The objective assessments of left ventricular (LV) and right ventricular (RV) ejection fractions (EFs) are the main important tasks of routine cardiovascular magnetic resonance (CMR). Over the years, CMR has emerged as the reference standard for the evaluation of biventricular morphology and function. However, changes in EF may occur in the late stages of the majority of cardiac diseases, and being a measure of global function, it has limited sensitivity for identifying regional myocardial impairment. On the other hand, current wall motion evaluation is done on a subjective basis and subjective, qualitative analysis has a substantial error rate. In an attempt to better quantify global and regional LV function; several techniques, to assess myocardial deformation, have been developed, over the past years. The aim of this review is to provide a comprehensive compendium of all the CMR techniques to assess myocardial deformation parameters as well as the application in different clinical scenarios. Myocardial deformation imaging has shown to detect early contractile dysfunction in a number of cardiovascular diseases. In an effort to better characterize biventricular function, several imaging techniques have been developed to assess myocardial deformation in the context of its very complex architecture –3. The lL, usually in end systole) and is expressed as a percentage. It is determined by the following formula:Myocardial strain (MS) measures the degree of deformation of a myocardial segment from its initial length  to its maximum length (There are various definitions of strain: 1) Lagrangian LagrangiLongitudinal strain represents the longitudinal shortening from the base to the apex, and it is expressed by negative values. Radial strain is the radially directed myocardial deformation towards the centre of the LV cavity and indicates the LV thickening and thinning motion during the cardiac cycle; it is expressed by positive values. Circumferential strain derives from LV myocardial fibre shortening along the circular perimeter observed on a short-axis view, and it is consequently represented by negative values. Strain rate represents the rate at which those deformations occur [Following the different directions in which the myocardium deforms, longitudinal, circumferential and radial strain can be calculated. ns occur , 7. LV tns occur  and is dns occur  (Table 1Cardiovascular magnetic resonance (CMR) has emerged as the reference standard for the evaluation of biventricular morphology and function. In the last decades, several CMR techniques have been developed to measure cardiac muscle motion and deformation –13. FromCMR tagging was first introduced by Zerhouni et al. . It consVisual assessment of tag movement provides immediate information on regional wall motion abnormalities (WMA). However, for quantitative analysis, several post-processing semi-automated methods have been developed. The FINDTAGS software is based on the detection and tracking of tag lines in the image. Optical flow techniques are based on the tracking of pixels from frame to frame based on constant brightness, which means that they identify the brightness of a pixel and then look for a nearby pixel that has a similar signal intensity. Harmonic phase (HARP) analysis tracks pixels from frame to frame, based on a constant phase; due to its almost fully automated nature, HARP is the most widely used method . AlthougPhase velocity mapping (PVM) was first used to measure velocities inside the heart, more than 30 years ago . It is bDisplacement encoding with stimulated echoes (DENSE) is a technique that encodes tissue displacement into the phase of an image. It consists of three radiofrequency pulses used to generate a stimulated echo, while gradients encode displacement into the signal phase . The seqStrain-encoded (SENC) imaging is a special modification of the CMR scanner software that enables the quantification of regional deformation of tissue. To calculate myocardial strain, SENC uses magnetization tags parallel to the image plane  combined with out-of-plane phase-encoding gradients along the selected direction , 27. TheFeature-tracking technology is a post-processing method that can be applied to routinely acquired cine CMR images. It is an optical flow  method, Many studies have provided normal values for myocardial strain assessed with CMR-FT Table , showingAdvantages of CMR-FT are mainly related to its post-processing nature as (1) it does not require additional image acquisition time in the scanner, (2) it can be easily applied to all CMR routine scans as it uses standard SSFP cine CMR images, normally acquired to measure biventricular volumes, and (3) it is rapid and semi-automated, with a short post-processing time. However, as previously stated, it is subjected to through-plane motion artefacts, and a good tracking requires high image quality with adequate spatial and temporal resolution . CMR tagSpeckle tracking echocardiography (STE) has been considered an accurate and convenient method to assess myocardial strain, being easy to perform and largely available . It is bClinical application of myocardial strain imaging has been increasingly assessed over the past few years.The application of myocardial deformation has been widely studied in ischemic heart disease (IHD). All myocardial strain components are impaired in infarcted territories, as compared to both adjacent and remote territories , 52, 53,Segmental analysis of strain also allows the identification of myocardial segments that will recover in function after an acute ischemic event , 52, 53;An emerging role of strain is in the assessment of myocardial ischemia. Dobutamine stress CMR (DS-CMR) with the addition of tagging has shown to be superior to DS-CMR without tagging in the detection of new regional WMA . AnalysiMyocardial strain is impaired also in non-ischemic heart disease (NIHD). Circumferential shortening is less than a third in patients with dilated cardiomyopathy (DCM) as compared to healthy volunteers ; as mid-Myocardial strain was impaired in patients with clinically diagnosed acute myocarditis and no other abnormal findings on CMR and in patients with CMR findings of myocarditis but preserved left ventricular ejection fraction (LVEF) , 64. CheFinally, myocardial strain might play a future role in tailoring treatment. Patients with severe aortic stenosis have impaired myocardial strain, irrespective of symptom severity, which is one of the criteria to time surgery ; therefoThe right ventricle has a complex anatomy  and function which makes it difficult to assess –70. CMR Similar to what it has been observed for LV strain, normal values of RV strain differ slightly between different studies, as a consequence of the different techniques used for the analysis. A recent study used the newer FT technique to determine normal values for RV myocardial strain; it estimates radial and circumferential strain from the short-axis images and longitudinal strain from cine long-axis images , pulmonary hypertension (PH) and arrhythmogenic right ventricular cardiomyopathy (ARVC).CMR-FT has been used in patients with repaired tetralogy of Fallot (rTOF) and compared to STE , 75, shoCMR tagging with SPAMM showed that all myocardial strain components are reduced in PH patients . The RV The assessment of both global and segmental RV functions is pivotal for the multi-parametric diagnosis of ARVC, and RV myocardial strain has proved to be an extremely useful tool –79. RV gAtrial function has been more and more recognized as an important element in many cardiac diseases, especially those characterized by high filling pressure and diastolic dysfunction. It consists of three components: reservoir function (collection of blood from pulmonary veins), conduit function (during the passage of blood to the left ventricle) and contractile pump function . Global measures, such as volumes and areas, are not enough to describe this complex function , 81, andThe analysis of myocardial deformation has shown to provide important prognostic information. A study on more than 500 patients referred to CMR for suspected cardiomyopathy, most of whom had no cardiovascular risk factors, showed that LVEF, the presence of LGE and impaired global circumferential strain were all associated with a worse outcome ) ; more inAssessment of both LV and RV myocardial strain has shown to be a useful tool to predict major adverse cardiovascular events (MACE); in a FT study on more than 300 patients, adding biventricular strain analysis to conventional ejection fraction assessment increased the detection of patients experiencing adverse outcome: LV global transverse strain and RV global radial strain proved to be the strongest predictors of MACE .Finally, in large populations of patients with repaired TOF, longitudinal and circumferential strains were associated with NYHA class, while bi-ventricular systolic function was not able to stratify patients according to their symptoms; moreover, both LV circumferential strain and RV longitudinal strain were predictors of adverse arrhythmic outcome , 88.Many CMR modalities have been developed to assess myocardial deformation, and the introduction of newer CMR software that allow myocardial deformation analysis based on post-processing methods, with no need to acquire extra pictures, has prompted the clinical application of myocardial strain imaging. However, in order to allow exclusion from the analysis of segments with suboptimal image quality, standardization in the manual contouring and automated evaluation of tracking quality is needed. Similarly, agreement between different vendors is mandatory, to ensure a comparable technological ground between different studies. Therefore, the limitations of each technique need to be considered before the data can be used in the clinical decision-making process.


