reader at 550/650 nm.Peripheral blood samples for EPC culture were obtained from healthy young volunteers. Details of the culture of EPCs were provided in the Supplement. In brief, EPCs were seeded at approximately 1 × 102O2 and oxidative stress, the EPCs were treated with the 2′,7′- dichlorodihydrofluorescein diacetate probe  for 1 hour. The fluorescence intensity was measured at the excitation wavelength of 485 nm and the emission wavelength of 530 nm by an Infinite® 200 plate reader (TECAN). The intracellular nitric oxide (NO) release from EPCs was quantified using the 4-amino-5- methylamino-2′,7′-difluorofluorescein diacetate (DAF-FM) (Life Technologies). Fluorescence excitation and emission maxima were 495 nm and 515 nm, respectively. The results of ROS/NO production were expressed as the percentage of their fluorescence intensity compared to controls (%).After the cells had been treated with different concentrations of TMAO for 24 hours, the medium of culture was then collected for cytokine measurement. The concentrations of IL-6, CRP, and tumor necrosis factor-α (TNF-α) in the medium were determined using ELISA (Sigma-Aldrich), which was performed according to the manufacturer’s protocol. To detect the intracellular Hin vitro Angiogenesis Assay Kit (Chemicon). ECMatrix gel was mixed with ECMatrix diluent buffer and placed in a 96-well plate at 37 °C for 1 hour to allow the matrix solution to solidify. Totally 1 × 104 EPCs were placed on a matrix solution with medium and incubated at 37 °C for 16 hours. Tubule formation was inspected under an inverted light microscope (×100). Six random fields were taken and counted by using computer software, Image-Pro Plus. In addition, the migratory function of EPC was evaluated by a modified Boyden chamber . In the lower chambers, stromal cell-derived factor 1 (SDF-1) (50 ng/mL) was supplemented to the medium and 4 × 104 EPCs were placed in the upper chambers of transwell plates with serum-free endothelial growth medium placed at 37 °C incubation for 24 hours. The membrane of chamber was washed by phosphate buffered saline (PBS) twice and stained using hematoxylin (Merck Millipore). Then the upper membrane side was scraped with a cotton ball and fixed with 2% parafor-maldehyde. The migrated cells in lower membrane side were counted by 8 random high-power (×100) microscopic fields by light microscopy.To access the function of EPC, cell tube formation was performed with an p-value less than 0.05 was regarded as statistically significant.Data were expressed as the median (quartiles) for numeric variables and as a number (percent) for categorical variables. Clinical and laboratory data were compared using the Mann-Whitney U test for continuous variables and Fisher’s exact test for categorical variables. Spearman’s rank correlation test was used to assess the correlation between TMAO, FMD, and other variables. Survival curves were generated with the Kaplan–Meier method, and survival among groups was compared by the log-rank test. Linear regression analysis was performed to investigate the relationships of various factors and FMD, which was logarithmically (log) transformed to achieve a normal distribution before analysis. Factors with statistical significance by univariate regression analysis were further entered into multivariate regression analysis. Data were analyzed using SPSS version 18.0  and MedCalc version 11.4.2.0 . A Supplement


Currently, nearly 250,000 patients suffer from heart failure in the Netherlands  [What can we do to prevent heart failure hospitalisation? First of all, we need to ‘Get with the Guidelines’. For patients with heart failure with reduced ejection fraction  many effective interventions are at our disposal  and thisWith our nurse-led heart failure outpatient clinics, we have an excellent infrastructure in the Netherlands to deliver this complex care . Recent The heart failure outpatient clinic also allows proper patient education and easy access to medical care in case the clinical condition worsens. Self-management and early intervention may prevent hospitalisation , 5.Even though the concept of ‘the nurse-led heart failure outpatient clinic’ is very successful, the number of heart failure hospitalisations remains high . Also, pWe simply need better ways to detect early derangements in heart failure. Here, CardioMEMS may hold promise. This implantable device allows for daily recordings of pulmonary artery pressures, which are then transmitted to the heart failure clinic. Changes in these pressures are a proxy for changes in left ventricular filling pressures, generally considered one of the first things to increase when heart failure worsens. Active monitoring based on these haemodynamic measurements has been very successful and could reduce heart failure hospitalisations by half .In the CHAMPION trial, heart failure medication was very frequently adjusted (both up- and down-titration) . This deVoorlopige Toelating), the (cost-) effectiveness of CardioMEMS will be evaluated in the Dutch health care system. Details of this multicentre randomised trial can be found in this issue [The results of the CHAMPION trial were obtained in both HFrEF and HFpEF patients . Furtheris issue . ResultsWe eagerly await the results of the MONITOR-HF trial. Hopefully CardioMEMS will fulfil its promise in revolutionising heart failure management, also for the Dutch situation.


