Dynamic first pass contrast-enhanced myocardial perfusion is the standard CMR method for the estimation of myocardial blood flow (MBF) and MBF reserve in man, but it is challenging in rodents because of the high temporal and spatial resolution requirements. Hyperemic first pass myocardial perfusion CMR during vasodilator stress in mice has not been reported.k-t PCA). One week later the mice underwent repeat anaesthesia and LV injections of fluorescent microspheres at rest and at stress. Microspheres were analysed using confocal microscopy and fluorescence-activated cell sorting.Five C57BL/6 J mice were scanned on a clinical 3.0 Tesla Achieva system . Vasodilator stress was induced via a tail vein catheter with an injection of dipyridamole. Dynamic contrast-enhanced perfusion imaging (Gadobutrol 0.1 mmol/kg) was based on a saturation recovery spoiled gradient echo method with 10-fold k-space and time domain undersampling (Mean MBF at rest measured by Fermi-function constrained deconvolution was 4.1 ± 0.5 ml/g/min and increased to 9.6 ± 2.5 ml/g/min during dipyridamole stress (P = 0.005). The myocardial perfusion reserve was 2.4 ± 0.54. The mean count ratio of stress to rest microspheres was 2.4 ± 0.51 using confocal microscopy and 2.6 ± 0.46 using fluorescence. There was good agreement between cardiovascular magnetic resonance CMR and microspheres with no significant difference (P = 0.84).First-pass myocardial stress perfusion CMR in a mouse model is feasible at 3 Tesla. Rest and stress MBF values were consistent with existing literature and perfusion reserve correlated closely to microsphere analysis. Data were acquired on a 3 Tesla scanner using an approach similar to clinical acquisition protocols, potentially facilitating translation of imaging findings between rodent and human studies. Myocardial blood flow (MBF) is one of the most relevant parameters in cardiovascular disease. While coro nary autoregulation maintains resting MBF constant over a wide range of physiological and pathological states, MBF reserve is impaired in several disease processes including atherosclerosis , systemiThe aim of this study was to test the feasibility of myocardial perfusion CMR in C57BL/6 J mice during dipyridamole-induced hyperemia and validate the method against the reference test of injectable microspheres.Five 6-month-old homozygous C57BL/6 J male mice (weight 25-30 g) were acquired from Charles Rivers Laboratories  and housed within the Animal Unit of the Rayne Institute at King’s College London. The housing and care of the animals and all the procedures used in these studies were performed in accordance with the guidelines and regulations of the United Kingdom Home Office under the Animals (Scientific Procedures) Act, 1986.Mice were anesthetized and maintained under inhalational anesthesia via a nose cone . Rectal temperature was monitored continuously and a warm air flow  was adapted to maintain temperature at 37°C. All experiments were conducted at a similar time of the day and in the same climate conditions. Two ECG leads  were placed subcutaneously on the left and right side of the thorax. For electrocardiogram (ECG) synchronization a dedicated small-animal ECG device, 1025-MR  and for signal reception, a microscopy receive coils  was used.Imaging was performed on a clinical 3.0-T system  equipped with a clinical gradient system . Mice were imaged under isofluorane anesthesia and in prone position. The in-built ECG triggering unit of the CMR scanner was modified to permit synchronization of heart rates of up to 600 beats/min.2, matrix 160, slice thickness 1 mm, 5 fold k-t SENSE acceleration with 11 interleaved training profiles, pulse repetition time/echo time 12/6.3 msec, flip angle 20°). From these images, a true mid-ventricular short-axis view of the left ventricle was planned for subsequent perfusion imaging.All data were acquired during free breathing of the animals. For localization of the heart, low-resolution gradient echo scout scans were acquired in the coronal and transverse orientations followed by pseudo two- and four-chamber gradient echo cine scans acquired with a prospective ECG-triggered spoiled gradient echo sequence , preparation pulse delay 100 msec (to the centre of k-space), acquisition window 43 msec. The preparation pulse delay was reduced if required to enable acquisition at higher heart rates, particularly when during stress. Data were acquired for 200 heart beats. To improve temporal fidelity of the data at the high undersampling factors, k-t principal component analysis (k-t PCA) was used for image reconstruction [The perfusion pulse sequence parameters were similar to a previously published method : two-dimtruction .A customised catheter was placed in the tail vein of the mouse and 0.1 mmol/kg bodyweight Gadobutrol (Gd-DTPA)  was injected after the perfusion scan was started (volume of contrast injection 2.5 to 3.0 μL based on the weight of the mouse). To ensure a reproducible bolus injection, the contrast agent, as well as 25 μL of saline, was preloaded into small-bore tetrafluoroethylene tubing and injected manually.For stress perfusion imaging, dipyridamole  0.56 mg/kg was injected via a tail vein catheter 1 minute prior to the perfusion acquisition and into the same tail vein catheter as used for contrast delivery. Contrast injection was performed in the same standardized way as for rest scans. Stress and rest scans were performed in random order to minimize any potential bias from residual contrast agent and were separated by 15 minutes. Following imaging of stress perfusion, a slow hand injection of intravenous aminophylline  was given in order to minimize any effects of dipyridamole on subsequent estimation of resting blood flow. The total volume of injection during CMR perfusion imaging was 105-106 μL.Image quality was scored from 1 to 4 . Quantitative analysis of MBF was performed using custom prototype image analysis software . Endocardial and epicardial contours were drawn on images with best blood to myocardium contrast and copied to all other dynamic images. Any subendocardial dark rim artifacts were excluded from the contours. The myocardium was divided into four eqiangular sectors, starting from a reference point placed at the anterior septal insertion of the right ventricle. To obtain the arterial input function, a region of interest was drawn inside the left ventricular (LV) blood pool. Signal intensity (SI)/time curves were generated for the LV blood pool, for the four myocardial sectors and an average for the myocardium as a whole. The maximal upslope of the profiles was generated using best-point fitting. SI profiles were then generated for each sector and the region of interest in the LV blood pool. Enhancement ratio of signal increase and normalized SI upslope ratios between the blood pool and myocardium were calculated as (enhancement ratio = (SI max – SI baseline)/SI baseline) and .In addition, absolute MBF was computed from the LV blood pool and myocardial tissue SI vs. time curves, using in-house software, with previously described methods based on Fermi constrained deconvolution .6 beads/ml) of yellow-fluorescent microspheres  (excitation/emission 515/534 nm) were injected at rest. One minute following dipyridamole stress, 25 μl (1.0 × 106 beads/ml) scarlet (excitation/emission 645/680 nm) microspheres were injected, followed by a slow hand injection of intravenous aminophylline . The total volume of injection for the microsphere experiment was 77.8-78.4 μL.One week after MR scanning, all 5 mice mice underwent repeat anesthesia and injection of fluorescent microspheres at dipyridamole hyperemic stress and at rest in the same order and using the same stress regime as for the CMR scans. 25 μl  to establish the absolute number of microspheres injected at rest and stress. This was used to establish a myocardial perfusion reserve  for each mouse.The remaining myocardium was processed using standardised methods  and analt-test was used. For linear regression a Pearson’s correlation coefficient was used and for comparison of multiple variables a one-way analysis of variance (ANOVA) was used. Bonferroni post-hoc analyses were used to compare the calculation of the perfusion reserve using different techniques. A Bland-Altman analysis was performed to determine the mean bias and limits of agreement between CMR and microsphere estimates of MPR. Statistical significance was considered for P < 0.05 and high significance was considered for P < 0.01.Statistical analysis was performed using SPSS 19.0 . All data were expressed as mean ± standard deviation. For comparing hemodynamics and continuous variables a All mice tolerated the scanning without complication and rest/stress first-pass myocardial perfusion imaging was successfully performed. The mean overall imaging time was 34.6 minutes (± 7.4 minutes).Dipyridamole was successfully injected in all 5 mice via the tail vein. The mean heart rate increased following the injection, but not to a statistically significant degree .k-t PCA algorithm. Typical transient subendocardial dark rim artifacts were noted in 2 studies, affecting in particular the inferolateral segments. These banding artifacts persisted for three to seven heartbeats during peak signal in the LV and affected 30–60% of the myocardial thickness.Overall image quality was 2.6 ± 0.5 and quality was sufficient to outline myocardial contours for quantitative analysis in all studies Figure . BreathiIn three animals, stress imaging was performed first, and in two animals rest was performed first. Signal intensity/time profiles derived during stress and rest showed similar features to human profiles Figures . At restAt hyperemic stress, mean LV signal increased from 118 ± 37 before contrast delivery to a peak of 1854 ± 209, resulting in an enhancement ratio of 15.9. Mean myocardial signal increased from 91 ± 34 to 787 ± 187, with an enhancement ratio of 8.0. The mean estimated hyperemic MBF was 9.6 ± 2.5 mL/g/min . Bonferroni post-hoc testing did not show any significant difference between the results derived from different techniques (CMR and histology).Using ANOVA to compare the perfusion reserve using the different techniques, there was no significant difference between the quantitative CMR data, manual counting of spheres and using confocal microscopy,  and temporal resolution (43 msec and acquisition at every heart beat) by using highly accelerated data acquisition. The k-t PCA framework for image reconstruction has been shown to improve temporal fidelity and in this study allowed reliable assessment of signal enhancements in the blood pools and in the myocardium and quantitative MBF measurements. The rapid acquisition (<30 seconds) of a first pass method compared with spin labeling methods meant that both stress and rest acquisition could be performed in the same study and in the same animals.The present study used a first pass CMR technique on a clinical scanner with a high spatial  and research support from Bayer (Switzerland).EN receives grant support from Bayer Healthcare and Philips Healthcare.RJ designed the study protocol, carried out the MR studies, analyzed the data and drafted the manuscript. SK designed and updated the perfusion sequence and helped to draft the manuscript. MM, AP, ASP, CJ and RB participated in the study design, helped to perform the MR studies and perform analysis of the results. AC and NZ performed the MRI quantification analysis of the results, together with Professor EN helped draft the manuscript. Professor SP is the chief investigator and conceived the idea of this murine stress perfusion protocol, analyzed the data and drafted the manuscript. All authors read and approved the final manuscript.