Myocardial performance index (MPI) or Tei index is a Doppler-derived index of combined systolic and diastolic myocardial function, calculated as the sum of isovolumetric relaxation time (IRT) and isovolumetric contraction time (ICT) divided by the ejection time (ET).To evaluate the right and left ventricular systolic and diastolic function using MPI in children before and after liver transplantation.A cross-sectional study was conducted on 30 children with liver cirrhosis before liver transplantation, 30 age-matched comparison group at least 6 months after liver transplantation, and 30 aged-matched children without history of heart disease in Nemazi Liver Transplant Center, Shiraz, Iran, from April 2012 to April 2014. Echocardiographic evaluation was carried out with a GE Vivid 3 echocardiographic machine, using a 3-MHz probe with tissue Doppler imaging (TDI) software using conventional and TDI method.The mean±SD left ventricle Tei index in patients was 0.33±0.02 before liver transplantation, 0.34±0.02 after liver transplantation, and 0.33±003 in the comparison group (p=0.36). The mean±SD right ventricular Tei index was 0.35±0.04 in patients before transplantation, 0.36±0.46 after liver transplantation, and 0.28±0.04 in the comparison group (p<0.001). In addition, when TDI was used, the mean±SD left ventricular Tei index was 0.39±0.50 in patients before transplantation, 0.37±0.42 after liver transplantation, and 0.38±006 in the comparison group (p=0.32). The tissue Doppler-derived Tei index for the right ventricle was 0.37±0.04 in patients before transplantation, 0.37±0.04 after liver transplantation, and 0.33±0.05 in the comparison group (p=0.031). The left ventricular Doppler-derived Tei index had a significant (p=0.03) correlation with Child-Turcotte-Pugh (CTP) score (r=0.57).Left ventricular MPI with Doppler echocardiography was correlated with CTP score. Right ventricular MPI was significantly increased in patients with cirrhosis and did not improve 6 months after transplantation. Cirrhosis is a potential end-result of any progressive liver diseases, defined histologically by the presence of bands of fibrous tissue that link the central and portal areas and form parenchymal nodules. It can be post-hepatitis (after acute or chronic hepatitis) or post-necrotic (after toxic injury), or it can caused by intra-hepatic or extra-hepatic obstruction of bile flow . In chilCirrhosis is a condition that has a variety of clinical manifestations and complications, some of which can be life-threatening such as cardiovascular complications, portal hypertension, hepatorenal syndrome, hepatic encephalopathy, and porto-pulmonary hypertension .Cardiovascular complications of cirrhosis present with (a) reduction in afterload and then in preload caused by the central, splanchnic and peripheral circulation aberrancy and hemodynamic alterations triggered by humoral and nervous dysregulation; (b) cirrhotic cardiomyopathy characterized by presence of increased baseline cardiac output, systolic and diastolic dysfunction and electrophysiological abnormalities; and (c) porto-pulmonary hypertension , 5.Liver transplantation should be considered for patients with decompensated cirrhosis . The mosMPI was firstly introduced by Chuwa Tei and colleagues in 1995, as a simple and reproducible Doppler index of combined systolic and diastolic myocardial performance in patients with primary myocardial systolic dysfunction, calculated as the sum of the isovolumetric relaxation time (IRT) and isovolumetric contraction time (ICT) divided by the ejection time (ET) .The objective of this study was to evaluate the right and left ventricular systolic and diastolic function, using MPI, in children before and after liver transplantation.In this cross-sectional study 30 children with liver cirrhosis before liver transplantation, 30 age-matched comparison group at least 6 months after liver transplantation, and 30 aged-matched children without a history of heart disease were investigated in Nemazi Liver Transplant Center, Shiraz, Iran, from April 2012 to April 2014. The patients’ demographic data including weight, age, and sex were recorded. PELD-MELD score and the Child-Turcotte-Pugh (CTP) scores were calculated to evaluate liver disease severity. [Study ProtocolThe study was approved by the research ethics committee of the university, and written informed consents were obtained from patients’ guardians. Age-matched pediatric patients who had no heart disease, underwent the same echocardiographic studies as the comparison group.Echocardiographic ExaminationEchocardiography was performed with a GE Vivid 3 echocardiographic machine, using a 3-MHz probe with tissue Doppler imaging (TDI) software. Tei index was obtained by conventional and TDI method. For Doppler interrogation, we measured three consecutive beats, averaging the values, and assessing the interval from the cessation to the onset of mitral or tricuspid inflow, equal to the sum of the isovolumetric contraction time (ICT), ejection time, and isovolumetric relaxation time (IRT), designated as ‘a’ in the equation shown below. The duration of ventricular ejection from the onset to the end of aortic or pulmonary ejection was designated as ‘b’ in the equation. The Doppler-derived Tei index, combining systolic and diastolic function of either ventricle, was then calculated as (a–b)/b.TDI was obtained with the sample volume placed on the lateral corner of the mitral annulus and, subsequently, on the medial  corner from the apical four-chamber view. In each region, systolic (S) wave, early diastolic (Ea), and late diastolic (Aa) velocities and ejection time (ET) were recorded. Also, the ICT and the IRT were measured from the end of the mitral annular velocity pattern to the onset of the S wave and from the end of the S wave to the onset of the mitral annular velocity pattern, respectively. The TDI-derived Tei index (TDI-Tei), sum of ICT, and IRT divided by ET, was determined for the lateral mitral annulus. Time interval measurements were obtained from three consecutive beats, and then the data were averaged.Statistical Analysis® for Windows® ver 16 using one-way ANOVA, Student’s t test, and Pearson’s correlation analysis. A p value <0.05 was considered statistically significant.Statistical analyses were performed by SPSSThe median age of the three studied groups was 5.0 (range: 0.6–18) years. Sixteen (53%) patients were male and 24 (46%) were female. Laboratory data before and after liver transplantation are summarized in M-mode echocardiographic findings of patients before liver transplantation were not significantly different from those of the comparison group . In all Doppler echocardiographic parameters are shown in Tissue Doppler echocardiographic parameters are shown in We also evaluated the correlation between echocardiographic parameters, demographic data and blood tests. The left ventricular Doppler-derived Tei index had a significant (p=0.03) correlation with CTP score (r=0.57). The PELD-MELD score did not have any significant correlation with LVMPI measured by Doppler echocardiography.We studied cardiac systolic and diastolic function before and after liver transplantation in children with cirrhosis. We found that the echocardiographic parameters of children with cirrhosis measured before and after transplant did not have significantly different. This means that the right and left ventricular systolic and diastolic function did not improve six months after liver transplantation. Furthermore, the left ventricular MPI echocardiography showed a correlation with CTP score level. In addition, the right ventricular MPI in patients before and after transplantation was significantly higher than the that in the comparison group. Cirrhosis-associated cardiomyopathy is defined as impaired contractile responsiveness to stress or altered diastolic function with electrophysiologic abnormalities in the absence of other known cardiac disease. This syndrome is seen in approximately 40%–50% of adult patients with cirrhosis . The incClinical characterization of cirrhosis-associated cardiomyopathy includes systolic dysfunction, diastolic dysfunction, pulmonary hypertension, and electrophysiological dysfunction. The high resting cardiac output and lower filling pressures in patients with cirrhosis are partially explained by low systemic vascular resistance and increased arterial compliance . Diastolic dysfunction is a prominent feature of CAC. This describes impairment of ventricular filling as a result of alterations in the receptive ventricular properties. The underlying mechanism of diastolic dysfunction in cirrhosis is increased myocardial wall stiffness, most likely due to myocardial hypertrophy, fibrosis, and sub-endothelial edema , resultiHepatic dysfunction is categorized by CTP score; we can see more increase in cardiac output in response to exercise in patients with mild liver damage compared to patients with moderate to severe liver damage .et al [et al [et al [et al [Hepatic cirrhosis is associated with systemic circulatory and cardiac changes that are hyperdynamic circulation with increased cardiac output and heart rate and reduced systemic vascular resistance over time due to splanchnic arterial vasodilation . Patientet al , reportel [et al , also rel [et al , reportel [et al , reportePulmonary acceleration time is increased in post-transplantation period that could be an indirect evidence of decreased pulmonary pressure in post-transplant recipients. Increased left ventricular posterior wall diameter and inter-ventricular wall thickening in pre- and post-liver transplantation patients may represent positive response to increase in the end-diastolic volume. In conclusion, left ventricular MPI measured with Doppler echocardiography is correlated with CTP score level. Right ventricular MPI is significantly increased in patients with cirrhosis and does not improve six months after transplantation.