Advances in the medical and surgical management of Tetralogy of Fallot have led to marked increase of the number and age of survivors. Imaging in patients with Tetralogy of Fallot plays a crucial role in the diagnosis and follow up, and essentially guides management and intervention in this entity. This study systematically reviews the imaging modalities used in patients with Tetralogy of Fallot in the evaluation of preoperative and postoperative anatomic and hemodynamic lesions, as well as disease progression in this diagnosis. Various invasive and noninvasive imaging modalities, most commonly echocardiography and cardiovascular magnetic resonance, computed tomography and angiocardiography provide the imaging information required for diagnosis, management and follow up in Tetralogy of Fallot. The choice of the appropriate imaging tool or their combination is guided by the clinical question, the patient’s clinical condition and contraindications as well as the strengths and weaknesses of each imaging modality. Tetralogy of Fallot is the most common complex congenital heart disease with long term survivors that need close follow up and complicated management, including multiple surgical and transcatheter interventions. Knowledge of the role and protocols of imaging in Tetralogy of Fallot is extremely important for the clinical as well as the imaging physician in order to optimize patients’ management and long-term prognosis. Tetralogy of Fallot (TOF) represents 7–10% of congenital heart disease (CHD) occurring in 0.5/1000 live births and is the second most common form of complex CHD. Although frequently fatal without surgical intervention, advances in one or two-stage surgical repair in the recent era facilitates survival of the affected patients into adulthood with good quality of life, albeit with long-term complications and residual lesions , in ordeDespite its name suggesting four anatomic defects, TOF is produced solely by anterior deviation during embryogenesis of the infundibular septum which separates the outflows of the two ventricles . Such anThe clinical picture in preoperative TOF evaluation depends on the degree of obstruction to pulmonary blood flow and is characterized by various grades of cyanosis and, more rarely, by heart failure when left to right shunt predominates. The degree of pulmonary blood flow determines the size and morphology of the pulmonary arteries, which are frequently hypoplastic, stenotic or inadequately arborized. Associated anomalies in TOF include atrial or additional ventricular septal defects, mirror-image right aortic arch without hemodynamic significance in 25% of subjects, tricuspid valve abnormalities, aortopulmonary collaterals, and anomalous origin and course of coronary arteries that may impact on surgical strategy .Surgical palliation in TOF is achieved by creation of systemic to pulmonary artery shunts to improve cyanosis prior to repair. Surgical, usually transatrial/transpulmonary, repair in TOF is increasingly used primarily even in small infants, and consists of ventricular septal defect closure and relief of RV outflow tract obstruction by a combination of RV muscle resection, infudibulotomy and patch enlargement of the RV outflow tract and the pulmonary arteries when needed . AttemptThe ideal imaging tool in TOF should be able to adequately assess all its structural and functional abnormalities both pre and postoperatively. Before operation, it is thus important to depict the size, morphology, arborization and possible stenoses of the pulmonary arteries, the infudibular obstruction, the presence of additional ventricular or atrial septal defects, the origin and proximal course of the coronary arteries, the source of extracardiac pulmonary blood flow and the size, morphology and function of the RV and the tricuspid valve. Additionally after repair, the imaging tools should evaluate RV volume and pressure overload due to tricuspid and pulmonary regurgitation or stenosis, RV and LV systolic and diastolic dysfunction, presence of postoperative scars, RV aneurysms and fibrosis, and associated anomalies such as aortic root dilation and aortic insufficiency. Coronary anatomy and coronary artery disease may need to be assessed in older patients with comorbidities such as hypertension and atherosclerosis.No single diagnostic modality suffices for complete evaluation of TOF at any stage. All the diagnostic tools discussed below have their strengths and weaknesses Table  and shouThe chest radiograph is usually one of the first studies performed, especially when initially suspecting the diagnosis of TOF. It is inexpensive, readily available, and quickly provides information on gross cardiac and mediastinal size and configuration, situs of the aortic arch, abdomen and thorax, pulmonary vascularity, presence of calcifications or thoracic cage abnormalities and postoperative changes .Preoperatively in the neonatal period, the chest radiograph is mainly used to assess pulmonary vascularity and degree of pulmonary blood flow, while, as time evolves, the cardiac silhouette progresses to the classical “boot-shaped heart” explained by the narrowing of the mediastinum due to hypoplasia of the RV outflow tract