Intraventricular pressure gradients have been described between the base and the apex of the left ventricle during early diastolic ventricular filling, as well as, their increase after systolic and diastolic function improvement. Although, systolic gradients have also been observed, data are lacking on their magnitude and modulation during cardiac dysfunction. Furthermore, we know that segmental dysfunction interferes with the normal sequence of regional contraction and might be expected to alter the physiological intraventricular pressure gradients. The study hypothesis is that systolic and diastolic gradients, a marker of normal left ventricular function, may be related to physiological asynchrony between basal and apical myocardial segments and they can be attenuated, lost entirely, or even reversed when ventricular filling/emptying is impaired by regional acute ischemia or severe aortic stenosis.Animal Studies: Six rabbits will be completely instrumented to measuring apex to outflow-tract pressure gradient and apical and basal myocardial segments lengthening changes at basal, afterloaded and ischemic conditions. Afterload increase will be performed by abruptly narrowing or occluding the ascending aorta during the diastole and myocardial ischemia will be induced by left coronary artery ligation, after the first diagonal branch.Patient Studies: Patients between 65-80 years old (n = 12), both genders, with severe aortic stenosis referred for aortic valve replacement will be selected as eligible subjects. A high-fidelity pressure-volume catheter will be positioned through the ascending aorta across the aortic valve to measure apical and outflow-tract pressure before and after aortic valve replacement with a bioprosthesis. Peak and average intraventricular pressure gradients will be recorded as apical minus outflow-tract pressure and calculated during all diastolic and systolic phases of cardiac cycle.We expect to validate the application of our method to obtain intraventricular pressure gradients in animals and patients and to promote a methodology to better understand the ventricular relaxation and filling and their correlation with systolic function. Normal diastolic function of the left ventricle (LV) can be defined as the ability of the ventricle to adequately fill under low filling pressures. The hallmark of diastolic dysfunction is the impaired capacity to fill or maintain stroke volume without a compensatory increase in filling pressures ,2. StudyAs early as 1930, Katz  already Therefore to describe LV diastolic function comprehensively, it is crucial the precise characterization of the transmitral and intraventricular pressure-flow relation. Early diastole is not amenable to analysis with simple passive-filling models, and any complete description of diastole must account for ventricular suction and for the presence of regional pressure oscillations which play an important role in normal ventricular filling . In factThese observations suggest the critical importance of IVPG to ensure efficient LV diastolic filling and allow us hypothesizing that any condition which interferes with the normal sequence of regional relaxation might be expected to change the physiological IVPG pattern. Actually, several studies have demonstrated that LV function is nonuniform in healthy hearts ,14. PeakA variety of other disorders are associated with diastolic dysfunction, such as hypertrophy, structural alterations of the myocardium with increased fibrosis, myocardial scarring, or infiltrative processes . In addiDespite the apparent importance of IVPG in diastolic function evaluation, they have never been utilized in clinical cardiology, due to the complexity of their acquisition. Whereas regional pressure differences between the LV, the LV outflow tract, and the aorta during ejection have been recognized for some time , the impIn conclusion, we hypothesize that systolic and diastolic IVPG, a marker of normal left ventricular function, may be related to physiological asynchrony between basal and apical myocardial segments and that they can be attenuated, lost entirely, or even reversed when ventricular filling/emptying is impaired by acute regional ischemia or pressure overload, such as severe aortic stenosis.1) Characterize IVPG along the cardiac cycle (systole and diastole);2) Evaluate the effects of the ischemia and modulation by afterload;3) Correlate the IVPG with myocardial segmental asynchrony, in basal, afterloaded and ischemic conditions.1) Validate the invasive measurement of IVPG for systolic and diastolic function evaluation in patients with severe AS;2) Apply this methodology to evaluate whether the IVPG improve in AS patients immediately after AVR;3) Establish if IVPG changes correlate with the reduction in LV obstruction and improvement in LV function;4) Correlate catheter measurements with preoperative echocardiography;5) Evaluate the potential clinical applicability of the concepts derived from the experimental studies.The investigation conforms to the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health .3 in 500 ml of 0.9% NaCl is administrated at a rate of 8 ml·kg-1·h-1 to compensate for perioperative fluid losses. A tracheostomy is performed, and mechanical ventilation is initiated , delivering oxygen-enriched air. Respiratory rate and tidal volume are adjusted to keep arterial blood gases and pH within physiological limits. Anesthesia is maintained with a perfusion of midazolam (0.07 mg·kg-1·h-1), fentanil (0.003 mg·kg-1·h-1) and vecuronium (0.1 mg·kg-1·h-1). A 20-gauge catheter is inserted in the right femoral artery and connected to a pressure transducer to monitor heart rate and arterial pressure and to obtain samples for blood gas analysis. The heart is exposed by a median sternotomy, and the pericardium is widely opened. One silk suture is placed around the ascending aorta and then passed through a plastic tube to perform transient aortic occlusions during the experimental protocol. A limb electrocardiogram (DII) is recorded throughout.Male New Zealand White rabbits  are premedicated with ketamine hydrochloride (50 mg/kg im) and xylazine hydrochloride (5 mg/kg im). A femoral vein is cannulated, and a solution containing 20 meq KCl and 40 meq NaHCOmin) and at peak systole (LVPmax). Peak rates of LV pressure rise (dP/dtmax) and pressure fall (dP/dtmin), as well as, time to dP/dtmin are measured too. Relaxation rate are estimated with the time constant tau (τ) by fitting the isovolumetric pressure fall to a monoexponential function. We pretend to record continuously IVPG as apical minus outflow-tract LVP. Peak and average (area) IVPG are calculated during diastolic and systolic phases of cardiac cycle.Two 3-F high-fidelity micromanometer  are inserted through an apical puncture wound into the LV cavity. One is pulled carefully back toward the endocardium and secured in place with a purse-string suture to measure apical LVP. The other is introduced until we can see the impact from the aortic valve on the pressure trace. The catheter then is pulled back 5 mm below the aortic valve so that it is located in the LV outflow-tract to measure basal LVP. The pressure transducers are calibrated against a mercury column and zeroed after stabilization for 30 min in a water bath at body temperature. The zero is set at the level of the right atrium. Recordings are made with respiration suspended at end expiration. Parameters are converted on-line to digital data with a sampling frequency of 1 kHz. LV pressures are measured at end-diastole (LVPED), at pressure nadir . At the end of the experiment, the animals are sacrificed with an overdose of anesthetics, and the position of the crystals and micromanometers are verified at necropsy. Segment lengths are measured at the end diastole (ED Length), at dP/dtmax and at mitral valve opening (MVO). Minimum segment length (Lengthmin) was measured as the minimum length preceding or coinciding with peak -dP/dt. Fractional shortening was calculated as the percent segment length change from end diastole to dP/dtmin at the outflow tract.After complete instrumentation, we allow the animal preparation to stabilize for 30 min before the beginning of the experimental protocol. This consists in measuring apex to outflow-tract pressure gradient and apical and basal myocardial segments lengthening changes at basal, afterloaded and ischemic conditions.Sudden afterload elevations are performed by abruptly narrowing or occluding the ascending aorta during the diastole, as previously described ,35. In sMyocardial ischemia is induced by left coronary artery (LCA) ligation, after the first diagonal branch. Visible collateral arteries are tied as well to induce an antero-apical ischemia. Recordings are performed after 30 min. Mortality is documented.Full ethical approval for this study has been obtained from Ethics Committee of Centro Hospitalar de Vila Nova de Gaia, EPE. It is conducted in accordance with the principles of The Declaration of Helsinki, with the Portuguese laws and rules and subscribes to the principles outlined in the International Conference on Harmonisation of Good Clinical Practice .All patients receive full explanation of study objectives, the operations to be performed, its risks and benefits and signed the informed consent form.Any death or major complication during the study period requires the hospital ethical commission to be informed.2) referred for aortic valve replacement (AVR) are selected as eligible patients. Patients with any one of the following are excluded from the study: concomitant severe mitral regurgitation; mitral stenosis, regardless of severity; any prosthetic heart valve; coronary artery disease; concomitant aortic regurgitation; a history of surgical or percutaneous aortic valvuloplasty; history of ethanol abuse; and chronic obstructive pulmonary disease that are worse than mild as assessed clinically and/or confirmed by pulmonary function testing. (Table Patients between 65-80 years old n = 12), both genders, with severe aortic stenosis  is positioned from a small ascending aorta stab incision across the aortic valve. The 2 pressure sensors are positioned in the LV cavity in apex and in outflow-tract  position. Appropriate anatomic placement is confirmed through the use of transesophageal echocardiography and visualization of appropriate chamber-specific waveforms.All patients undergo routine induction of general anesthesia, median sternotomy, and pericardiotomy. After great vessel cannulation and systemic heparinization, a high-fidelity pressure-volume catheter  beginning. After adequate data collection, the catheter is removed and placed in warm saline, myocardial arrest with full CPB support is obtained, and each patient undergoes biological AVR. After completely weaned from CPB and volume infusions from the CPB circuit to obtain adequate hemodynamics by increasing preload, after rezeroing, the catheter is repositioned across the aortic valve, and multiple hemodynamic measurements are obtained in several intervals during different stages of physiological stabilization. To compared with pre-CPB measurements catheters are matched at same LV end-diastolic pressure. During this period of data collection, no patient should require vasopressor, inotropic, or external pacing support. After data collection, the catheter is removed, systemic heparinization is reversed, and the operative procedure is concluded in the conventional fashion.All patients will have standard two-dimensional echocardiographic examinations before and after AVR. LV ejection fraction is assessed visually by a trained echocardiographer and entered into a database at the time of the examination. Anatomic and Doppler examinations and measurements are performed according to the recommendations of the American Society of Echocardiography. The aortic valve area is calculated using the continuity equation utilizing flow velocities in the LV outflow tract and across the valve. The pulmonary artery systolic pressure is calculated from the tricuspid regurgitation velocity signal using the simplified Bernoulli equation and estimated right atrial pressure based on inferior vena caval size. Doppler flow data is acquired from the LV outflow tract region in pulsed wave mode and from the aortic valve in continuous wave mode in the 5-chamber view. Peak velocities, calculated with resident software at the time of imaging, is used to calculate pressure gradients according to the modified Bernoulli equations and valve orifice areas according to the continuity equation approach.All analyses are performed using SPSS statistical software .Group data are presented as means ± SE and are compared using two-way ANOVA. Student-Newman-Keuls test is selected to perform pairwise multiple comparisons when significant differences are detected.A two-tailed paired t test is used to compare patients before and after AVR. Differences are considered statistically significant at P < 0.05.We expect 1) to validate the application of our invasive method to characterize the IVPG along cardiac cycle in physiological and pathological conditions; 2) to find a correlation between AS severity, diastolic dysfunction and IVPG impairment; 3) to provide new insights into the mechanical adaptation of LV to chronic afterload elevation and its response to unloading after AVR; 4) to show if the degree of hypertrophy parallels the severity of overload and if the assessment of IVPG can identify subtle contractile dysfunction; and 5) to promote the use of IVPG in clinical practice as another index of diastolic function and ventricular filling.min: left ventricular pressure nadir; LVPmax: left ventricular pressure at peak systole; dP/dtmax: peak rates of left ventricular pressure rise; dP/dtmin: peak rates of left ventricular pressure fall; τ: time constant tau; ED Length: segment length at the end diastole; MVO: mitral valve opening; Lengthmin: minimum segment length; LCA: left coronary artery; AVA: aortic valve area; CPB: cardiopulmonary bypass.LV: left ventricle; IVPG: intraventricular pressure gradients; AS: aortic stenosis; AVR: aortic valve replacement; LVPED: left ventricular pressure at end-diastole; LVPThe authors declare that they have no competing interests.MG and MJA contributed equally to this work. MG, MJA, JCM and ALM conceived and designed the protocol. MG and ALM contributed to the draft and final version of the manuscript. ALM and LV supervised the research project. All authors have read and approved the final manuscript.