The study of myocardial viability is of great importance in the orientation andmanagement of patients requiring myocardial revascularization or angioplasty.The technique of delayed enhancement (DE) is accurate and has transformed thestudy of viability into an easy test, not only for the detection of fibrosis butalso as a binary test detecting what is viable or not. On DE, fibrosis equal toor greater than 50% of the segmental area is considered as non-viable, whereasthat below 50% is considered viable. During the same evaluation, cardiacmagnetic resonance (CMR) may also use other techniques for functional andperfusion studies to obtain a global evaluation of ischemic heart disease. Thisstudy aims to highlight the current concepts and broadly emphasize the use ofCMR as a method that over the last 20 years has become a reference in thedetection of infarction and assessment of myocardial viability. Using a quick protocol, we are able to obtain information onanatomy, function, tissue characterization, perfusion, and viability, with excellentspatial resolution and image quality. CMR uses different techniques to assessviability, and the technique of delayed enhancement, 2 and, consequently,have improved survival.4The precise determination of myocardial muscle with or without viability is ofextreme importance in the management of a patient with cardiac dysfunction. Viablemuscle has a potential for contractile recovery and, therefore, a patient withischemic cardiomyopathy and ventricular dysfunction may improve his functionalcapacity after myocardial revascularization6 becoming one of the most importantcauses of sudden death.The identification of infarcted muscle, even in silent (occult) infarction, isimportant because this tissue can be a substrate for ventriculartachyarrhythmia,CMR presents a state of continuous development, with new tools added at each year toimprove this already powerful technology.This article aims to highlight the current concepts and, in a general way, emphasizethe use of CMR as a method that has become over the past 20 years a reference in thedetection of myocardial infarction and assessment of viability.7 Asillustrated .Drug treatments (beta-blockers), thrombolysis, and/or adequate reperfusion byangioplasty can modify the relationship between the duration of the coronaryocclusion and the final size of the infarction. The current problem is that manystudies have demonstrated this in animal models, but have failed to demonstratethe same in clinical studies.7 when hequestions the final results of these studies since the reduction of theinfarction was measured in the animal model as a fraction of the area at risk.The area at risk is a portion of the myocardium that was hypoperfused duringcoronary occlusion but did not "die" (infarcted). Some studies have attempted touse sestamibi in the emergency room to assess the area at risk,10 but were unable to do so. Weconsider this outcome as a methodological problem. CMR should be used in thisclinical situation, since it does not interfere with the decay of theradiotracer throughout week and time and may, in addition to using the techniqueof delayed enhancement to quantify the size of the infarction, resort to the T2technique (edema) in order to assess the area at risk.11We agree with Arai12 the final setting after an injury induced by hypoxia in thelong term is the replacement of the tissue by fibrosis, defined as replacementfibrosis. In this fibrosis, the area of the infarction is replaced by a scarcontaining collagen, lacking proteins or structures required for a normalsegmental contraction. However, the process of regeneration and the infarct sizemay influence the possibility of the infarction developing changes in thesegmental contractility. In other words, a small myocardial infarction (< 25%of the segment area) probably will not lead to changes in myocardialcontractility; on the other hand, a large myocardial infarction (> 75% of thesegment area) will promote segmental or regional hypokinesia/akinesia. Thus, thedetection of the infarct as present or absent is essential but equally importantis the infarct size. Therefore, this replacement and the absence of the tissularactin-myosin mechanism promote loss of contraction and diastolicproperties,13 whichmay or may not be macroscopically undetectable by the contractile capacity ofneighboring tissues and by the regeneration induced in the segment.In addition to evidence of the existence of some level of myocardial regenerationafter acute myocardial infarction,15 This knowledge is adifferential, because even very small areas with delayed positive enhancement,such as approximately 1% of the left ventricular mass, have large prognosticimplications.17The most important thing is that CMR, with the technique of delayed enhancement,is able to detect myocardial infarction (fibrosis) not detected by clinicalevaluation or other methods, such as ECG, echocardiography, andscintiscan.20The detection of viable myocardium reflects the presence of living myocytes, andthis does not depend on the existence or not of contractile dysfunction orresponsiveness of the muscle to external stimuli. Therefore, it is already wellestablished the disconnection between viable myocardium and its pattern ofcontractility, with several studies demonstrating that the viable muscle couldbe hypokinetic by chronic cardiomyopathy due to hypoperfusion or acute ischemiccardiomyopathy.21The study of myocardial viability is recommended for patients with ischemiccardiomyopathy, and the interest is to know whether a possible revascularizationprocedure will promote improvement in left ventricular systolic function. Inthis case, the potential for improvement in contractility will depend on twoconditions: first, the muscle must be alive (absence of delayed enhancement);second, the muscle must be ischemic, being this the mechanism of dysfunction.Therefore, myocardial viability is said to be present when a hypokinetic orakinetic muscle features areas without necrosis whose coronary supply is knownto be reduced. With this, we imagine that a procedure that restores the bloodflow is one that removes the infarct from a hibernating state.25The terms "stunned" and "hibernating" myocardium are used to describe thisphenomenon of a condition that is viable, albeit dysfunctional. The reversiblephenomenon of the stunned myocardium is identified when the contractiledysfunction develops during acute and intense ischemia, persisting even afterrestoration of the coronary flow, typically for a period of days to weeks. Thereversible phenomenon of the hibernating myocardium, in turn, is identified whenthe contractile dysfunction takes place during chronic ischemia that is notstrong enough to cause cellular necrosis. In this case, the phenomenon fits intothe hypothetical concept of pathophysiologic mechanisms capable of inducingadjustment in perfusion-contraction coupling, at a very low level of both,reducing its contractility due to low oxygenation, and avoiding itsdeath.26 The microvascular obstruction is a marker of severemyocardial injury, which is also associated with worse prognosis after acutemyocardial infarction.27Also noteworthy was the demonstration, as early as 1998, of the CMR ability todetect and quantify the area of microvascular obstruction (no-reflow) associatedwith an acute myocardial infarction.Unfortunately, the myocardial viability is still highly associated with thedetection of segmental or regional contractile dysfunction and is still widelyused in the reasoning of clinical cardiologists when they think about thepotential of contractile recovery, most likely because the echocardiography isthe method most commonly used in clinical practice. With this, we demonstrate in28 summarized themost accurate markers of infarction, classifying them from less to more preciseor perfusional (first-pass perfusion) alterations, respectively, oreven perform combined protocols for multimodal assessment of themyocardium.The use of cine magnetic resonance (cine MRI) can assist in theassessment of segmental and global contractility, or even parietalsegmental thickness. These data continue to be of great importance,but there are studies, such as that of Perrone-Filardi etal.,Even with all of the sequences described above, the gold standard inmagnetic resonance for the assessment of myocardial viability is thedelayed myocardial enhancement study, as discussed below.39 This approach is simple andbased on the assumption that infarcted tissue or tissue with increasedextracellular space accumulates gadolinium and appears with increased signal onmagnetic resonance images , mainly in the images acquired10 minutes after infusion of the contrast medium.Studies of delayed myocardial enhancement using T1-weighted magnetic resonancetechniques have been reported in the literature since the mid-1980s.40 and Simonetti etal.41 developed atechnique able to override gray muscle , highlighting the muscle thataccumulates the contrast (infarcted muscle). This technique is currently used ona large scale and is part of all protocols of cardiac examination by magneticresonance. This has enabled high-resolution images of acute and chronicinfarction, demonstrating a high correlation with histopathological studies andvirtually equal measurement of myocardial size and viability(myocytes).42Initially, the shades of gray and white representing the normal and infarctedmuscle overlapped due to the inability of the old sequences in detecting lesionswith mild to moderate contrast accumulation. In the late 1990s and early 2000s,Kim et al.The acquisition of delayed contrast-enhanced images is relatively simple and doesnot require pharmacological or physical stress. Using only a peripheral venousline, we can perform infusion of the intravenous contrast medium gadolinium.After obtaining the scout images, we perform a global and segmental functionalstudy of the right and left ventricle with the cine MRI technique (see specificsection). We can, at this moment, infuse gadolinium 0.10 or 0.20 mmol/kg and,after approximately 10 minutes, acquire images of viability (delayedenhancement) of the myocardium in the short, long two-chamber, and outflow axes,as the acquisition of the cine MRI images. Each acquisition of delayedenhancement takes approximately 10 seconds and one apnea, with the entireexamination taking an average of 30 minutes .45 The besttechnique is chosen and adapted depending on the clinical condition of thepatient, the manufacturer of the available equipment, and the experience of thelocal group.Delayed enhancement is a technique that can be acquired in different ways, suchas 2D, 