and upward displacement of the RV apex due to its hypertrophy Fig. . After rFluoroscopy can be helpful in evaluation of postoperative abnormalities, such as paralysis of the hemidiaphragm, or in assessment of associated vascular anomalies compressing the trachea and esophagus using barium esophagram . FluorosTransthoracic echocardiography is the cornerstone of imaging in TOF both pre and postoperatively, as it provides information on septal anatomy, RV and LV size and function, tricuspid and pulmonary stenosis and regurgitation, proximal pulmonary artery anatomy and stenosis, aorta size and insufficiency, and hemodynamic indicators such as estimated RV and pulmonary pressures. It is also widely available, portable, reproducible and safe , with wiThe scanning protocol in transthoracic echocardiography should include all the standard echocardiographic views in the subxiphoid, apical, parasternal and suprasternal windows in a combination of complete sweeps as well as multiple selected single planes. In order to avoid oversights, data acquisition should follow a standard protocol including the preferred order, the imaging tools recorded in each view and the recommended measurements  for a pePreoperatively, especially in the neonate, echocardiography can depict site and number of septal defects, degree of septal malalignment and resultant subpulmonary and pulmonary obstruction, anatomy of proximal pulmonary arteries, origin and proximal course of coronaries, presence without full delineation of aortopulmonary collaterals, and RV, tricuspid and pulmonary valve size and qualitative function. This information is usually adequate for planning surgical repair in the average patient, while further imaging is reserved for more complex cases, especially with hypoplastic or stenotic pulmonary arteries or need to visualize coronary course and aortopulmonary collaterals.Postoperatively, echocardiography is very useful in evaluation of the RV outflow tract anatomy, size and dynamic or anatomic obstruction Fig. , presencSeveral echocardiographic parameters have been shown to have reasonable correlation with CMR measured PR with variable specificity and sensitivity . PR may Tricuspid regurgitation (TR) presence can be depicted using color and spectral Doppler in several views, while severity is assessed mostly qualitatively or measuring the vena contracta width . Using tRV size and function is usually evaluated qualitatively by echocardiography in several views, despite known poor interobserver agreement . ObjectiIndirect measures of RV function such as rate of pressure rise in the RV (dP/dt), myocardial acceleration during isovolumetric contraction and the myocardial performance index (Tei index) have not been validated in TOF . TricuspEchocardiography evaluation in TOF has shown abnormalities in right atrial size and emptying , as wellTransesophageal echocardiography (TEE) in the hands of a skilled operator in CHD plays an important role in preoperative evaluation of the tricuspid valve and septal defects, in intraoperative assessment of the repair and postoperative imaging of vegetations, RV to pulmonary artery conduits, implanted pulmonary valves, and functional assessment of ventricles and valves, especially in the case of poor acoustic windows in transthoracic studies. Stress echocardiography, either with exercise or dobutamine, may provide useful information on biventricular function in TOF, especially in a population with increasing age that may develop coronary artery disease .CMR is invaluable for TOF imaging preoperatively and, most importantly postoperatively. Traditional “black-blood” techniques, such as turbo or fast spin-echo and double inversion recovery fast spin echo sequences can demonstrate static images of cardiac and pericardiac anatomy with high spatial resolution and contrast between elements . “BrightCMR has no ionizing radiation, can be performed irrespective of patient’s body habitus or imaging windows. Unlike echocardiography that is mostly used qualitatively, CMR provides objective, accurate and reproducible quantitative measurements of RV size and function, valve regurgitation, pulmonary and systemic flows, differential pulmonary artery flow and myocardial scar tissue detection , all parCMR is less frequently used in preoperative TOF in young patients, where echocardiography offers good imaging and is usually sufficient for surgical planning. Preoperatively, CMR is reserved for complex anatomy, such as pulmonary atresia for better delineation of the frequently hypoplastic pulmonary branches and the aortopulmonary collaterals. Postoperatively, CMR is rarely needed in preadolescent patients unless ventricular dysfunction or right heart failure necessitates further workup and possible intervention. The role of CMR becomes crucial in older postoperative TOF patients, where serial evaluations guide management and planning of surgical or interventional pulmonary valve replacement according to well validated, heavily relying on CMR criteria.The CMR protocol in repaired TOF includes cine evaluation of valve function and anatomy of the RV, the RV outflow tract, the LV and the ventricular septum. Measurement of ventricular volumes and of mass