The European Society of Cardiology recently proposed a new algorithm "How to diagnose heart failure with normal ejection fraction". Central element of the diagnostic strategy is the demonstration of diastolic dysfunction, either by tissue Doppler-derived indices in first line, or in second line by a combination of elevated blood levels of natriuretic peptide with abnormal tissue Doppler findings. We thought to use this diagnostic flowchart in a population-based cohort of elderly women, in whom the prevalence of diastolic dysfunction and heart failure is believed to be high. The purpose was to evaluate the association of dyspnea with the presence of diastolic dysfunction.2). Quality of life was assessed by the Minnesota living with heart failure questionnaire, and actual symptoms by a structural questionnaire; the examination consisted of a physical examination, measurement of B-type natriuretic peptide, ECG and tissue Doppler echocardiography. Diastolic dysfunction was assumed when the E/E' ratio exceeded 15 as derived from tissue Doppler. In case, tissue Doppler yielded an E/E' ratio ranging from 8 to 15, additional non-invasive parameters had to be fulfilled: left atrial volume index > 40 ml/m2 body surface, or left ventricular mass index > 122 g/m2 body surface, or transmitral E/A ratio < 0.5 plus deceleration time > 280 ms, or blood level of brain natriuretic peptide (BNP) > 200 pg/mL.The study cohort recruited from a cross-sectional follow-up examination of the SALIA cohort . Participants with cardiac or pulmonary disease were excluded, 291 participants formed the final study group . In a logistic regression model, the symptom dyspnea was best predicted by systolic pulmonary artery pressure, followed by left atrial volume index, BNP, and body mass index.The examinations were concordant with the presence of diastolic dysfunction in 122/291 participants (41.9%). The diagnosis based in 94% of cases on two criteria: in 50 cases on the criterion "E/E' ratio > 15", and in 65 cases on the criterion "15 > E/E'>8 and LV mass index > 122 g/mThe demonstration of diastolic dysfunction showed only a poor association with the symptom dyspnea in a cohort of elderly women with otherwise normal systolic function. Additional structural or hemodynamic changes are necessary to "explain" the symptom dyspnea. It is unclear whether these additional factors are secondary to a more advanced stage of diastolic dysfunction, or are related to cardiovascular co-morbidities, or both. In the last two decades, there is growing evidence of prevalence and prognosis of heart failure with normal ejection fraction (HFNEF), also referred to as diastolic heart failure . HFNEF iDiagnostic evidence of diastolic dysfunction can be obtained invasively, or - which is probably more accepted in clinical routine - non-invasively by tissue Doppler. A central parameter derived from tissue Doppler is the ratio E/E' . When this ratio exceeds 15, the LV filling pressures are elevated, and - in the presence of normal systolic LV function - highly suggestive for the presence of diastolic dysfunction ,5. A "grWe thought to use this diagnostic flowchart in a population-based cohort of elderly women, in whom the prevalence of diastolic dysfunction and heart failure is believed to be high ,7. The pThe SALIA cohort  was initiated as part of the Environmental Health Surveys introduced by the North Rhine Westfalia government between 1985 and 1994. The study population comprised 4874 women aged 55 at the time of entering the study who were living in predefined residential areas. The study areas were chosen from the highly industrialized Ruhr region which represents a range of high-polluted areas and two rural counties in the north-west of the Ruhr region as reference areas [A cross-sectional cardiovascular examination was realized in 344 of 402 participants (86%). The examination consisted of medical history, physical examination, measurement of B-type natriuretic peptide, electrocardiography, and echocardiography.2; further 9 participants were excluded with pulmonary diseases requiring a specific therapy. These latter exclusion criteria were chosen to focus on participants with a normal left ventricular systolic function and normal left ventricular enddiastolic diameter, and to exclude those participants with a significant pulmonary disease. Thus, a total of 291 participants formed the final study group.Exclusion criteria for further analysis were a.) previous heart surgery and/or PCI (n = 5), b.) severe heart valve disease (n = 6), c.) typical angina pectoris ≥ II CCS (n = 3), d.) previous or actual atrial fibrillation or flutter (n = 8), e.) permanent pacemaker stimulation (n = 3), and f.) poor image quality in the echocardiographic examination (n = 10). Nine participants were excluded with a LV EF ≤ 50% and/or LVEDVI ≥ 97 mL/mIn a structured interview each participant was asked for detailed medical history, particularly for cardiovascular risk factors, cardiovascular diseases and medication. The Minnesota living with heart failure questionnaire (MLHFQ) was used to assess quality of life . SummatiDyspnea was assessed by combining results of the standardized questionnaire and an interview. Participants were asked to asses their degree of functional impairment due to dyspnea and level of activity. With this, dyspnea was categorized according to the New York Heart Association classification.Physical examination comprised measurements of blood pressure, height, and weight. Arterial hypertension was diagnosed by medical history, medication and blood pressure measurement (systolic pressure > 140 mmHg and/or diastolic blood pressure > 90 mmHg).Plasma B-type (brain) natriuretic peptide levels (BNP) were measured at the same day as electrocardiography and echocardiography. The blood samples were collected in EDTA-containing tubes. After prompt centrifugation, BNP was measured using a chemiluminescent immunoassay kit . Electrocardiography was analyzed for arrhythmias.Transthoracic echocardiography was performed according to the guidelines of the American Society of Echocardiography  using a Inter- and intraobserver correlation for echocardiographic measurements variables reached in our laboratory 0.92 and 0.96, respectively. For assessment of pulmonary artery pressure (PA sys), the systolic pressure gradient between right atrium and ventricle was obtained from the tricuspid regurgitant jet envelope; and the value of 5 mmHg for right atrial pressure was added .2 body surface, or left ventricular mass index > 122 g/m2 body surface, or transmitral E/A ratio < 0.5 plus deceleration time > 280 ms, or blood level of brain natriuretic peptide > 200 pg/mL.According to the diagnostic flowchart , diastolt test  or Mann-Whitney U test . Chi-square analysis was used to compare categorical variables. All reported probability values were 2-tailed, and p < 0.05 was considered statistically significant. Stepwise logistic regression analysis was used to estimate the impact  of the variables history of hypertension, systolic and diastolic blood pressure, heart rate, body mass index (BMI), BNP, the echocardiographic parameters E/E' ratio, left atrial volume index (LAVI), left ventricular endsystolic/enddiastolic volume indices (LVESVI/LVEDVI), left ventricular mass index (LVMI), right atrial diameter, systolic pulmonary pressure, and TAPSE on the dependent variable dyspnea .Continuous variables were compared between groups using an unpaired 2 body surface).The final study group with 291 participants was homogenous regarding sex , age (range 69 to 79 years), heart rhythm , and left ventricular systolic function and size  were concordant with the presence of diastolic dysfunction in 122 participants (41.9%). The diagnosis of diastolic dysfunction based in the majority of cases only on two criteria: in about 17% of cases (50/291) on the criterion "E/E' ratio > 15", and in about 22% of cases (65/291) on the criterion "15 > E/E'>8 and LVMI > 122 g/m2; p = 0.014), more frequent a history of arterial hypertension  and of hospitalization for congestive heart failure , poorer quality of life , and higher BNP blood levels  as compared to those participants without signs of diastolic dysfunction. The number of participants complaining exertional dyspnea, however, was similar distributed among the subgroups with and without signs of diastolic dysfunction  (Table The participants with diastolic dysfunction had on average a higher body mass index (28.34 ± 4.50 vs. 27.01 ± 4.55 kg/mParticipants with diastolic dysfunction complained about dyspnea in 49 cases 40.2%). It was hypothesized that the participants with dyspnea suffer from a more advanced stage of diastolic dysfunction, i.e. the parameters used to define diastolic dysfunction should be more abnormal as compared to cases without dyspnea. Table %. It wasA logistic regression model was used to disclose the parameters which predict best dyspnea in participants with diastolic dysfunction. The parameters age, LV ejection fraction and LV volume indices were