3D, gradient-echo or inversion-recovery techniques, in addition to thoseperformed in apnea or free breathing.In practice, an assessment of delayed enhancement (viability) with a short andobjective protocol can also be carried out. With this, we are able to abolishthe use of cine MRI images and infuse gadolinium alone, acquiring the delayedcontrast-enhanced images, which can take only 15 - 20 minutes to be carriedout.46 The mostfrequently used ones are gadopentetate dimeglumine, gadodiamide,gadoversetamide, and gadoterate meglumine. There is an increasing need for theadministration of lower doses of these contrasts to avoid possible adverseeffects . These findings havealso been identified with high reproducibility in the clinical setting inacute48 andchronic49infarction.Clinical and animals studies have shown that areas with high signal intensity inthe technique of delayed enhancement are highly reproducible when compared withthe pathology, especially if the inversion time is properly used. In an animalmodel, Amado et al.27 In accordance with theclinical definition, viability is deemed as present when below 50% of the areaof the affected segment, and absent when greater than 50%. We know that this isa categorization of an almost linear phenomenon and that the smaller thenecrosis, the greater the probability of improvement in contractility of thesegment after revascularization. The reverse is also true, since the greater thenecrosis, the smaller the probability of contractile recovery afterrevascularization.The assessment of viability by magnetic resonance may be performed by adichotomous approach, strengthened by the Brazilian guidelines.50In addition to assessment and quantification of fibrosis/global viability, CMRroutinely evaluates the potential of contractile recovery in a segmental manner,attempting to characterize the 17 segments of the left ventricle. We divide thegroups of quantification of delayed enhancement into five, according to theprobability of contractile recovery of the studied segment :21,50i.e., zero fibrosis/infarction, with a highprobability (around 80%) of contractile improvement.The first is the myocardium without any delayed enhancement,The second comprises a group with 1 - 25% of the area of the segmentwith delayed enhancement. In this group, the probability ofimprovement decreases to 60%.The third group includes between 26 - 50% of delayed enhancement,compromising the cardiac muscle, with a probability of improvementin contractility after revascularization of around 40%.The fourth group has 51 - 75% of compromised muscle and may presentan improvement in contractility in up to 10% of the cases. In thisgroup, we believe that the decision between revascularization andclinical treatment should be widely discussed. The risks ofangioplasty or surgery may outweigh the benefits ofrevascularization, and this depends greatly on the experience andstructure of each institution.The fifth group comprises those having more than 75% of the area ofthe myocardial segment compromised, with the potential ofcontractile recovery of less than 1%.51In addition to this segmental evaluation, we must consider a probabilistic issuerelated to a certain degree of biological uncertainty, but which we can apply tothe 17 segments of the left ventricle. This should be done because theimportance will lie in the degree of global systolic functional improvement ofthe left ventricular ejection fraction. In this way, the improvement in theglobal function after revascularization may be predicted with great accuracywhen considering the threshold of at least 10 viable or normal segments amongthe 17 segments of the left ventricle according to the classification of theAmerican Heart Association (AHA).52 in order to facilitate thecorrelation with other imaging methods.The report of a study of myocardial viability must necessarily include themeasurement of the left ventricular mass, quantify the area of fibrosis and thetransmural extent of infarction, and identify the 17 segments of the leftventricle, according to the studies of Cerqueira et al.,53 or by means of a manual software(planimetry),47semiautomatic 54 or automatic .56There are several ways to quantify myocardial fibrosis, all of which withscientific value, with some applications being more accurate than others. Weencourage the description in the report of the method used to quantify thefibrosis, which may be visual Multi-Ethnic Studyof Atherosclerosis) study in the work by Rizzi et al.,57 several techniques are mostlyused to quantify the infarction. We have the visual technique, planimetry, the techniques of standard deviation,54 full-width half maximum (FWHM),58 and the possible correction ofthe image noise.59 We mustremember that all scientific studies exclude images with low technical qualityand with artifacts from breathing or acquisition of images, not being possiblethe analysis by these techniques. Of course, the semiautomatic analysis withmanual correction and discard of artifacts becomes the method of choice forquantifying fibrosis and infarction in the day-to-day clinicalsetting.68As already well studied and characterized by the MESA . Other studies had very similar results, and webelieve that the use of CMR in post-infarction must be routinelyencouraged.72CMR has the ability to differentiate these two clinical situations using thetechnique of delayed enhancement. This concept was very well studied in the workof Choi et al.,21 In In addition to the ability to characterize the infarction, the technique ofdelayed enhancement is able to modify in practice some diagnosis in ourday-to-day clinical setting. As an example, it is relatively common for patientswith suspected infarction and normal catheterization to have a definitiveetiologic diagnosis demonstrated by CMR, such as myocarditis, vasospasm withreperfusion or, in other cases, small myocardial infarctions caused by occlusionof small vessels undetected in the first analysis on catheterization .50 demonstrated theimportance of this technique in predicting segmental and global functionalimprovement after revascularization by surgery or angioplasty.For over 14 years, magnetic resonance with the technique of delayed enhancementhas been used in patients with chronic ischemic disease. The work of Kim etal.The transmural extent of infarction is currently of high efficacy to identifythose patients who will or will not respond to revascularization. CMR must beused routinely in centers that have this technology.73 the inverse relationship between the transmural extentand functional recovery after revascularization was significant (p <0.002).In a study published by Schvartzman et al.,Based on these data, we consider as not being important the use of cutoff values,as currently used, dichotomizing the viability over 50% of the transmural extentas non-viable muscle and results inferior to that as viable muscle. We believethat this is not physiological and may harm some patients who could respond torevascularization even when more than 50% of the transmural extent is affected,since each segment may have an interdependent microcirculation with a certaindegree of functional improvement.When we think of treatment for ischemic disease, we must also include chroniccases of patients with established cardiac failure who depend on theoptimization of the clinical treatment.74 magnetic resonance was used in patients with chroniccardiac failure and an ejection fraction of 26 ± 11% before and after 6months of therapy with beta-blockers. These authors demonstrated improvement inmyocardial remodeling and global and segmental function of viable segments.The use of delayed enhancement and measurement of the transmural extent ofinfarction has been demonstrated to be a great predictor of response to clinicaltreatment. In the work by Bello et al.,Surgical Treatment for Ischemic Heart Failure) study wasthe lack of use of magnetic resonance imaging in the identification ofmyocardial viability since this is a method currently proved to have greatreproducibility and increased accuracy. The study randomized patients withischemic cardiomyopathy who randomly underwent myocardial revascularization orclinical treatment. This scientific design prevents the confusion betweenmedical decision and clinical condition of the patients, and has a greatstatistical ability to identify the real benefit of choosing between one orother therapy. Unfortunately, even using methods known in the literature such asstress echocardiography and myocardial scintigraphy, the study of viability bythese two methods had no ability to identify patients who would benefit from thetherapy. Therefore, the STICH study was a negative study for the concept ofanalysis of viability, which left open the possibility of this hypothesis beingtested by magnetic resonance.21One of the major criticisms in academia regarding the design of the STICH(75 showed that the viability, as detected by CMR, was of greatimportance in differentiating the group with ischemic cardiomyopathy and severedysfunction of the left ventricle who would benefit from myocardialrevascularization. Currently, CMR should be performed in all patients withischemic cardiomyopathy with left ventricular dysfunction for characterizationof myocardial viability.27The viability by CMR has been tested, and the results were very different fromthe STICH study. One of the main studies published in the Journal of theAmerican College of CardiologyMagnetic resonance is able to assess the myocardial viability through a series ofdifferent techniques and methods. These techniques can assess metabolic, functional,and morphological alterations and tissue characteristics, in addition to evaluatingcellular viability.The technique most widely used and with the greatest potential for clinical use isdelayed myocardial enhancement. This technique is able to identify in a simple andobjective way areas of hyperintense signal in the myocardium after administration ofthe contrast agent, with excellent histologic correlation to characterize areas withinfarction/fibrosis.The technique of delayed enhancement can evaluate myocardial viability not only by adichotomization between absent and present but also by an almost linear continuumbased on the ability of each tissue to recover the contractile capacity.In addition to the viability, the delayed myocardial enhancement has the ability todetect occult infarcts, characterize lesions that increase markers of myocardialnecrosis, and establish an etiological diagnosis of cardiomyopathy, and it maypredict an arrhythmogenic potential and risk of death in patients with ischemic ornonischemic myocardiopathy.