is then performed with special attention to complete chamber coverage, especially in the basal sections as well as correct determination of end-diastole and end-systole for each ventricle given the usual RV conduction delay . ImagingMagnetic resonance (MR) angiography with gadolinium contrast is then used for depiction of pulmonary arteries, branches and collaterals Fig. a as wellSubsequently, flow measurements are performed in planes perpendicular to the blood flow to quantify pulmonary or other valve regurgitation, differential pulmonary artery flow and pulmonary and systemic flow Fig. a. FractiLastly, late gadolinium enhancement (LGE) 10 to 20 min after contrast injection evaluated in multiple planes assesses myocardial viability and presence of scar tissue in the myocardium Fig. . MyocardCMR objectively evaluates right atrial size, function and emptying influenced by TR and RV function, depicts arch sidedness and anomalies and offers excellent visualization and serial measurements of the aortic root and ascending aorta that are frequently dilated in TOF. CMR also assesses size, global and regional dysfunction of the LV, present in the late stages of repaired TOF due to ventricular-ventricular interaction, which has been associated with adverse outcome, death and ventricular tachycardia .Multidetector CCT in the current era offers excellent spatial and reasonable temporal resolution producing static and cine imaging as well as 3D reconstructions and can be very helpful in TOF evaluation. Cardiac gating is not always necessary for extracardiac structures but is of the utmost importance for intracardiac or coronary imaging and heart rate control with β-blockers is advocated for optimal acquisition, when not contraindicated.Compared to CMR, CCT provides superior delineation of small vessels, aortopulmonary collaterals and pulmonary arteries, is less affected by stainless steel artifacts and has shorter acquisition times reducing the need for sedation, all qualities that may prove important in selected TOF patients . CoronarDisadvantages of CCT include its inability to provide reliable flow rate or velocity data and the use of ionizing radiation with its possible risks. Recent advances and experience with variable pitch and low kilovolt techniques tailored to the pediatric population have led to a tenfold reduction in radiation dose and permit cardiac gated CCT in children with low doses in the order of 1 mSv . Newer tThe protocol for CCT assessment in TOF includes visualization of pulmonary artery anatomy, size and arborization, especially in cases with prior aortopulmonary shunts , as wellDespite the good imaging quality of CCT in TOF, it should be reserved only for patients with absolute contraindications to CMR, given its ionizing radiation, the young age of the patients and the need for serial imaging throughout their lifespan.3D printed reconstruction using high resolution CT  or blood99mTc-labeled macroaggregates of albumin embolizing at the capillary level provides an accurate picture even in patients < 10 years of age or very small pulmonary arteries, except in cases of multiple sources of pulmonary blood flow [Traditionally, nuclear scintigraphy has been used in TOF for assessment of RV and LV size, function and myocardial viability at rest and during exercise, quantification of intracardiac shunts, and differential pulmonary perfusion between right and left lung . Most ofood flow . Nuclearood flow . It alsoood flow , frequenood flow .Cardiac catheterization and angiocardiography (CCA) has been the cornerstone for the diagnosis and management of CHD over the past 50 years, albeit increasingly replaced by the noninvasive modalities developed the last 25 years, initially echocardiography and, more recently, CMR. CCA provides invasive pressure and oximetry data in the pulmonary and systemic circulations, evaluates stenoses, direction and volume of shunts between the two circulations, pulmonary and systemic cardiac outputs by thermodilution or the Fick method, as well as pulmonary and systemic vascular resistances. Morphologic imaging is achieved usually by biplane cine angiograms in angulated views, using iodinated contrast material and ionizing radiation. Although invasive, CCA is relatively safe with few risks such as hematomas, arterial and venous injuries, renal function deterioration, contrast reactions, radiation exposure, and very low but definite mortality . Still, The protocol for CCA assessment in preoperative TOF Fig.  depicts In repaired TOF CCA evaluates, depending on the indication, the degree of PR, RV size and function qualitatively, the RV outflow tract and the pulmonary arteries and branches using multiple biplane angled views Fig. a. AorticRotational angiography with 3D reconstruction is a relatively new technique that can be very helpful in diagnostic and interventional CCA in TOF, especially in complex RV outflow tract anatomy and proximal pulmonary artery stenosis . Data arAs becomes obvious from the strengths and weaknesses of each imaging tool Table , no singEchocardiography represents the main imaging tool used at least on a yearly basis because it provides good functional assessment of the RV, pulmonary and