not added to this analysis, because these parameters were used as pre-selection criteria. The parameters history of hypertension, systolic and diastolic blood pressure, heart rate, the echocardiographic parameters E/E' ratio and TAPSE did not show a significant association with the variable dyspnea (data not shown). Dyspnea was predicted best by the systolic pulmonary artery pressure, followed by left atrial volume index, BNP, body mass index, and the parameters right atrial diameter and LV mass index Table .Diastolic heart failure is characterized by impaired left ventricular relaxation, increased left ventricular stiffness, increased interstitial deposition of collagen, and modified extracellular matrix proteins ,3. It haA prerequisite in the diagnosis of HFNEF is the evidence of diastolic dysfunction. The reported prevalence of LV diastolic dysfunction in the general population varies from 11.1 to 34.7% ,17-20, a2 (for women)" was positive in our study cohort in 22.3% of cases . Taken together, the diagnosis of diastolic dysfunction based in our study population in 94% of cases on two criteria only.A key element in the diagnosis of HFNEF is the evidence of elevated LV filling. Three ways have been proposed to diagnose raised LV filling pressures: a. invasive measurements, b. unequivocal tissue Doppler measurements, and c. a combination of Doppler echocardiographic parameters and elevated BNP blood levels . ConventThe flowchart allows an alternative pathway to diagnose diastolic dysfunction: the use of the biomarkers brain natriuretic peptide (BNP) or NT-proBNP in first line, in combination with an E/E' ratio > 8. In our study population, 7.6% of participants fulfilled this criterion (data not shown). This number is in sharp contrast to the above mentioned cases with diastolic dysfunction diagnosed by tissue Doppler indices in first line (42%).Somewhat unexpected, the diagnosis of diastolic dysfunction (using tissue Doppler in first line for diagnosis) showed only a poor association with the symptom "dyspnea". In fact, approximately 40% of elderly women in the present study cohort complained dyspnea: this symptom, however, was similar distributed among the subgroups with and without signs of diastolic dysfunction. The "key parameters" for the diagnosis of diastolic dysfunction  did not further discriminate those women with diastolic dysfunction and dyspnea. Additional echocardiographic parameters such as the systolic pulmonary pressure, left atrial volume index, right atrial diameter, and left ventricular mass index were more helpful to characterize participants with dyspnea. This observation suggests that the demonstration of elevated LV filling pattern by tissue Doppler alone may be not sufficient to "explain" the symptom dyspnea in elderly patients, and other factors have to be taken into consideration. Several causes of dyspnea in elderly have been described . ShortneAs a limiting factor we have to consider, that we can not thoroughly generalize our data to the community because of the study exclusion criteria. However, we wanted to analyze the interplay between diastolic function and dyspnea without apparent underlying diseases.2). The demonstration of diastolic dysfunction showed only a poor association with the symptom dyspnea. Additional structural or hemodynamic changes are necessary to "explain" the symptom dyspnea in this cohort of elderly women. It is unclear whether these additional factors are secondary to a more advanced stage of diastolic dysfunction, or are related to cardiovascular co-morbidities, or both.In summary, our population-based cross-sectional study in elder women confirms a high percentage of participants with signs of diastolic dysfunction, as assessed by the actual diagnostic guidelines of the ESC. According to the guidelines, the diagnosis of diastolic dysfunction based in the majority of cases on two criteria  natriuretic peptide; CCS: Canadian Chest Society; DT: deceleration time; EF: ejection fraction; HFNEF: heart failure with normal ejection fraction; LAVI: left atrial volume index; LV: left ventricular; LVESVI: left ventricular endsystolic volume index; LVEDVI: left ventricular enddiastolic volume index; LVMI: left ventricular mass index; MLHFQ: Minnesota living with heart failure questionnaire; PAsys: Systolic pulmonary artery pressure; PCI: percutaneous coronary intervention; RAD: right atrial diameter; TAPSE: tricuspid annular plane systolic excursion.The authors declare that they have no competing interests.AG, MG and AM had full access to all of the data in the study and take responsibility for the integrity of data and the accuracy of data analysis. Study concept and design: AG, AM. Acquisition of data: AG, MG. Analysis and interpretation of data: AG, MG, TS, AV, UR, UK, AM. Preparation of the manuscript: AG, MG, TS, AV, UR, UK, AM. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2318/11/71/prepub


HeartMate II (HM II) and HeartWare (HW) Left Ventricular Assist Devices have been successfully used in end-stage heart failure patients as a bridge to transplantation, recovery, or decision. We set out to compare their effect in off-loading the left ventricle and its geometry.The left ventricular end diastolic (LVEDD) and end systolic (LVESD) diameters were compared between first time HM II (n = 25) and HW implantations (n = 24) before and after the operation at 1, 3, and 6 months. A p value of less than 0.05 was considered as significant.Post-operative LVEDD and LVESD at 1, 3, and 6 months were significantly reduced in comparison with pre-operative values in both HM II and HW groups. No significant difference was found comparing HM II and HW groups together before and after the operation.Our study shows that both HM II and HW can significantly reduce the left ventricular systolic and diastolic dimensions and off-load the left ventricle. The miniaturized nature of HW does not affect its performance and it could be as effective as HM II. Mechanical circulatory support for patients with advanced heart failure has evolved considerably during the past 30 years and is now the standard therapy at many medical centers worldwide. VentricIn the last decade, the smaller second generation continuous-flow assist devices have successfully replaced their first generation pulsatile predecessors. They have proved to be more reliable, smaller in size, and have lower rates of adverse events . The most common second generation devices currently used are HeartMate II (Thortec Inc.), MicromeAnother recent addition to this family is HeartWare VAD (HeartWare Inc). It is a miniaturized centrifugal blood pump that could be placed intra-pericardially, thereby avoiding abdominal surgery and pump pocket formation. It has proved to provide satisfactory long term survival with excellent quality of life, low rate of adverse events and feasibility for implantation via minimally invasive incisions-10. TherFirst time HM II and HW implantations for Dilated Cardio-Myopathy performed at Harefield Hospital from April 2008 to October 2010 were included in this study. Pre-operative and post-operative (first month and then three-monthly) echocardiography is performed at Harefield Hospital as a routine follow up procedure for all patients with a VAD implantation. Echocardiography data is inclusive of the left ventricular systolic diameter and the left ventricular diastolic diameter at baseline VAD pump speed (9600 rpm for HM II and 2800 rpm for HW).This data was part of Harefield Hospital post VAD surgery data collection and outcome evaluation. The study was categorized as a Service Evaluation by the Ethical Committee and required no need for ethical approval.Fisher’s exact test was used for comparing the demographic factors, and the mortality. Pre-operative left ventricular parameters were compared with the post-operative left ventricular parameters at 1, 3, and 6 months after the operation, using Analysis of Variance (ANOVA) test. A p value of less than 0.05 was considered as significant. The study design was a retrospective review of the prospectively collected data.HM II and HW groups contained 25 and 24 patients respectively. All patients had a history of Dilated Cardio-Myopathy with NYHA class 4 symptoms. Table Ventricular Assist Device systems have revolutionized the management of end stage heart failure. They are used as a bridge to transplantation, recovery, or decision,2,7-9,11Our study shows that both HM II and HW can significantly reduce the left ventricular systolic and diastolic dimensions and off-load the left ventricle. The miniaturized nature of HW does not affect its performance and it could be as effective as HM II.The authors declare that they have no competing interests.MTH and AFP designed the study, collected the data, wrote and revised the manuscript. MA, and ARS carried out the surgical procedures, and revised the manuscript. TB carried out the surgical procedures, co-wrote and revised the manuscript, supervised and lead the study. All authors read and approved the final manuscript.