Increased levels of ADC were associated with reduced peak systolic and early diastolic circumferential strain rates across all subjects. Contrast-free DW-CMR is an alternative sequence to ECV for the evaluation of fibrosis extent in HTN LVH and HTN non-LVH, while native T1 has limited value.This study assessed the extent of fibrosis and the relationship between the ADC value and systolic strain in hypertensive patients with left ventricular hypertrophy (HTN LVH) and hypertensive patients without LVH (HTN non-LVH) using cardiac diffusion-weighted imaging and T1 mapping. T1 mapping was performed in 13 HTN LVH , 17 HTN non-LVH , and 12 normal control subjects  with 3.0 T MRI using cardiac diffusion-weighted imaging and T1 mapping. HTN LVH subjects had higher native T1 (1233.12 ± 79.01) compared with controls (1133.88 ± 27.40) (p < 0.05). HTN LVH subjects had higher ECV (0.28 ± 0.03) compared with HTN non-LVH subjects (0.26 ± 0.02) or controls (0.24 ± 0.03) (p < 0.05). HTN LVH subjects had higher ADC (2.23 ± 0.34) compared with HTN non-LVH subjects (1.88 ± 0.27) or controls (1.61 ± 0.38), (p < 0.05). Positive associations were noted between LVMI and ADC  and between LVMI and ECV . ADC was also related to an increase in ECV (R LVH is a relatively independent high-risk factor to increase mortality and cardiac morbidity in certain HTN patients6.Hypertension (HTN) is a common cardiovascular disorder and a primary cause of mortality and morbidity worldwide. Afterload and increasing arterial stiffness results in arterial hypertension, which leads to myocardium remodeling due to cardiomyocyte hypertrophy, fibroblast stimulation and increased collagen constitution. A progressive accumulation interstitial collagen fibers and left ventricular hypertrophy (LVH), which present with diffuse myocardial fibrosis, was demonstrated in necropsy examinations8. Reliance on LV hypertrophy (LVH) and its regression to stratify risk has limitations10. Therefore, evaluating cardiomyocyte hypertrophy non-invasively and tissue fibrosis in pathological LV remodeling specifically with therapies targeting these fundamental pathologies would be fundamental to pre-clinical drug evolution and the targeting of patients with the greatest potential benefit.Hypertensive heart disease may exhibit different extents of fibrosis in different disease stages. Therapies specifically directed at hypertrophy and interstitial fibrosis may exhibit limited efficacy because of late therapy application 12, post-contrast T1 mapping15 and ECV mapping17. The latter two techniques provide quantitative measures  that further characterize the degree of fibrosis. However, contrast is required in these conventional techniques, and contrast is contraindicated in patients who suffer renal insufficiency. Contrast-free quantitative cardiovascular magnetic resonance techniques, such as pre-contrast T1 mapping18, diffusion imaging21, T1 ρ imaging22, and creatine chemical-exchange imaging23, have revealed myocardial fibrosis  in chronic myocardial infarction patients. Pre-contrast T1 mapping24 and diffusion-weighted imaging26 demonstrated extra value in the detection of diffuse myocardial fibrosis.Recent cardiovascular magnetic resonance approaches to determine diffuse myocardial fibrosis involve a sequence of LGE imagingConsequently, the estimates of ADC may also be useful for the identification of diffuse and replacement fibrosis when an adequate extent of fibrosis appears (≥20%). We hypothesized that HTN LVH patients would exhibit diffuse myocardial fibrosis as evaluated by an ADC value compared to normotensive controls and HTN non-LVH. We also postulated that HTN LVH subjects would exhibit greater fibrosis, reduced systolic strain, and early diastolic strain rate compared to the other 2 groups.2, or reduced systolic function (ejection fraction [EF] <45%) were excluded. Subjects with a history of HTN with diastolic blood pressure (DBP) greater than 90 mmHg or systolic blood pressure (SBP) greater than 140 mmHg on at least two office readings27 or who were taking 1 or more medications for hypertension were included. Subjects were classified as having LVH if their LV mass index (LVMI) using cardiac MRI was >81 g/m2 in men or >61 g/m2 in women as defined previously by Olivotto et al.28. Hypertensive subjects not meeting the criteria for LVH as defined in the preceding text were included in the HTN non-LVH group. Healthy volunteers who were normotensive with no history of HTN were enrolled in the control group.Seventeen subjects with HTN non- LVH , 13 subjects with HTN LVH (56.23 ± 3.30 years), and 12 normotensive controls  were enrolled between November 2014 and October 2015. The Ethics Committee of Shanghai Renji Hospital approved all protocols, which were performed in accordance with approved guidelines. Informed consent was obtained from all subjects before the study began. Patients with a history of HTN and confirmed LVH using any imaging modality were considered for this study. Patients with any other causes of LVH, known coronary disease, significant valvular disease, patients with renal impairment with a glomerular filtration rate no greater than 45 ml/min/1.73 m2, but modified to minimize artifacts as needed and voxel size 1.2 × 1.2 × 7 mm3). Standard short-axis and long-axis orientations were obtained. A single breath-hold, steady-state free precession modified look-locker inversion recovery (MOLLI) technique30 used to generate T1 mapping. This protocol is a robust 5 s(3 s)3 s, which indicates at least 5 seconds for acquisition with images in 2 inversions, at least 3 seconds for recovery, and at least 3 seconds for acquisition with images in a second inversion. The starting TI (to the first image readout) was 100 ms with an increment of 80 ms for the subsequent look-locker trains. The pulse sequence parameters included: TE 1.1 ms, TR 2.5 ms, flip angle 35°, FOV 300 × 300 mm2, and voxel size 2 × 2 × 10 mm3. T1 mappings were obtained in basal and mid-ventricular short axis slices pre-contrast and 15 min after a bolus intravenous injection of 0.15 mmol/kg gadopentetate dimeglumine (Gd-DTPA) . Hematocrit (Hct) was measured in all included subjects. LGE images were obtained approximately 10 minutes after bolus injection of 0.15 mmol/kg Gd-DTPA. A 2D Phase-Sensitive Inversion-Recovery sequence was used . Diffusion encoding of the DW-CMR31 was performed during the most quiescent period of the cardiac cycle, which was identified using standard CINE imaging , and mapping was phased to match the T1 and LGE breath-hold positions by the exhalation respiration. The following parameters of the compensated spin echo diffusion encoding sequence  were used: flip angle, 90°; repetition time msec/echo time msec, 4.1/2.0; bandwidth, 1449 Hz/pixel; echo train length, 61; 152 × 122 matrix; field of view, 230 × 230 mm; and voxel size, 1.2 × 1.2 mm2. The section thickness was 10 mm.Cardiac MR was performed using a 3.0-Tesla MR machine . A steady-state free precession sequence was used to evaluate LV mass and cardiac function analysis for cine imaging. The following sequence parameters were used: repetition time (TR) 2.8 ms, echo time (TE) 1.4 ms, flip angle 45°, field of view (FOV) , and mapping was phased to match the T1 and LGE breath-hold positions by the exhalation respiration. The following parameters of the DW single-shot EP imaging sequence were used: flip angle, 90°; repetition time msec/echo time msec, 800/77; bandwidth, 1449 Hz/pixel; echo train length, 61; 152 × 122 matrix; FOV, 230 × 230 mm; and voxel size, 1.2 × 1.2 mm2. The section thickness was 10 mm.Analyses were performed  using cvi42 . End-systolic endocardial and end-diastolic and epicardial cavity regions were plane-metered for each slice of the short-axis. The LV mass, end-diastolic volume, and end-systolic volumes were determined and indexed to body surface area. LV mass was measured from the end-diastolic image frames using the validated CVI42. We included papillary muscles in measurements of LV mass as suggested in the recent Society for Cardiovascular Magnetic Resonance guidelinesAll continuous data are presented as the means ± standard deviation (SD). All statistical analyses were performed using SPSS version 18 . Continuous variables were analyzed using a two-sided Student’s non-parametric or t-tests when suitable. Statistics of variance (ANOVA) with Bonferroni correction were performed for multiple comparisons. Pearson’s correlation coefficient was used for correlation analyses for linear associations, and the Spearman’s rank correlation coefficient was used for monotonic nonlinear associations. A p value < 0.05 was regarded as statistically significant.2 in women or 81 g/m2 in men as measured by CMR. A total of 30 patients were included in the study, and these subjects were further divided into 13 HTN LVH subject (56.23 ± 3.30 years) and 17 HTN non-LVH subject . Twelve normal volunteers  were also included in the study. Table Thirty-five HTN patients were primary involved in the analysis. The average age was 55 ± 5.56 years, and 63% were female. Five of the 35 HTN subjects were excluded because they did not meet the criteria for LVH as an LVMI that was greater than 61 g/mThe T1 values were significantly higher in the HTN LVH subjects versus controls . No significantly differences were found in T1 values between HTN LVH and HTN non-LVH . No significant differences were found in T1 values between HTN non-LVH and normal controls . ECV values were greater in HTN LVH subjects versus the normal control group  and HTN non-LVH subjects . There were no significant differences in ECV values between normal control and HTN non-LVH subjects. ADC values were significantly higher in HTN LVH subjects versus controls  and HTN non-LVH . There were no differences in ADC values between normal control subjects and HTN non-LVH subjects (Table 2 = 0.210)  Fig.  and betwPeak circumferential strains at basal and mid-ventricular levels were reduced in all HTN LVH subjects compared to normotensive control subjects Table . ADC cor32. The ECV is calculated from a combination of native and post-contrast calculations and reveals the volume fraction of extracellular space on a pixel-wise basis. Therefore, native T1 and ECV are sensitive to different compartments within the myocardium and may each reflect different aspects of the pathological changes of hypertensive heart disease. DWI interprets the underlying changes in the extracellular and intracellular spaces of the myocardium. A low b value of DWI may reflect the extracellular compartments, which records the changes in extracellular fibrosis. This study clinically disclosed the ability of DWI to serve as an alternative contrast-free sequence to ECV and LGE for diffuse fibrosis assessment. The present study extends previous research of the ability of DWI to observe replacement fibrosis26 and illustrated an extra value to visualize diffuse myocardial fibrosis presentations compared to LGE and ECV. Our preliminary experience using DWI in HTN patients supports the use of DW-CMR to distinguish different extents of fibrosis.This study demonstrated that T1 mapping and DWI using CMR revealed greater diffuse fibrosis as measured by ECV and ADC values in subjects with HTN LVH compared to HTN non-LVH and control subjects. Higher ADC values were associated with reduced peak systolic circumferential strain and early diastolic circumferential strain rate across all