tricuspid valves with low cost, wide availability and absence of contraindications or ionizing radiation. CMR, CCT and CCA are not routinely used before adolescence unless specific issues arise, and are then performed under sedation or general anesthesia. CMR is initially recommended in early adolescence and repeated approximately every 3 years to objectively assess RV size and function and PR. CMR is performed yearly in case of progressive RV dilation and dysfunction or significant right heart failure symptoms. CCT or CCA is reserved for patients with contraindications to CMR, in case of interventions, or need for coronary angiography. Lung perfusion scan is performed in case of considerable pulmonary branch stenosis, where significant decrease in ipsilateral lung perfusion is suspected and may warrant intervention.Factors that should influence choice of imaging tool and adherence to the previously described protocol include availability and cost of each modality, local expertise and training, use of ionizing radiation and its potential risks, need for sedation in young patients, possible contraindications to a specific modality and, above all, the patient’s clinical condition and the parameters that need imaging for optimal diagnosis and follow up. These issues become increasingly important as we lack concrete data on the rate and predictors of disease progression in TOF, while economic factors greatly affect allocation of funds and resources in our current environment.Imaging in pre and postoperative TOF relies on multiple imaging tools used with variable frequency depending on patient’s age, clinical question, availability, cost and operator’s expertise. Further research is needed on the factors influencing disease progression in TOF concerning PR, RV dilation and dysfunction and aortic dilation in order to optimize management and follow up as well as timing of interventions in these patients.


Over the last 15 years, cardiovascular magnetic resonance (CMR) imaging has progressively evolved to become an indispensable tool in cardiology. It is a non-invasive technique that enables objective and functional assessment of myocardial tissue. Recent innovations in magnetic resonance imaging scanner technology and parallel imaging techniques have facilitated the generation of T1 and T2 parametric mapping to explore tissue characteristics. The emergence of strain imaging has enabled cardiologists to evaluate cardiac function beyond conventional metrics. Significant progress in computer processing capabilities and cloud infrastructure has supported the growth of artificial intelligence in CMR imaging. In this review article, we describe recent advances in T1/T2 mapping, myocardial strain, and artificial intelligence in CMR imaging. CMR enables non-invasive cardiac visualization with augmented temporal and spatial resolution along with high blood-to-tissue contrast2. Moreover, it allows detailed tissue characterization which is pivotal to its ability to not only diagnose cardiovascular disease but also facilitate management and treatment. It can precisely determine myocardial and vascular injury2. Recent advances in software and technological hardware have propelled the development of new methods that can substantially augment cardiovascular diagnosis, prognosis, and risk stratification3. CMR permits visual assessment through a variety of approaches, which include late gadolinium enhancement (LGE), T1 mapping, and T2 mapping1. Strain imaging is an emerging diagnostic modality that can serve as a prognostic imaging marker to evaluate myocardial function beyond the ejection fraction4. Artificial intelligence (AI) has opened new frontiers in cardiology by leading to data-driven discoveries in CMR imaging6.Cardiovascular magnetic resonance (CMR) imaging has rapidly emerged as a robust diagnostic option for evaluating a number of pathological entities in cardiology. Furthermore, CMR is the gold standard for non-invasive measurement of left ventricular and right ventricular volumes and ejection fractionIn this review article, we aim to assess advances in CMR evaluation of various cardiovascular conditions over the last few years. This will include T1/T2 mapping, the role of AI in CMR, and the significance of myocardial strain in CMR.7. Although it is a valuable tool, it identifies only localized areas of tissue damage, often where there is irreversible replacement fibrosis7. This technique requires an area of normal myocardium as a reference point in order to highlight the areas of fibrosis and this limitation can be viewed as the Achilles’ heel of LGE. Therefore, there is substantial interest in approaches that permit identification of early fibrosis as well as more diffuse fibrosis. T1 mapping can characterize the myocardial tissue on a pixel-to-pixel basis to generate a map of T1 values. T1 mapping is able to identify earlier diffuse fibrosis and can detect subtle changes in heart muscle pathology in a non-invasive manner7. In addition, T1 mapping may allow more precise quantification of an area of infarction1. T1 mapping also enables extracellular volume measurement (ECV) which can also measure myocardial fibrosis in reference to left ventricular volume7.Over