Clinical studies have demonstrated the predictive values of changes in electrocardiographic (ECG) parameters for the preexisting myocardial ischemic infarction. However, a simple and early predictor for the subsequent development of myocardial infarction during the ischemic phase is of significant value for the identification of ischemic patients at high risk. The present study was undertaken by using non-human primate model of myocardial ischemic infarction to fulfill this gap. Twenty male Rhesus monkeys at age of 2–3 years old were subjected to left anterior descending artery ligation. This ligation was performed at varying position along the artery so that it produced varying sizes of myocardial infarction at the late stage. The ECG recording was undertaken before the surgical procedure, at 2 h after the ligation, and 8 weeks after the surgery for each animal. The correlation of the changes in the ECG waves in the early or the late stage with the myocardial infarction size was analyzed. The R wave depression and the QT shortening in the early ischemic stage were found to have an inverse correlation with the myocardial infarction size. At the late stage, the R wave depression, the QT prolongation, the QRS score, and the ST segment elevation were all closely correlated with the developed infarction size. The poor R wave progression was identified at both the early ischemic and the late infarction stages. Therefore, the present study using non-human primate model of myocardial ischemic infarction identified the decreases in the R wave and the QT interval as early predictors of myocardial infarction. Validation of these parameters in clinical studies would greatly help identifying patients with myocardial ischemia at high risk for the subsequent development of myocardial infarction. The early diagnosis and identification of high-risk patients with myocardial infarction is a practical problem in clinical setting. Improved electrocardiographic (ECG) recordings became an attractive approach for the diagnosis of myocardial infarction. Extensive efforts have been made to define criteria of alterations in different ECG waves associated with location and areas of myocardial infarction QT-prolongation is a parameter that can be used as a marker for myocardial infarction The Selvester QRS score translates subtle changes in ventricular depolarization measured by the ECG into information about myocardial scar location and size R wave amplitude also changes in association with myocardial infarction. R wave amplitude decreases in patients with acute anterior wall myocardial infarction Currently available parameters of the changes in ECG are of diagnostic values only for the preexisting myocardial infarction. The early prediction of myocardial tissue at high risk for myocardial infarction is of significant value for prevention or precaution for the adverse outcome under ischemic condition. A simple and quick screening procedure that can be indicative of further development of myocardial injury under ischemic condition is thus a valuable addition to currently available diagnostic procedures.The highly human-resembling distribution of coronary arteries makes Rhesus monkeys unique substitutes for humans to study myocardial ischemic infarction Male Rhesus (Macaca mulatta) monkeys, aged 2–3 years old and weighed 4.5 to 6.0 kg, were obtained from Chengdu Ping-An experimental animal breeding and research center, a Chinese government accredited non-human primate center in Sichuan province. The animals were acclimatized to the laboratory condition for a period of at least one month in the Association for Assessment and Accreditation of Laboratory Animal Care accredited facility. They were housed in individual stainless steel cages (0.8×0.9×0.78 m) in a controlled environment (at 18–28°C and 40–70% relative humidity) under controlled light-dark cycle (lights on at 8:00 and off at 20:00). Monkeys were fed completely formulated feed , purchased from Beijing Ke’ao Xieli Feed Co., Ltd (license number SCXK-2009-0012), and were allowed free access to drinking water produced by a reverse osmosis system. In addition, they were provided with seasonal fresh fruits including apple, banana, watermelon, and orange (100–250 g each time) three times weekly. Fruits were soaked in 0.4% disinfectant solution for 15 min followed by washing with clean water. The environment enrichment included a metal mirror attached to each cage, video watching twice a week (30 min each time) and toy playing . All monkeys were handled in strict accordance with good animal practice under supervision of veterinarians, and monitored for evidence of disease and changes in attitude, appetite, or behavior suggestive of illness. Every effort was made to alleviate animal discomfort and pain by appropriate and routine use of anesthetic and/or analgesic agents. To ameliorate pain after surgery, analgesics tramadol (2 mg/kg) were injected intramuscularly once daily for 3 days. Animals were sacrificed under anesthesia (10 mg/kg ketamine and 0.2 mg/kg midazolam) at the end of the experiment. All animal procedures were approved by the Institutional Animal Care and Use Committee at the Sichuan University West China Hospital, following the guideline of the US National Institutes of Health.Prior to experimental procedure, all subjects received an intramuscular injection of 10 mg/kg ketamine and 0.2 mg/kg midazolam to induce sedation. Hairs covering chest and limbs at electrode attachment sites were shaved thoroughly for better ECG recording. The standard bipolar and unipolar limb leads were recorded. Animals displaying abnormal ECG, such as tachycardia (more than 200 beats per minute), arrhythmia, and obvious ST segments deviated from the base line were excluded from this study.−1·min−1) and propofol (4–12 mg·kg−1·min−1) using an infusion pump. Noninvasive monitoring procedures including electrocardiography, cuff blood pressure, pulse oximetry, and capnography  were used, and vein catheters were established.All of the monkeys (n = 20) subjected to surgical procedure were intubated after anesthesia induced by intravenous infusion with fentanyl (10 µg/kg), midazolam (0.2 mg/kg), propofol (1 mg/kg), and vecuronium (0.1 mg/kg). Animals were intubated and maintained with fentanyl  in the chest wall. Two groups were divided: sham-operated control (n = 4) and myocardial infarction . The sham-operated controls were subjected to the same surgical procedure with the exception of the LAD ligation. The left anterior descending artery (LAD) was occluded for 1 min followed by a 5-min reperfusion, and this occlusion-reperfusion was repeated 3 times before the eventual ligation. The pericardium, sternum and skin were closed after the cardiac hemodynamic became stable. In preparation for recovery, analgesic tramadol (2 mg/kg) was used by intramuscular injection to alleviate suffering. The endotracheal tube was retracted after the spontaneous breathing was restored. The incision was covered with sterile gauze and bandage. The bandage change was performed on alternate days and sutures were removed one week after the operation.Monkeys received an intramuscular injection of 10 mg/kg ketamine and 0.2 mg/kg midazolam to induce anesthesia. A 12-leads ECG  was recorded on the supine position of each monkey at the time before, immediately after the ligation , and eight weeks after the operation using pediatric electrodes at 25 mm/s paper velocity and 10 mm/mV amplitude. The chest wall of the Rhesus monkey was not wide enough to allow 6 precordial leads at the same time even with the pediatric electrodes. Therefore, the 6 precordial leads were divided into two groups; V1, V3, and V5 were recorded in one group, and V2, V4, and V6 in another group, as reported previously R wave amplitude (millimeter) was measured as the vertical distance from the peak of the R wave to the baseline . The sum of R wave amplitudes for anterior wall (V2 through V5) was calculated. Since the heart rate of Rhesus monkeys is about twice of the human, modified Selvester QRS score were used . QRS durMonkeys received an intramuscular injection of 10 mg/kg ketamine and 0.2 mg/kg midazolam to induce anesthesia and were sacrificed by intravenous injection of potassium chloride and a complete autopsy was performed. Harvested hearts were inspected grossly for visible lesions. Then the hearts were fixed in 10% formaldehyde solution and paraffin block was prepared. Thin sections were cut and stained with Masson's trichrome for microscopic examination, as reported previously The infarction size was visualized using the tissue sections stained with Masson's trichrome and captured as digital images followed by computerized analysis. The following parameters of each image were measured using Image-Pro Plus 6.0 software: the epicardial infarction length , the endocardial infarction length , and the epicardial and endocardial circumferences. The infarction size was calculated as [/2]×100 t” test. Pearson correlation coefficients were used to evaluate the relations among the ECG parameters and the myocardial infarction size. Linear regression models were used to generate formulas from these parameters to predict the infarction size. A SPSS 18.0 statistical package  was used and significant difference was assumed when P values were <0.05.Data are presented as mean ± SD for measurement variables. Comparison between groups was performed with the Student’s ”There were 20 male Rhesus monkeys subjected to left anterior descending (LAD) artery ligation at different locations along the LAD artery, along with 4 male monkeys served as sham-operated controls. The variations in the ligation position resulted in varying sizes of myocardial ischemic infarction. The results presented in The analyses of correlation between the ECG wave changes at 2 h or 8 wks and the size (%) of myocardial infarction were conducted for R wave amplitude, QRS score, QT interval, and ST segment elevation. The results presented in At 8 wks after the LAD ligation, an inverse correlation between the R wave amplitude depression and the increase in the myocardial infarction size remained observable. However, other parameters including the QRS score and the ST segment elevation showed a positive correlation with the increase in the myocardial infarction size. In contrast to the inverse correlation between the QTc and the myocardial infarction size observed at 2 h after the surgery, a positive correlation between the QTc and the myocardial infarction size at 8 wks was observed, as shown in It appears that the R wave amplitude depression at both early and late time points was a consistent change. To further verify this change, we analyzed the R wave progression. As shown in The present study took an advantage of the non-human primate animal model as a surrogate for human cardiac disease to identify the early predictors of the ECG parameter changes for the risk of myocardial ischemic infarction. The data show that there were persistent changes in the ECG parameters that occurred both in the early and in the late stage of myocardial ischemia, such as the R wave depression. Other parameters such as the QRS score and the ST segment elevation were not changed regularly in the early stage of myocardial ischemia, but altered correlatively with the size of myocardial infarction at the late stage. An interesting change in the QT interval was that it was shortened in the early stage of myocardial ischemia, but prolonged in the subsequent development of myocardial infarction. In both cases, there was a good correlation between the change in the QT interval and the size of myocardial infarction.Clinical studies have reported the diagnostic values of the ST segment elevation In the comprehensive analyses presented in this study, the R wave amplitude changes were identified to be correlative with the size of myocardial infarction at both the early and the late stage of myocardial ischemia. This finding is of significantly clinical relevance. There is at present no useful parameter of the ECG changes at the ischemic stage for the subsequent development of myocardial infarction. As discussed above, all of the clinically available parameters are predictive for the preexisting infarction or the infarction already developed. At this stage, other noninvasive procedures such as magnet resonance imaging and echocardiography are also available to detect the extent or size of the infarction in the heart. An easy and early predictor for the infarction developed in the late stage after myocardial ischemia is thus a valuable addition to the diagnostic procedures of myocardial ischemic infarction. In addition, this early prediction would help making preventive or precautious decision to minimize the risk for the subsequent development of severer myocardial infarction.The depressed R wave amplitude has been observed in clinical studies, and suggested to be a predictor for myocardial infarction The QT interval changes observed in the present study were interesting. At the early stage, right after myocardial ischemia, QT shortening took place and the extent correlated with the severity of ischemia and the subsequent development of myocardial infarction. In clinical observation, the short QT syndrome (SQTS) was identified to be an inherited arrhythmia disorder associated with family history of sudden cardiac death, short refractory periods, and inducible ventricular fibrillation in the absence of structural heart disease At the late stage, after the development of myocardial infarction, QT prolongation took place. The long QT syndromes (LQTS) were known for several decades In summary, the present study using non-human primate model of myocardial ischemic infarction identified the early predictors of myocardial infarction. The decreases in the R wave and the QT interval are simple measurements of the ECG changes during the early stage of myocardial ischemia. Validation of these parameters in clinical studies would greatly help identifying patients at high risk for the subsequent development of myocardial infarction.