subjects. Native T1 levels were longer in HTN LVH subjects compared to normotensive controls. ADC, ECV and native T1 values exhibit different sensitivities to underlying changes in the intracellular and extracellular spaces within the myocardium. Native T1 is a function of the relaxation of water in the extracellular and intracellular compartments, and it may reflect changes in cellular hypertrophy and extracellular fibrosis. There is a fast water exchange between these compartments, and the contribution of the intracellular and extracellular compartments cannot be separated without contrast administration. Gadolinium contrast agents accumulate solely in the extracellular space. Therefore, the post-contrast T1 shortening is primarily due to a shortening of T1 relaxation time in the extracellular space 33. The mechanisms of the evolution and progression of different LVH patterns are not completely defined but involve the duration and severity of hypertension, the effects of cytokines and neurohormones, development factors, and hereditary predisposition34. Myocardial fibrosis leads to systolic and diastolic disorders, myocardial ischemia, and ventricular and atrial arrhythmias35. A solid correlation was demonstrated between increased myocardial collagen content and left ventricular diastolic disturbance using echocardiography36. This study also demonstrated that losartan treatment decreased the left ventricular stiffness and collagen content. This result suggests that the diffuse fibrosis observed in hypertensive patients is reversible using certain antihypertensive therapies. Reduction in diffuse fibrosis may improve diastolic function, systolic function, and outcomes. Therefore, measurement of diffuse fibrosis levels may serve as a therapeutic target of the efficacy of antihypertensive and other therapies.Myocardial fibrosis is a usual end point of numerous cellular and non-cellular pathological processes in hypertensive heart disease. The pathogenesis of hypertensive heart disease involves myocardium remodeling within the perivascular space, muscle fibrosis, medial hypertrophy of the intra-myocardial coronary vasculature, and cardiomyocyte hypertrophy37. The current research enhanced previous results because it examined the behavior of circumferential myocardial mechanics in relation to the extent of fibrosis and hypertrophy. The three subgroups  exhibited different degrees of replacement fibrosis, interstitial fibrosis and hypertrophy. We further revealed a positive correlation among the peak systolic circumferential strain, average e’SR, and increasing levels of diffuse fibrosis as measured using ADC, which is consistent with the expected relationship between myocardial function and fibrosis. One possible mechanism linking ADC to reduced systolic strain in HTN LVH patients may be increased extracellular matrix deposition, which leads to increased LV stiffness and results in reduced end diastolic muscle fiber length, cardiac muscle contraction and LV systolic strain. Previous studies demonstrated that diffuse fibrosis was associated with worsening systolic/diastolic function and adverse LV remodeling35. However, further larger multi-center studies are required to verify this hypothesis. Unlike other groups have found higher correlations, ADC vs ECV correlations were quite low. As we know varying amounts of fibrosis were frequently seen in hypertrophic cardiomyopathy (HCM), and can be detected by T1 mapping. But in some cases myocardial injuries also may be found in patients with HCM39. We guess the reason why other groups have found higher correlations than ADC vs ECV is that the myocardial injuries may influence the excellular volume.The present study demonstrated that HTN LVH subjects exhibited decreased peak systolic and significant e’SR and circumferential strain compared to normal control subjects. Our results are consistent with a previous study42, and it is a feasible method to overcome bulk motion. We used compensated spin echo diffusion encoding to ensure that the sequence was sufficiently insensitive to systolic bulk motions of the heart. Nguyen et al.43 also used DWI technique to detect diffuse myocardial fibrosis in hypertrophic cardiomyopathy patients and compare its performance with established T1 mapping. They reported that DWI is sensitive to determine diffuse myocardial fibrosis and is capable of characterizing the extent of fibrosis in HCM patients. The main outcome is similar as ours, the present study found DW-CMR is an alternative sequence to ECV for the evaluation of fibrosis extent in HTN patience. However, the presented work demonstrated several additional findings. The subgroup analysis of the ADC measurement for HTN LVH and HTN non-LVH patients confirmed the DWI was capable of characterizing the extent of fibrosis in HTN patient. Furthermore, the relationship between ADC and systolic strain in HTN patient was also analyzed. We noted that higher ADC values were associated with reduced peak systolic circumferential strain and early diastolic circumferential strain rate across all subjects. Which was consistent with the expected relationship between myocardial function and fibrosis.Conventional cardiac DWI sequence is highly sensitive to bulk motion, which may cause some false-positive results. It is also sensitive to some artifacts, especially artifacts associated with geometric distortions due to magnetic susceptibility differences across the imaging of different tissues and bulk motions. The ultimate signal intensity may be an invalid estimate for the mentioned artifacts. The magnetic susceptibility may be addressed using parallel imaging with zonal excitation. The DWI sequence used in the present study was compensated spin echo diffusion encoding. This sequence was used in several studiesUnlike conventional T1 MOLLI sequences, such as the 3(3)3(3)5 protocol, the sequence used in our research was a robust 5 s(3 s)3 s, which indicates that there were at least 5 seconds for the acquisition of images in 2 inversions, at least 3 seconds for a recovery, and at least 3 seconds for acquisition of images in a second inversion. Our MOLLI approach used “seconds” instead of “beats”. Therefore, the scan time was virtually independent from the heart rate. This method is unlike schemes that use “beats”, in which scan time depends strongly on heart rate. A new scheme is preferable over the original 3-3-5 scheme (3b(3b)3b(3b)5b) because of the significantly shorter breath-hold scan time and increased accuracy. The effect of variable heartbeats on T1 values may be excluded by using the new T1 MOLLI sequence in our research. The large spread of the HTN LVH group compared to the HTN non-LVH and controls may be attributed to the extent of myocardial fibrosis.The small sample size of the total and subset categories is the first limitation of the study, The effect of variables, such as age and gender, could not be assessed. A larger multicenter study is required to confirm our results for widespread clinical use. Secondly, there are circumstances in which good quality T1-maps are not obtainable. We could not perform native T1-mapping in 3 patients in our study because of significant arrhythmia. There are different methods of T1 mapping, and further research is needed to establish a standardized method of T1 mapping for clinical use, despite the recently published consensus guidelines for the use of T1 mapping. Our method used the standard MOLLI technique and produced similar results. Thirdly, the DWI method in the current study was based on the artificial result of the most quiescent period, which may generate diffusion preparation compensated by motion. Discrete triggering and/or the duration of end diastole was substantially shortened by the high and unstable heart rates of the subjects. Therefore, approximately half of the subjects required end systolic triggering. The automatic or semi-automatic techniques are more likely to be push-button techniques because of the triggering determinants of the ideal cardiac phase. Another predominantly realistic fault of the DWI method in the current research was the relative low spatial coverage (8-mm thickness x 4 slices with 32-mm coverage). Entire coverage (~80 mm) was realized using this DW-CMR method, but it required no less than 12.5 min of scan time. HTN subjects with greater LV masses are required to have a minimum scan of approximately 15 min to contain the entire LV (~100 mm) adequately. Consequently, the overall research design is limited by this technique. An estimate of the whole LV fibrosis load could not be assessed in the general research design.Contrast-free non-invasive quantitative DWI is a feasible alternative to the native T1 value and established contrast-enhanced ECV-CMR for the identification of diffuse myocardial fibrosis in HTN patients. HTN LVH patients exhibited greater diffuse fibrosis and reduced circumferential strain and circumferential strain rates compared to HTN non-LVH and control subjects. Diffuse fibrosis is linearly related to a worsening of circumferential strain, but variations in ADC among patients with LVH may provide insight into the differential expression of fibrosis and myocyte hypertrophy among patients with HTN. ADC measurement may be a useful novel target to monitor the efficacy of therapies for HTN patients.Supplementary Figure Legends


The timing of surgery in asymptomatic patients with aortic stenosis (AS) is controversial. Adverse LV remodeling is related to prognosis in AS. Cardiovascular magnetic resonance (CMR) can identify diffuse and focal myocardial fibrosis, by T1 mapping and late gadolinium enhancement (LGE) respectively, as well as myocardial perfusion reserve (MPR), which is inversely related to symptoms and an independent predictor of exercise capacity in severe AS. The aim of this study was to determine whether MPR and other CMR markers of LV remodeling are of prognostic value in asymptomatic AS.Asymptomatic patients with moderate to severe AS and matched healthy controls were recruited in this prospective, multi-centre study, and underwent echocardiography and a stress CMR at 3T. CMR analysis was blinded and undertaken in a core lab. Investigations were not reported unless there was a clinical indication. Patients were followed for 12-30 months and outcomes were adjudicated by 2 independent Cardiologists, blinded to test results. Clinical outcome was a composite of: the development of typical symptoms, major adverse cardiovascular events or aortic valve replacement over a median follow-up of 18 months.174 patients and 23 controls were recruited. Compared to controls, LV volumes, mass, MPR and LGE were significantly different in patients, but there was no significant difference in ECV. 60 patients had a clinical event during follow-up (34.5%). There was no difference in comorbidities between those with and without an outcome. After adjusting for sex: AS severity, MPR, valvulo-arterial impedance and LV mass/volume were univariate predictors of the outcome. CMR measures of fibrosis  did not predict outcome. On stepwise multivariate analysis, severe AS (HR 0.17 (0.07-0.43) p = 0.0002) and MPR (HR 0.60 (0.40-0.92) p = 0.0197) were independent predictors of outcome.MPR, but not markers of fibrosis, is a predictor of outcome in initially asymptomatic patients with AS. Further randomized trials are needed to determine whether MPR can improve outcomes in asymptomatic AS.