the last few decades, LGE has been used to detect focal areas of fibrosis in the myocardium. The presence of diffuse fibrosis has been linked to diastolic dysfunction, heart failure, and sudden deathet al. explored the role of non-contrast myocardial T1 mapping for recognizing cardiac involvement in 53 patients with amyloid light-chain amyloidosis and 53 control subjects8. The myocardial T1 was substantially higher in the patients with amyloidosis  than in the other patients. A non-contrast myocardial T1 cutoff of 1020 ms showed an accuracy of 92% for revealing cardiac involvement in patients with amyloidosis. Furthermore, there were significant associations between myocardial T1 values and systolic and diastolic dysfunction indices.Involvement of the myocardium can occur in systemic light-chain amyloidosis. Although LGE can identify characteristic amyloid patterns, these are evident in later stages of the disease. Karamitsos9. Rosaet al. assessed diffuse interstitial myocardial fibrosis measured by T1 mapping in LFLG AS patients with and without FR in 41 LFLG AS and 24 high-gradient AS patients9. The authors showed that indexed ECV was higher in patients with LFLG AS with and without FR in comparison with high-gradient AS . The indexed ECV and ECV levels were comparable in LFLG AS patients with and without FR . Rosaet al. concluded that the degree of fibrosis is the same in patients with and without FR, suggesting that myocardial fibrosis may not explain the lack of FR in patients with LFLG AS.Low-flow low-gradient aortic stenosis (LFLG AS) has high operative risk for surgical intervention and poor prognosis with medical management. However, there is a paucity of data on the degree of fibrosis in these patients. Dobutamine stress echocardiography is traditionally used to evaluate the left ventricular flow reserve (FR) to confirm the severity of AS, although there are conflicting data on FR mortality predictive valueet al. examined the histological correlation of native T1 and ECV measurement for assessing myocardial fibrosis in dilated cardiomyopathy in 36 patients10. T1 and ECV both demonstrated significant correlation with the biopsy-proven collagen volume fraction . In addition, ECV showed a substantial association with the biopsy extracellular space component (r = 0.86). Nakamoriet al. finally stated that T1 and ECV had comparable efficacy in measuring histological collagen volume fraction in dilated cardiomyopathy.Although T1 mapping allows quantification of myocardial fibrosis, in dilated cardiomyopathy, there is a relative scarcity of studies comparing ECV and T1 with concurrent histological examination. Nakamori11. Treibelet al. evaluated the relationship between clinical outcomes and various indices such as ECV, native T1, post-contrast T1, and the partition coefficient in 1714 consecutive patients without amyloidosis or hypertrophic cardiomyopathy11. The authors showed ECV demonstrating highest log-rank statistics and best separation of Kaplan–Meier curves. Furthermore, ECV was strongly linked to clinical outcomes in univariate and multivariate analyses. Treibelet al. stated that ECV measurement of myocardial fibrosis was closely associated with outcomes in relation to other CMR metrics.Although a number of metrics exist in CMR for measuring myocardial fibrosis, only limited data for stratification purposes are available7. There is no consensus in the CMR community’s methodology and approach7. Some form of standardization along with histological validation is required for universal implementation. The absence of reference values for normal and abnormal myocardium for vendor-specific sequences hinders its approval12. T1 mapping does not have any inbuilt features for heart rate modification12. Furthermore, standardization of the acquisition phase is needed as it can affect T1 and ECV values because of the oscillating myocardial blood volume12.Although T1 mapping has clearly shown its potential for quantitative tissue characterization, there are still issues that need to be overcome for widespread acceptance13. As a result, the created map mirrors calculated T2 relaxation time at each pixel. This can be performed in any cardiac slice and position13. T2 mapping holds considerable promise for more precise inflammation/edema imaging compared with traditional T2-weighted imaging. Additionally, T2* mapping can be used for quantification of myocardial siderosis in disease states that can lead to myocardial iron overload.T2 mapping is a CMR approach used to generate a parametric image or map from a series of input images and calculations13. There is growing evidence that suggests that T2 mapping may be more indicative for acute inflammation than T1 mapping14. T2 mapping is also sensitive to identification of water in a more chronic setting such as scarring or ischemia14. Interestingly, in the MyoRacer trial, T2 mapping was the only CMR parameter with acceptable diagnostic accuracy (73%) for recognizing biopsy-proven myocarditis for patients with chronic symptoms longer than 14 days15.Acute inflammatory cardiomyopathy is a cardiovascular condition that requires biopsy to detect disease activity. Some studies have suggested that T2 mapping