In patients with severe aortic stenosis (AS), long-term data tracking surgically induced effects of afterload reduction on reverse LV remodeling are not available. Echocardiographic data is available short term, but in limited fashion beyond one year. Cardiovascular MRI (CMR) offers the ability to serially track changes in LV metrics with small numbers due to its inherent high spatial resolution and low variability.We hypothesize that changes in LV structure and function following aortic valve replacement (AVR) are detectable by CMR and once triggered by AVR, continue for an extended period.Tweny-four patients of which ten  with severe, but compensated AS underwent CMR pre-AVR, 6 months, 1 year and up to 4 years post-AVR. 3D LV mass index, volumetrics, LV geometry, and EF were measured.2, p < 0.005) and continued trending downwards through 4 years (127 ± 32 g/m2). Similarly, EF increased pre to post-AVR ) and continued trending upwards, remaining stable through years 1-4 (66 ± 11 vs. 65 ± 9%). LVEDVI, initially high pre-AVR, decreased post-AVR  trending even lower by year 4 (66 ± 10 ml/m2). LV stroke volume increased rapidly from pre to post-AVR  continuing to increase non-significantly through 4 years (49 ± 14 ml) with these LV metrics paralleling improvements in NYHA. However, LVmass/volume, a 3D measure of LV geometry, remained unchanged over 4 years.All patients survived AVR and underwent CMR 4 serial CMR's. LVMI markedly decreased by 6 months (157 ± 42 to 134 ± 32 g/mAfter initial beneficial effects imparted by AVR in severe AS patients, there are, as expected, marked improvements in LV reverse remodeling. Via CMR, surgically induced benefits to LV structure and function are durable and, unexpectedly express continued, albeit markedly incomplete improvement through 4 years post-AVR concordant with sustained improved clinical status. This supports down-regulation of both mRNA and MMP activity acutely with robust suppression long term. In patients with severe aortic stenosis (AS), compensatory left ventricular hypertrophy (LVH) is the predominate mechanism manifest to attempt to normalize the markedly elevated afterload imposed at the aortic valve level . Overtimet al demonstrated that if one wished to be able to detect a 10 gram regression in LV mass with an alpha of 0.05 and a beta of 0.80 it would require 550 patients, whereas only 17 patients were necessary by CMR [Cardiac magnetic resonance imaging (CMR) is the 'gold standard' for measuring cardiac volumetrics LV mass and offers the ability to track changes in LV metrics with innordinantly small numbers due to its inherent high spatial resolution and low intraobserver variability . Indeed,y by CMR . This reWe hypothesize that progressive LV reverse remodeling changes following AVR are detectable by CMR and changes in LV structure and function, once triggered by AVR, continue for an extended period.Patients referred for AVR were enrolled after institutional review board (IRB) approval and signed consent obtained. All patients were identified via standard clinical metrics independent of CMR evaluation chiefly through cardiac catheterization and/or echocardiography. To provide homogeneity in the pathology of AS, patients were excluded if there was aortic or mitral regurgitation assessed by echocardiographic imaging as greater than moderate (>2+), mitral stenosis, prior valve replacement, myocardial infarction, history of hypertension, coronary artery bypass grafting (CABG) or angioplasty. Specific contraindications to CMR were presence of a pacemaker, defibrillator, history of metal fragments, implants, cerebrovascular clips or claustrophobia.2, matrix 256 × 192, flip angle 45°. The temporal resolution was 30 ± 3 ms,100% phase FOV and 0.75 NEX, TR 3.2 ms and TE 1.4 ms. From the short-axis images, LV end-diastolic volume (LVEDV), LV end-systolic volume (LVESV), LV stroke volume (LVSV), LV ejection fraction (EF), and LV mass were measured and indexed to BSA. LV mass was derived via Simpson's method multiplied by the specific gravity of myocardium (1.055 g/ml). Image acquisition was kept constant to include LV basal plane-registration throughout the study and between patients to minimize variability in measurements.The 3D CMR methodology has been described elsewhere ,16. BriePhase velocity mapping (PVM) was employed to quantitate 3D peak and mean aortic transvalvular gradients in the through and in-plane slices. Velocity encoding was set at 350-550 cm/sec with encoding in the x, y and z directions. PVM was resolved into 60 phases/cardiac cycle achieving high temporal resolution(19 ± 3 ms). ROI's were manually drawn encircling the entire supravalvular plane for complete interrogation of all velocities, as opposed to the 'ice-pick' view employed by echocardiography. 2D transthoracic and/or transesophageal echocardiography was also performed for independent clinical assessment of AS.All images were analyzed offline on semi-automatic MASS Plus and Flow programs . CMR imaging was performed (5 ± 3 days) prior to AVR, 6 month and 1 year and up to 4 years post-AVR. An independent comparison of AS degree assessed by each modality (CMR and echocardiography) was performed for future reference and was recorded, see image  dynamic cine sequence at each time point. Measurements of the mitral annulus, valve tenting angle and valve tenting area were meaured using standard approaches in 2D from the vertical and horizontal long-axis.Continuous variables were reported as mean ± 1 SD. Categorical variables were reported as percentages with 95 percent confidence intervals. Serial comparisons pre- to post-AVR were performed by the paired t-test. Effects across groups were analyzed using one-way analysis of variance (ANOVA) and repeated-measures ANOVA was performed for comparisons over time. Statistical analyses were performed using SPSS for Windows, version 11.0 . All statistical comparisons were performed using two-tailed significance tests with a 'p' value of < 0.05 considered statistically significant.Twenty-four patients underwent pre-AVR CMR. A random subset of patients who were imaged at the 6 month and 1 year time point were specifically invited back to be imaged at a fourth very late time point and underwent post-AVR imaging at 6 ± 2mo and 1 yr ± 2mo and up to 4 years (one patient imaged at 3.5 years) for 40 total time points. Thus, ten patients  with severe, but reasonably well compensated AS, underwent CMR pre-AVR and 3 subsequent time points post-AVR. Two patients were classified as NYHA class III, all others were < NYHA II. Four patients had concomitant CAD but were without significant differences in their peak and mean transvalvular gradient by either echocardiography or CMR. There was no significant difference between the CMR derived mean and peak transvalvular gradients  vs. the mean and peak gradients as measured by echocardiography  though CMR velocities tended to be higher, p=NS). Stated alternatively, there was no difference in the number of patients with >4 m/s peak transvalvular gradient as measured by CMR and echocardiography (7 vs. 7 patients). The mean NYHA pre-AVR was 2.5 ± 1.2.2, p < 0.005) and continued to further trend downward at 4 years , see Figures 2, p < 0.05) trending even lower by year 4 but again remaining statistically insignificant (66 ± 10 ml/m2).All patients had severe LVH prior to undergoing AVR. Following AVR, LVMI markedly decreased at 6 months  trending to increase at 4 years (49 ± 14 ml/m2) but also remaining statistically insignificant as compared to the 6 month time period.LV stroke volume index increased rapidly from pre to post-AVR (40 ± 11 to 44 ± 7 ml/m2) [However, despite the relatively long term follow-up there remained incomplete LV mass regression, failing to return to historic age-matched control level (59 ± 11 g/m2) , see Fig2) .relative wall thickness (RWT), an indicator of 1D LV geometry, is the mass/volume ratio. As a 3D metric, the mass/volume ratio has obvious advantages over any 1D measurement and accordingly is used to more definitively relate changes in LV geometry over time. The mass/volume ratio demonstrated no change initially (1.9 to 2.0 at 6 months) remaining unchanged at 1 year (2.0) and out to 4 years (1.9), p = NS between all.The 3D CMR equivalent to echocardiographic While all metrics except for EF were markedly elevated as compared to normals, despite substantial metric approaching within 2 standards deviations of normal. LV mass index specifically remained >5 standard deviations above normal.within the first 6 months. For instance, for LVMI, 76% of the mass that regressed by year 4 did so in the first 6 months while for LVEDV, 88% of the reduction occurred within the first 6 months. Likewise, nearly all (91%) of the final EF achieved was present within the first 6 months with no significant changes apparent afterwards. Due to the near parallel changes in LVMI and LVEDVI, by definition, there would be no discernable temporal pattern in the mass/volume ratio over the entire 4 years.The temporal pattern for regression for all stand-alone metrics including EF demonstrated that a minimum of nearly 50% of the change that was to be evident by 4 years occurred a priori excluded. Nevertheless, a biologic signal to assess whether the degree of mitral regurgitation (MR) could be favorably influenced might be deducible from this population. Pre-AVR, the grade of MR was '0' through '2+' (moderate MR). Post-AVR the MR remained stable or decreased late in 80% and increased in two patients (0-trace in one patient and trace to 2+ another patient (both in patients who had the least amount of reverse remodeling), see Figure It should be noted that the primary objective of the study was to interrogate a pure human pressure afterload model of AS induced concentric LVH pathology, such that any significant amount of potential eccentric LVH due to volume overload was Paralleling improvements in CMR derived LV volumetrics and morphometrics including mitral regurgitation, there were concordant improvements in NYHA class. Pre-AVR NYHA was 2.5 ± 1.2 and rapidly improved to 1.6 ± 0.9 at 6 months and 1.6 ± 0.9 at 1 year but remained statistically insignificantly improved out to 4 years as compared to the interim time points (1.4 ± 1.1). However, as compared to pre-AVR, there was an important significant difference over time by 4 years (p < 0.05).Due to excessive afterload imposed on the LV from the markedly restricted valvular narrowing in patients with severe but compensated AS, substantial LVH is typically apparent. While initially a favorable compensatory response to the often extraordinary intraventricular pressure, left unchecked, LVH heralds a slow inexorable deterioration in cardiac function promulgated by further changes at the myocardial and interstitial level. To the extent that these now pathologic process are reversible is unclear. To be sure, it is well known that the epidemiological post-surgical effect is extremely favorable nearly restoring survival by actuarials back to the pre-morbid state. However, the nature, extent and temporal pattern of these surgically induced reverse remodeling effects are much less clear. Limited attempts to track LVH regression after AVR have been performed by 2D echocardiography but generally over short periods of time, often under one year post-AVR. To our knowledge this is the first attempt to apply the long known reference standard CMR, interrogating LV volume, EF and LV mass, incorporating long-term remodeling to this issue.14.CMR has an ability to detect exceedingly small aliquots of myocardial mass change (intraobserver variability of 2.5 g) while detecting changes in volumetrics such that EF changes of 1.5%, while at lower limits of intraobserver variability, are discernable and relevant. This provides for an unparalleled ability for CMR to be used to interrogate pre and post-AVR changes in a