Genetic and epigenetic programs regulate dramatic structural changes during cardiac morphogenesis. Concurrent biomechanical forces within the heart created by blood flow and pressure in turn drive downstream cellular, molecular and genetic responses. Thus, a genetic-morphogenetic-biomechanical feedback loop is continually operating to regulate heart development. During the evolution of a congenital heart defect, concomitant abnormalities in blood flow, hemodynamics, and patterns of mechanical loading would be predicted to change the output of this feedback loop, impacting not only the ultimate morphology of the defect, but potentially altering tissue-level biomechanical properties of structures that appear structurally normal.The goal of this study was to determine if abnormal hemodynamics present during outflow tract formation and remodeling in a genetically engineered mouse model of persistent truncus arteriosus (PTA) causes tissue-level biomechanical abnormalities.Fgf8;Isl1Cre conditional mutant embryonic mouse hearts and controls. Control and mutant experimental results were compared by a strain energy metric based on the measured relationship between pressure and aspirated height, and also used as target behavior for finite element models of the ventricles. Model geometry was determined from 3D reconstructions of whole-mount, confocal-imaged hearts. The stress-strain relationship of the model was adjusted to achieve an optimal match between model and experimental behavior.The passive stiffness of surface locations on the left ventricle (LV), right ventricle (RV), and outflow tract (OFT) was measured with a pipette aspiration technique in Fgf8;Isl1Cre hearts, its passive stiffness was the same as in control hearts. In contrast, both the LV and RV showed markedly increased passive stiffness, doubling in LVs and quadrupling in RVs of mutant hearts. These differences are not attributable to differences in ventricular volume, wall thickness, or trabecular density. Excellent agreement was obtained between the model and experimental results. Overall our findings show that hearts developing PTA have early changes in ventricular tissue biomechanics relevant to cardiac function and ongoing development.Although the OFT is the most severely affected structure in  Normal vertebrate cardiac development requires precise integration of genetic, molecular, and mechanical signaling events throughout its complex morphogenesis. Disruption of these complex events that permit normal cardiac development results in congenital heart malformations, the most common type of birth defect (>1% of live births). Many genes regulate the molecular pathways critical for normal cardiac development. Disruption of their function frequently causes defects in the outflow tract such as membranous ventricular septal defect (VSD), double outlet right ventricle, transposition of the great arteries, and persistent truncus arteriosus (PTA). In humans, many of these defects are lethal if not surgically repaired.In multiple organisms, it has been shown that blood flow and other hemodynamic forces interact with local mechanical properties of developing cardiovascular tissues to engender responses at the genetic, molecular, and cellular levels that direct subsequent morphogenesis –5  technique, although still novel, has seen increasing use over the last decade since it can successfully deal with many of these problems. PA involves contacting the tissue with the flat end of a small pipette to create a watertight seal. Vacuum pressure is applied within the pipette to aspirate a small amount of tissue; the relationship between pressure and tissue height in the pipette provides information about the tissue mechanical properties. The technique was recently validated on soft polymeric shams with elastic moduli of 10–370 kPa through comparison with nanoindentation, uniaxial tension, and uniaxial compression [This study questioned whether abnormal blood flow and hemodynamics present during PTA formation cause tissue-level abnormalities. We examined passive tissue mechanical properties, because they have been shown to depend on hemodynamic loads in the developing heart ,16, are pression , and wasExtracting basic material properties from the relationship between pressure and aspirated height measured in PA requires analysis of a mathematical model. In the case of thin, layered substrates, such as the embryonic heart wall tested here, computational numerical analysis of the models, usually with finite element methods, is required –28. GeomWhole-mount confocal imaging was used to obtain geometrical measurements for the mathematical models. We employed tissue autofluorescence, enhanced with paraformaldehyde processing, to provide adequate signal for structural resolution, as has previously been shown for stage HH29 chick heart . BecauseIn this study, passive stiffness at locations on the epicardial surface of the left ventricle, right ventricle, and outflow tract was measured with PA. The results were compared in terms of a strain energy metric based on the measured load-deflection relationship between pressure and aspirated height, and also used as target behavior for finite element models of the left and right ventricles. The hyperelastic material properties of the model were optimized to match the calculated pressure versus aspirated height curve to the experimental results. Both the strain energy metric and calculated model material parameters showed a doubling of stiffness in the left ventricle and quadrupling in the right ventricle in mutants compared to control, while stiffness in the outflow tract itself was unchanged despite its severely abnormal morphology.Fgf8fl/fl females were mated with Fgf8+/-;Isl1Cre/+ males to generate Fgf8 conditional mutants  and littermate controls (Fgf8fl/+). The Fgf8;Isl1Cre mouse mutants are described in detail in Park et al. [All animals were maintained on a mixed genetic background. k et al.  and reprAll animal protocols were carried out in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. The protocol was approved by the Weis Center for Research/Geisinger Clinic IACUC, protocol number 203–17. Maternal euthanasia was achieved with cervical dislocation and diaphragm incision as per the 2013 AVMA Guidelines on Euthanasia: Recommended and Acceptable with Conditions. After maternal euthanasia, ED12.5 mouse embryos were removed into 1x PBS on ice. Hearts were dissected from the embryos, preserving the atria, ventricles, and outflow tract. Yolk sacs were used for genotyping.For imaging studies, dissected hearts were incubated at room temperature for 20 minutes with rocking in 4% verapamil (in 1x PBS) to arrest the hearts in diastole. They were then washed twice with 1x PBS and immersed in a red blood cell (RBC) lysis solution  at room temperature for 1 hr. Post RBC-lysis, hearts were fixed with 4% paraformaldehyde for 24–72 hr to increase cardiac tissue autofluorescence, followed by washing twice in 1x PBS, 20 minutes each. Fixed hearts were dehydrated in an ascending series of EtOH , 2 X 30 minutes in each solution, followed by one hr in 100% EtOH. Hearts were cleared in 2:1 benzyl alcohol: benzyl benzoate (BABB) with two changes of BABB with gentle continuous rocking for 30 minutes each. Once cleared, the hearts were stored in BABB in microcentrifuge tubes at 4°C until imaging.Hearts for pipette aspiration (PA) were prepared as described above through the RBC lysis step. Following RBC lysis, hearts were incubated in 1x PBS at 4° C for one hr twice and then stored at 4° C in PBS until assayed.Borosilicate glass pipettes  were shortened to 35–50 mm length. The tips were smoothed and flattened by grinding stone and the pipettes glued with cyanoacrylate adhesive to the inside wall of larger pipettes  with approximately 25 mm protruding. Hot glue filled the remaining opening of the larger pipettes for an airtight seal. Tubing  was pressed over the end of the Wiretrol II pipette and connected by T-connector to a pressure transducer (Honeywell SSCDRRM005PDAA5) and syringe.Under stereomicroscope viewing, hearts were placed ventral-side-up in a glass specimen chamber, which was then placed on a micromanipulator stage in the experimental setup as previously described . The pipL  were custom-manufactured of acetal plastic, which is inert to BABB. A glass coverslip  formed the bottom of a specimen well when mounted with clear silicone gel under a hole (4.76-mm diameter) drilled through the center of the slide.The contents of the microcentrifuge tubes (hearts and liquid) were transferred with a custom glass suction pipette to three glass block wells, where the heart were identified under epifluorescent illumination (Nikon SMZ 1500). Suction pipettes and wells were coated with 0.1% Triton X-100 to eliminate tissue adhesion. Hearts were then transferred by pipette to the slide chamber, covered in BABB, and gently positioned with dorsal side downward.Confocal imaging was done on a Leica TCS SP5 II inverted confocal microscope with LAS AF (Leica Application Suite) software. A dry 10X objective was used with a numerical aperture of 0.4 and a working distance of 2.2 mm. Relevant laser parameters were: Argon laser at 20% power, visible laser lines at maximum combined blue excitation of 458, 476, and 488 nm and 45% power, PMT2 activated with the Leica/ALEXA488 option and set to grayscale, and detection wavelength from 510 to 570 nm.Imaging proceeded with an 8-bit, 512 x 512 pixel format at 100 Hz scanning speed and a line average of 8. Gain and offset values were adjusted accordingly for each specimen to allow for maximum signal intensity and contrast in the image. Z-stack parameters were determined with the Z-Wide function to obtain 250–300 steps of 1.7–2.5 μm each in depth, depending on the individual heart dimensions. Scans ran for 3–5 hours to capture the assigned z-stack. The resulting data set was exported and saved as TIFF files with an overlay channels option.Images were imported into Amira 6.0 as sequential TIFF files through the Channel 1 conversion option. Pixel dimensions in the X, Y and Z directions were based on data from the Leica MetaData file and compensated for 20% isotropic shrinkage from BABB  and refrFor volume calculation, automatic thresholding by grayscale value separated tissue from background, followed by island removal and label smoothing (Gaussian filtering). Further segmentation of the left and right ventricles was done by manual tracing of the chambers with pen tablet on each image, omitting any portions of