may become an integral tool to facilitate evaluation of inflammation within the myocardium non-invasively4. Although ejection fraction is the conventionally used metric to assess cardiac function, there are a number of limitations to be acknowledged4. This can be attributed to the suboptimal reproducibility, volumetric nature, and inability to show regional left ventricular function16. Strain imaging is an emerging modality which provides direct information on myocardial deformation. Furthermore, myocardial strain is a marker of left ventricular health and mechanics beyond left ventricular ejection fraction, and it measures the transition from a relaxed to a contractile state17. This type of imaging may be helpful to detect preclinical left ventricular dysfunction prior to decreases in the left ventricular ejection fraction.Evaluating cardiac function has always been complex or cumbersome in cardiology and this applies particularly to ejection fraction18. There are a number of available tagging sequences, including spatial modulation of magnetization (SPAMM), delay alternating with nutations for tailored excitation (DANTE), complementary SPAMM (CSPAMM), harmonic phase (HARP), displacement encoding with stimulated echoes (DENSE), and strain encoding (SENC)18. Each of these methods has different versions for improved resolution, signal-to-noise ratio (SNR), scan time, anatomic coverage, image quality, and three-dimensional (3D) capabilities18. Unlike feature tracking (FT) strain, they require a separate dedicated sequence and post processing.CMR tagging is an approach that allows visualization of transmural myocardial involvement without using physical markers4. The process labels different areas of the myocardium with unique radiofrequency saturation planes to create dark lines19. Subsequently, a tagging formation is created which forms a grid of markers known as tags. As a result, tracking these tags facilitates visualization of myocardial deformation or strain. Tagging is inherently affected by the magnetic properties of the tissue.CMR tagging is a commonly accepted reference standard for strain quantification4. For instance, images with tags may have low temporal resolution. Strain may be underestimated if the tag does not correspond to the initiation of cardiac contraction. Strain values may be less precise if measured at the endocardial border or thin-walled areas of the left ventricle. Lastly, special software is necessary for strain and it is a laborious process.There are also a number of limitations of CMR tagging20. There are differences between FT and CMR tagging  images. This method does not require a dedicated separately acquired sequence or intricate post processingtagging . It deteet al. explored the role of FT strain in CMR for detecting subclinical systolic and diastolic dysfunction in 30 acute myocarditis patients with preserved ejection fraction21. In addition, 24 normal patients served as controls. The inter-observer variability in the 2D and 3D FT CMR had aP value greater than 0.42, intra-class correlation greater than 0.80, and n2 greater than 0.98. Interestingly, the inter-observer variability in global, radial, circumferential, and longitudinal strain showed no statistical difference between systolic and diastolic strain rate (P = not significant).Gattiet al. investigated the relationship of FT global longitudinal strain (GLS) during vasolidator stress CMR with major adverse cardiac events (MACEs) in 535 patients with a follow-up of 1.5 years22. Previous studies have indicated that blunted myocardial strain may be linked to an adverse prognosis during dobutamine stress echocardiography. Patients with stress GLS equal to or greater than the median had greatly decreased event-free survival compared with stress GLS of less than the mean (log rankP <0.0001) on Kaplan–Meier analysis. Furthermore, the stress GLS was substantially linked with MACE after adjustment for clinical and imaging variables . Romanoet al. concluded that FT GLS was an independent predictor of MACE during vasodilator stress CMR in patients with coronary artery disease.Romanoet al. examined the significance of right atrial (RA) dysfunction on pulmonary arterial hypertension (PAH) by using RA longitudinal strain in 80 PAH patients and 80 normal patients with CMR23. Compensated and decompensated states have been known to affect survival in patients with PAH. RA strain correlated with elevated RA pressure , right ventricular volume , biomarkers , and lower exercise capacity . In addition, RA passive strain was seen as the best predictor of composite adverse events . Lenget al. concluded that RA strains were associated with right ventricular decompensation and elevated risk of adverse events.Leng4. For any diagnostic or clinical test to be implemented, a normal range of values needs to be established4. Values for method and software cutoff need to be established. There is no validation against a universal reference standard. Each method and software must undergo rigorous testing before adoption into clinical practice. In general, data suggest that GLS should be used for assessing global ejection fraction rather than segmental strain, and validation and inter-vendor