reliable and clinically relevant manner. As described above, CMR retains the ability to discriminate such findings in historically smaller populations then previously considered via other modalities due to its ultra high spatial resolution often leading to log-fold less patient requirements to achieve statistical significance yet retaining preserved powerand, unexpectedly, show continued improvement up to 4 years concordant with sustained improvement in clinical status. That these finding have awaited recognition and substantiation for decades detracts nothing from the expected, even predicatable reasoning that they would be present since there is a clear survival advantage for those that do undergo AVR as compared to those that choose not to, .In this study, after the initial beneficial effects imparted by afterload relief by AVR in severe AS patients, there are as expected, marked improvements in LV reverse remodeling. We have shown, via CMR, that surgically induced benefits to LV structure and function, including favorable alterations in LV geometry, are definable, durable However, the observed pattern of reverse remodeling has never been defined before in this patient population and was unexpected in its temporal trajectory. Fully 75% of the LV mass regression that was to occur did so within the first 6 months following AVR. In fact, nearly 90% of the change in volumetrics (LVEDVI and LVEF) were completed in the first 6 months with clinically insignifcant changes detected subsequently. In that the first oportunity to detect the changes was by protocol defined at 6 months, it is conceivable that one or more of these metrics had their improvement at an even earlier time course.The most striking finding in this study was not the extent of LV reverse remodeling that was found but that, despite serial follow-up up to 4 years, there is a distinct failure to normalize LV mass. LV mass remained >5 standard deviations above normal for >85% of the population without explanations on the basis of age, sex, CAD, and pre-AVR metrics such as gradient, valve type, cross-clamp time via multivariate analysis as they were unable to account for the failure of LVH regression. Should this be surprising to us? Are there inferences in the literature that might guide us to this conclusion? Several avenues of support for this finding are available as well as some that require a more considered approach.First off, AVR itself does not restore the transvalvular gradient to normal. Despite the advent of increasingly lower profile aortic valves, to include the Toronto SPV (used in 40% of this patient group), residual gradients exist and to the extent that they remain, invariably contribute to residual afterload and obligatorily thwart complete LV mass regression. In most cases, however, the ratio of residual to initial gradient is likely to be low ( < 20%) thereby having only modest impairment of eventual LV mass regression.supravalvular afterload is likely to be increasing due to aortic and peripheral changes in compliance and arterial inelasticity due to aging. The surgically induced relief of afterload may be counterbalanced by the resultant increase another type of afterload; arterial hypertension [Secondly, at the same time the afterload is surgically relieved at the valve level, rtension .21. Thus, in advanced AS, pure myocyte hypertrophy is not the only pathology that must be accounted for and consequently regress post-AVR. Were both sarcomere hypertrophy and collagen expression to be finely governed by a common pathway, coordinate regression of both would be evident [in toto to ameliorate the expected regression of LVH.Another mechanism thwarting regression of LVH is less obvious. Classically, the hypertrophic process is thought to be composed chiefly of sarcomeres being laid down in parallel resulting in concentric hypertrophy. This process is governed mostly by mRNA expression. Naturally, LVH regression therefore would be thought as a reversal of this process following AVR. What has become clear however is that the pathologic perturbation in AS is not confined at the ventricular level only to the myocyte . The ext evident . However evident . The resPut into perspective, the surgeon who replaces the aortic valve now has a number of explanations to account for the lack of adequate LVH regression following AVR. Even in those admirable cases in which the post-AVR gradient is reduced to < 15-20 mmHg, substantial mechanisms are operative serving to thwart the otherwise expected beneficial effects of AVR at the level of the myocardium. In short, surgical success or failure to trigger LVH regression should no longer be placed in the surgeon's prerogative.Regarding concomitant mitral regurgitation  that often is associated with AS, AVR achieves improvements in MR in severe AS that are detectable by CMR and remains stable in up to 4 years of follow-up. Favorable changes appear attributable to LV and mitral valvular/annular geometry, LVH regression, less so on improved EF. Since considerable morbidity and mortality exists for simultaneous AVR and MVR, CMR suggests that AVR without MVR may be indicated in such patients.Patients with advanced AS upon surgical relief of valvular afterload, undergo rapid regression of LVH with corresponding improvements in many LV metrics measurable by CMR that is in conjunction with improvements in clinical sequelae. However, the preponderance of the surgical benefits appear early, almost truncated within the first 6 months and while durable, only minimally continue long-term out to 4 years. The long-term expected reverse remodeling appears thwarted by a myriad of so-named factors rendering incomplete the otherwise beneficial post-AVR effects. From a surgical perspective, it would seem initially apparent that any 'less then complete' normalization of LV mass after such an extended follow-up would be perceived potentially as a shortcoming of the surgical technique. From this data we can provide substantial evidence to support that this is an incorrect supposition. Whether longer-term follow-up would eventually reveal a normalized trajectory on course with historic controls is unknown but worthy of further investigation.The authors declare that they have no competing interests.RB conceived, designed coordinated and analyzed primary data, assisted in recruitment, IRB issues as well as wrote the manuscript. JM discussed the design of the study and performed the majority of the aortic valve replacements. SG was the nurse coordinator, recruited patients, coordinated follow-up CMR exams and all the IRB/HIPPA requirements as well as partially conceived of the secondary 4 year follow-up coordination principal study. RW performed the CMR exams and data analysis. JY performed the CMR exams and data analysis. DV statistical analysis. VR helped interpret CMR exams served as the second cardiologist on the study. GR assisted in primary data analysis and was the software engineer for the study. KC participated in the study as the cardiology fellow and separately analyzed mitral regurgitation data. MD helped to implement design, analysis and performance of the study as well as implemented optimization of the RF tissue-tagging sequence, critical discussions of the study results, critical analysis of the various drafts of the manuscript and review/approval of its' final draft. All authors read and approved the final manuscript.


Systemic hypertension is a highly prevalent potentially modifiable cardiovascular risk factor. Imaging plays an important role in the diagnosis of underlying causes for hypertension, in assessing cardiovascular complications of hypertension, and in understanding the pathophysiology of the disease process. Cardiovascular magnetic resonance (CMR) provides accurate and reproducible measures of ventricular volumes, mass, function and haemodynamics as well as uniquely allowing tissue characterization of diffuse and focal fibrosis. In addition, CMR is well suited for exclusion of common secondary causes for hypertension. We review the current and emerging clinical and research applications of CMR in hypertension. Systemic hypertension is a highly prevalent  chronic A number of imaging techniques are available in the assessment of hypertension, including echocardiography, cardiovascular magnetic resonance (CMR), cardiac computed tomography (CCT) and cardiac scintigraphy. 2D echocardiography is widely available and extensive literature supports its indication for left ventricular (LV) mass measurement. This technique can quantify global and regional systolic function, as well as diastolic function. 3D echocardiography has partially overcome problems with accuracy and reproducibility, while difficulties due to poor acoustic windows and attenuation still persist. CCT has a high negative predictive value for ruling out coronary artery disease and it is also appropriate for ventricular mass and volume measurement and for assessing vascular disease, while more extensive research is needed before its use for myocardial tissue characterization can be promoted. Modern CT scanners generate significantly lower doses of ionizing radiation, but these are not widely available and issues with the use of nephrotoxic contrast still remain. Equally, scintigraphic techniques can be used in the assessment of hypertensive heart disease but their use is greatly limited by the limited spatial resolution and thus limited accuracy in determining LV mass. Thus, CMR appears as the one technique to provide a comprehensive assessment of hypertensive cardiovascular disease, including accurate and reproducible measurement of biventricular function and volumes, the possibility of serial evaluation, assessment of valvular disease and vascular pathology, myocardial perfusion and tissue characterization.Cardiac specific sequences are usually implemented in 1.5 T scanners, though 3 T and 1 T open scanners can be also used. They all yield good image quality with high spatial resolution. Steady state free precession (SSFP) cines, phase contrast sequences, T2-weighted short-tau inversion recovery (STIR), T1- and T2-weighted fast spin-echo, perfusion and myocardial late gadolinium enhancement (LGE) sequences along with 3D-magnetic resonance angiography (MRA), are the most widely used sequences in hypertension. Other CMR techniques such as spectroscopy, myocardial tagging, T1 relaxometry-based techniques and myocardial velocity mapping could be useful in the future though at present they are limited to the research arena. The utility and advantages of CMR in the characterization of hypertensive cardiac and vascular disease, as well as in detection of secondary hypertension, are reviewed below.Longstanding hypertension has deleterious effects on several target organs, including heart, brain, kidneys, eyes and vessels. Regarding the cardiovascular system, hypertensive heart diseases includes left ventricular hypertrophy, myocardial fibrosis, diastolic prior to systolic ventricular dysfunction and heart failure, atrial myopathy, atrial fibrillation, microangiopathy with decreased coronary reserve, and development of epicardial coronary stenoses . With reCMR has a unique potential to visualize and assess all of these alterations in hypertensive patients, leading to an accurate diagnosis.According to the Joint National Committee VII report on the prevention, detection, evaluation and therapy of hypertension (JNC-VII) , two of The 2007 ESH/ESC guidelines  recommenA proposed standard CMR protocol in hypertension is depicted in Figure Both the heart and the aorta are target organs of systemic hypertension. Hypertensive heart disease is characterized by LVH, left atrial dilatation, myocardial fibrosis, diastolic prior to systolic dysfunction, and increased incidence of coronary artery disease. Hypertensive vascular disease manifests as aortic wall pathology such as increased prevalence of atheromatous plaques and higher risk of aneurysm, dissection, penetrating ulcer, intramural hematoma or peripheral obstructive disease.The Framingham Study showed that increases in LV mass are associated with significant increments in cardiovascular morbidity and mortality independent of the presence of coronary artery disease, systemic hypertension or other cardiovascular risk factors ,9, with Electrocardiographic criteria of LVH have been in use for several decades ,13 but tImplementation of echocardiography in its M-mode and especially 2D modalities dramatically changed cardiac assessment. This technique has great advantages such as availability, safety and price, for which it is considered the first line imaging technique in the assessment of heart dimensions and function. Nonetheless, it has several significant limitations such as its dependency on observer, patient anatomy and position, problems with acoustic window and with attenuation. M-mode echocardiography has been widely used in the past but, due to the need for geometric assumptions, its accuracy and reproducibility are very low . More reCMR is currently considered the gold standard for the measurement of right and left ventricular volumes, mass and function, boasting high accuracy and reproducibility ,19. RefeImportantly, recent data have shown that LV mass should be indexed to height to the power of 1.7, which is more sensitive than body surface area indexed LV-mass in identifying obesity-related LVH, and appears to be most consistently associated with cardiovascular events and all-cause mortality .CMR can not only quantify LV mass but also assess the pattern of hypertrophy, that is, LV geometry, which may have prognostic importance. The assessment of LV remodelling by echocardiography has the same limitations as related above. By contrast, the unfettered full myocardial coverage of CMR offers a precise measurement of LV wall thickness  and geomEjection fraction as well as endocardial and mid-wall fractional shortening have all been proposed as possible additional predictors of cardiovascular events in hypertension , though While LVH of whatever aetiology confers increased cardiovascular risk, regression of LVH has been shown to be associated with decreased risk . Due to Determination of the aetiology of LVH is a common clinical problem that can be challenging, because pathological forms of LVH present with overlapping cardiac hypertrophy phenotypes. A number of other conditions can mimic LVH such as infiltrative diseases, hypertrophic cardiomyopathy (HCM), Fabry’s disease, cardiac sarcoidosis, aortic stenosis, and exercise-induced ventricular hypertrophy or athlete’s heart. While aortic stenosis is a straightforward differential diagnosis, other conditions can be difficult. The unique capacity of CMR to non-invasively characterise myocardial tissue represents an important advantage over other non-invasive imaging modalities. Regarding infiltrative conditions, a specific pattern of late gadolinium enhancement has been described for amyloid heart disease ,40 with In a recently published study multiparametric CMR imaging was used to differentiate hypertensive LVH from HCM and distinctive hypertrophic phenotypes were detectable . While h2 /ml, is said to have a 99% specificity for sport-related LVH. However this finding requires further validation and confirmation in larger cohorts. Figure Also, athlete’s heart can be distinguished from other forms of pathological hypertrophy with the CMR-derived diastolic wall-to-volume ratio . A cut-oAnimal and human studies have shown that in hypertensive LVH accumulation of type I and III collagen fibres occurs both in the interventricular septum and free wall . This inInterest has recently grown in the possibility of assessing the degree of myocardial fibrosis in order to refine the ability to predict outcome in hypertensive LVH, and several methods have been proposed. Serum markers of fibrosis have been proposed, mainly the carboxyterminal propeptide of procollagen type I (PIP), a marker of collagen synthesis whose serum levels correlate with the presence of severe myocardial fibrosis . CollageLGE-CMR is able to show focal myocardial fibrosis, as demonstrated in several conditions including hypertension ,44,52-54In longstanding systemic hypertension, diastolic heart failure, characterized by heart failure symptoms, preserved ejection fraction and diastolic dysfunction, often develops and carries an ominous prognosis . The tecAtrial dilatation correlates with the chronicity of hypertension and with the severity of diastolic dysfunction. Importantly, atrial size is independently associated with cardiovascular morbidity and mortality  and withAssessing coronary disease in the hypertensive patient with chest pain is particularly challenging. Systemic hypertension is an established risk factor for epicardial coronary artery disease ,71, but,Saturation-recovery sequences acquired on first pass of gadolinium during vasodilator stress with either adenosine or dipyridamole have a good diagnostic yield for detection of ischaemia and significant epicardial coronary disease -79, whilSystemic hypertension is an established risk factor for aortic and peripheral vascular disease. On the other hand, the relationship between cardiovascular risk factors including hypertension ,83 and vPlaque imaging may be important as part of risk assessment, which may alter thresholds for treatment, and may be of utility in plaque-regression studies. It has been shown that patients with prior major cardiovascular events have greater plaque burden and plaque eccentricity . Likewisin vivo plaque imaging. Protocols for assessing aortic wall anatomy and structure usually include high resolution T1 and T2-weighted TSE and STIR sequences and/or 3D angiography. Images obtained are eventually processed in order to quantify plaque volume and characterize plaque composition, which have been histologically validated [Black blood CMR imaging is highly accurate and reproducible for assessment and volumetric quantification of atheroma plaques in the carotid arteries  and aortalidated ,92.A functional assessment of the aorta can be carried out with CMR by acquiring flow-sensitive and cine sequences. Blood flow affects arterial remodelling, and decreased arterial distensibility is an early manifestation of adverse structural and functional changes within the vessel wall . FurtherResistant hypertension is defined as failure to achieve target blood pressure when a patient adheres to optimal doses of three or more antihypertensive drugs usually including a diuretic . The preCommon secondary causes are renal parenchymal disease, renal arterial disease, primary hyperaldosteronism and obstructive sleep apnoea. Less common causes are Cushing’s syndrome, phaeochromocytoma, thyroid disease, aortic coarctation, and intracranial tumours. The main physiopathological mechanisms are depicted in Figure This may be present in up to 35% of patients with resistant hypertension . Of all Screening techniques for renal artery stenosis are warranted when there is a high level of suspicion (young women and older patients). There are a number of non-invasive tests available including duplex ultrasound, which provides anatomical information as well as flow velocity quantification and assessment of pressure wave morphology, CT-angiography, and nuclear captopril renal scintigraphy. The gold standard diagnostic test has traditionally been intra-arterial digital subtraction contrast angiography but this technique is invasive and not free of complications . While f2) chronic kidney disease, but also with other conditions such as liver failure, liver or kidney transplant, hypercoagulability, deep vein thrombosis and proinflammatory processes. NSF is a scleroderma-like fibrosing entity which affects the skin and several organs including pleura, pericardium, lungs, joints, and striated muscle including diaphragm and myocardium [In the context of renal artery stenosis, which is usually associated with a degree of renal impairment, the issue of nephrogenic systemic fibrosis (NSF) must be considered prior to administration of gadolinium contrast. NSF is an extremely rare but important complication of gadolinium administration, associated with acute renal failure or severe chronic renal failure due to advanced (glomerular filtration rate less than 30 mL/min/1.73 mocardium . Though ocardium . Thus, aThis is a much more common cause of hypertension than previously thought and is present in up to 20% of patients with resistant hypertension . Given tThe exact prevalence of Cushing’s syndrome amongst patients with resistant hypertension is uncertain, but it is estimated that approximately 3 to 6% of cases of secondary hypertension are due to corticosteroid overproduction . HyperteThis is an unusual but prognostically important secondary cause of hypertension. Again, the prevalence of this condition in resistant hypertension is unknown but it is considered to be up to 0.6% in the general hypertensive population . PhaeochThis congenital defect is present in 0.2% of hypertensive adults . CoarctaEchocardiography, both transthoracic and transoesophageal, is usually the imaging technique of choice for initial assessment , but forAortic coarctation is associated with functional aorto-ventricular disturbances, such as abnormal myocardial perfusion reserve with sub-endocardial ischaemia, and increased central aortic stiffness that leads to ascending aorta dilatation and increased LV mass. These conditions persist after surgery and may contribute to increase cardiovascular mortality and morbidity. Finally, re-coarctation of the aorta may lead to worsening systemic hypertension, coronary artery disease and/or congestive cardiac failure. CMR follow-up after coarctation repair will detect re-coarctation as well as those with aortoventricular disturbances, who require more frequent non-invasive surveillance .The unique potential of CMR in hypertensive heart disease implies a high number of indications to be developed in the future, both in diagnosis and in risk stratification of future cardiovascular events. These include analysis and quantification of regional myocardial mechanics, which will allow detection of subtle decay in systolic function, detection and quantification of diffuse myocardial fibrosis, assessment of atrial mechanics, and assessment and quantification of aortic flow mechanics.The prognostic value of measuring diffuse and focal myocardial fibrosis in predicting future cardiovascular events such as heart failure or arrhythmias also hold promise with a potential role for monitoring the response to antihypertensive, antifibrotic drugs. Parameters of atrial function and wall fibrosis should also be tested for prediction of developing atrial fibrillation.CMR provides a comprehensive assessment of hypertensive cardiovascular disease. In less than an hour, ventricular and aortic measurements are obtained with high accuracy and reproducibility, the pathophysiological consequences of hypertension can be assessed and several quantitative parameters can be obtained with high reproducibility and accuracy that can be of use in the follow up of these patients. Concurrently, several secondary causes of hypertension can be ruled out in the same study. With respect to prognostic assessment, the development of T1 mapping sequences for quantification of myocardial fibrosis might play an important role in the risk stratification of hypertensive heart disease.The authors declare that they have no competing interests.AMMG carried out the review of literature, manuscript design and drafting. RHM has been involved in revising the manuscript critically for important intellectual content, carried out the final revision and approved the manuscript to be submitted. Both authors have read and approved the final manuscript.