agreement are of less concern with GLS in comparison with other types of strain values4.Strain is largely used in the research setting, and a number of issues need to be resolved for successful integration into clinical practice24. Strain at baseline and follow-up needs to be measured by the same software and analysis for reproducible values.Furthermore, values from speckle tracking echocardiography may not always correlate with values from CMR strain. Other clinical factors such as blood pressure, heart rate, age, and gender may also affect strain values26. First and foremost, coronary artery disease is the most common cause of death in the developed world27. ML is not a distant concept on the horizon but an inevitable necessity in the evolutionary line of cardiovascular imaging and clinical care, especially in CMR. AI is exponentially expanding every sector of human information, from self-driving cars to speech recognition software28. The massive influx of large data emanating from wearable devices, medical apps, electronic health system, and imaging systems will supersede the capabilities of existing statistical software25. Nevertheless, ML can unravel information present within this vast data matrix to dramatically enhance disease prognostications and survival predictions29.Machine learning (ML), a subset of AI, has allowed the field of cardiology to escape the confines of conventional inquiry and embark on a new realm of multi-dimensional information occurring in real time leading to data discovery–driven research31. Two of the most frequently used ML algorithms are supervised learning and unsupervised learning  2009 left ventricular segmentation challenge. Interestingly, the deep learning approach accomplished outcomes comparable to or greater than those of human experts. These findings must be taken with a degree of caution because of the small sample sizes.A number of centers have explored the potential of ML in CMR recently. Wintheret al. explored the role of a convolutional network, a deep learning approach, for automatic segmentation of the left ventricle in all short-axis slices33. This ML approach was applied to a number of publicly available datasets, which included the left ventricular segmentation challenge dataset containing 200 CMR imaging sets with diverse cardiac pathology. Surprisingly, the authors obtained a Jaccard index of 0.77 in the left ventricular segmentation challenge dataset. In addition, they obtained a continuous ranked probability score of 0.0124 with the Kaggle second annual data science bowl. As a result, Tanet al. showed the potential of the ML algorithm in automatic left ventricular segmentation in CMR.Tanet al. used a fully convolutional network for automated analysis of CMR images from a large imaging database consisting of 93,500 images in 5000 patients for calculating left and right ventricular mass and volumes34. On a short-axis image test of 600 patients, the Dice metric measured 0.94 for left ventricular cavity, 0.88 for left ventricular myocardium, and 0.90 for right ventricular cavity. Furthermore, the average Dice metric measured 0.93 for the left atrial cavity in the two-chamber view, 0.95 for left atrial cavity in the four-chamber view, and 0.96 in RA cavity in the two-chamber view. Baiet al. showed that ML automated methods produce values comparable to those of human experts.Bai25. For successful integration into the clinical environment, a number of issues need to be addressed5. ML algorithms require extensive exposure to large datasets to gain accuracy, and obtaining such datasets can be difficult29. Data sharing among institutions can be difficult and laborious because of multiple institutional review boards, and datasets ideally should be publicly available.ML will become an inevitable necessity as the number of medical apps, wearable devices, and miniaturized devices continue to grow and prosper29. Although digital imaging and communications in medicine (DICOM) and picture archiving and communication system (PACS) are valuable for imaging data, there are differences in these programs between centers. There are a number of different classifications, protocols, and acquisition protocols among various institutions, and imaging and clinical data exist on separate user interfaces. As data become larger and more complex, manual data entry will become difficult. If newer software can successfully integrate clinical and imaging information, it can facilitate the expansion and utilization of ML in various academic centers.A universal standard is required for data standardizationAlthough echocardiography is used primarily as the first-line imaging test for a majority of cardiovascular pathology, the field of CMR imaging has been steadily growing in recent years. CMR provides valuable information on myocardial tissue and function. Recent developments in T1/T2 mapping, strain imaging, and AI show considerable promise in CMR as they can greatly improve diagnosis and patient welfare. Nevertheless, these options still require further validation before full integration into clinical care. As technology continues to grow and improve, the future of CMR imaging will be very bright in the years to come.