the developing valves, atria, or outflow tract, and dividing the ventricular septum between the chambers.Obtaining basic myocardial material properties from the PA test results requires modeling of the domain geometry, loading conditions, and boundary conditions, along with an assumed, parameterized constitutive model for the stress-strain relationship. We created finite element computational models of the PA tests on the LV and RV walls with the ventricular wall tissue represented by a bilayer consisting of compact myocardium on the top, contacting the pipette, perfectly bonded to a layer of trabeculated myocardium underneath. Each layer was assigned a thickness measured from the confocal microscopic reconstructions according to region (LV or RV) and treatment group (control or mutant) . The regThe pipette, with inner radius of 0.050 mm, wall thickness of 0.035 mm, and 0.005-mm circular fillet on both inner and outer wall edges, was assumed to be rigid and fixed with a flat bottom edge contacting the top surface of the compact myocardial layer. A roller boundary condition incorporated traction-free sliding between the myocardial surface and pipette. The outer edge of the cylinder representing ventricular wall was fixed in all directions.E and Poisson’s ratio ν by the equationsThe ventricular tissue was represented as isotropic and homogeneous with a nearly-incompressible, neo-Hookean constitutive relation defined by the Lamé parameter μ and the initial bulk modulus κ. In a neo-Hookean model, these can both be related to the small-strain tangent elastic modulus E was assumed to be the same for the compact and trabecular regions within each of the four geometries. A Poisson’s ratio ν of 0.49 incorporated the nearly-incompressible condition due to the high water content of the tissues. The material parameters of the stress-strain relationship for the trabeculated regions were multiplied by the solid tissue density percentage determined from the analysis of the confocal images. We also analyzed models of each of the four geometries with linear elastic properties to compare with the hyperelastic models, and models without the trabecular zone porosity.The modulus Axisymmetric analysis was implemented in COMSOL Multiphysics software . The region was meshed with approximately 1200 quadratic tetrahedral elements with a mixed formulation, i.e., pressure added as an independent degree of freedom, to account for the large Poisson’s ratio of 0.49. The use of tetrahedral elements facilitated mesh refinement in the area of largest stress near the contact of the pipette wall with the ventricle. Mesh convergence studies were performed to guarantee the quality of the final solution. The experimental aspiration pressure was applied as a uniform pressure with outward normal on the material surface inside the pipette and incremented from 0 to 3.5 kPa in 0.2-kPa steps to obtain the relationship between aspiration pressure and upward deflection in the aspirated bubble.E for the neo-Hookean constitutive models was iteratively adjusted until the finite element load-deflection curve for the four models best matched the mean experimental curve in a least-squares sense.To obtain the apparent material parameters of the dual-layer myocardium, the mean experimentally measured load-deflection curves for each group  were used as a target and the modulus Δp vs 2 values from a linear least-squares regression of 0.96 in control and 0.97 in mutant. A quadratic fit to the data raised the mean R2 across all locations by only 0.7%.The load-deflection curves of pressure . The aspComparison of stiffness between control and mutant hearts using the SED metric supported the major hypothesis of this study: in both the LV and RV locations, mutant hearts were significantly stiffer than control , Fig 4B.A comparison of PA measurements in control hearts among the three tested locations showed that the OFT was stiffest and the RV was least stiff , Fig 4B.The BABB clearing method and use of tissue autofluorescence for imaging allowed full laser penetration and capture through the dorsoventral extent of the ED 12.5 mouse hearts and subsequent 3D reconstruction .3, consistent with whole-mount images  and 10% of surface value at a depth of 0.22 mm (4-5ri) (o) from the centerline  . In the nterline . The modThe presence of the softer trabecular region under the compact layer influenced the height of the bubble. In analysis of models with identical material properties but no trabecular porosity, higher aspiration pressures were necessary to reach the same aspiration height as that of corresponding models that did not contain the softer trabecular layer . Also, tThis study used a novel method to measure passive ventricular and conotruncal wall stiffness in embryonic hearts of controls and mutants with developing PTA. We found greatly increased left and right ventricular stiffness in mutant hearts that cannot be attributed to wall thickness or trabecular density. Based on a strain energy measure, stiffness increased 2-fold in the LV and 4-fold in the RV in mutant hearts. Based on the mathematical model, elastic moduli increased by similar multiples of 2.1 in the LV and 3.9 in the RV.The strain energy density (SED) measure, equal to the area under the experimental pressure versus normalized deflection curve, is physically meaningful and allows direct comparison of fundamental behavior from the PA testing. A similar metric was proposed to compare PA measurements from day 5–8 chick AV cushions and compared well with uniaxial testing in determination of material properties . The useFgf8;IslCre mutants. LV progenitors are derived from Fgf8-expressing mesoderm in the primitive streak and early cardiac crescent [Isl1Cre is not active at this early stage [Fgf8;IslCre mutants have an intact Fgf8 locus and are recruited normally to the heart tube. In contrast, beginning at approximately ED 8.5, RV precursors are deployed from the second heart field, the pharyngeal mesoderm caudal to the pharynx, into the heart tube where they develop cellular and molecular features of RV myocardium. Autocrine Fgf8 signaling is required for normal proliferation, survival, and function of the RV progenitors prior to their differentiation and deployment to the heart [Fgf8;IslCre mutants, the embryonic RV is smaller than normal [When interpreting the increased stiffness of the LV and RV in mutants as a reflection of altered flow, pressure, and other biomechanical inputs, it is important to consider the lineage, genetic, and morphogenic features of the RV compared to the LV in crescent , the firly stage ,22 and the heart . In earlOFT progenitors, like those of the RV, derive from the second heart field and begin to accrue to the heart shortly after ED 8.5 –40. Unliin vivo measurements are virtually impossible. However, the ventricles and OFT remain intact in PA, whereas extracting strips to secure to a loading fixture would be more destructive. Another method of applying load, sealing the ventricles and creating internal pressurization, requires a means of applying and measuring inflation pressure, measuring surface strain, and modeling the geometry of the entire LV and RV, and would likely omit the OFT. Atomic force microscopy (AFM), or the related techniques of nanoindentation and microindentation, are not as well suited for soft biological tissues and generally involve very small tip sizes, down to tens of nanometers for AFM, with indentations on the order of microns. This may limit the sampling to only the epicardium. In vivo strain and strain rate have been estimated through variation of wall thickness in serial images from optical coherence tomography (OCT) in the tubular heart of the 3-day (HH18) chick embryo [Determining mechanical material properties of any structural material or biological tissue involves applying a known loading, measuring strain, calculating stress with a mathematical model based on physical principles, and implementing a mathematical representation of the stress-strain relationship. One of the simplest examples is the classical uniaxial tension test, where a rectangular strip of engineering material with constant cross-sectional geometry and isotropic elastic material properties is clamped and pulled from the ends. In contrast, the small size  relationship. This is otherwise slightly counterintuitive, since the load-deflection, or experimental pressure vs aspirated height, relationship is linear. Analysis of models with a linear stress-strain relationship, in contrast, showed a nonlinear pressure-height relationship . Model ale [The development of a whole-mount confocal imaging technique in this study allowed 3D reconstruction of the ventricles and outflow tract of the ED12.5 heart and subsequent calculation of ventricular tissue volumes and trabecular density. The BABB clearing method with tissue autofluorescence has the advantages of being fast, non-aqueous, and requiring no special equipment . Other cle , CLARITYle ) or limile , CUBIC [le ). Still le ), or invle ). The mele . Trabecule  and alsole . The meaGenetically-based outflow tract defects such as PTA are typically demonstrated through gross structural abnormalities, which in turn often lead to severe functional problems, such as cyanosis, ventricular hypertrophy, pressure anomalies, and eventual heart failure. The structural defects are primarily surgically repaired during the first days or months of life. However, if increased passive ventricular stiffness occurs during development, it may act to worsen the original defect and cause additional defects. If persisting postnatally, increased passive ventricular stiffness is detrimental to cardiac function. Ventricular end-diastolic pressure (EDP) is higher for a given end-diastolic volume (EDV). The passive relaxation phase of diastole is impaired, and the active relaxation phase may also be impaired if the cause of the increased passive stiffness resides partly in the myocardial cells, leading to reduced ventricular filling. Diastolic dysfunction or heart failure with preserved ejection fraction (HFpEF), defined as symptomatic HF with EF ≥ 40%, is now observed in 50% of hospitalizations for congestive HF .Fgf8;Isl1Cre hearts.In summary, our data indicate that increased tissue passive stiffness of the mutant LV is due to aberrant hemodynamics that changes the output of the genetic-morphogenetic-biomechanical feedback loop. We are in the process of determining the transcriptional and cellular alterations that occur in LV cells during evolution of the PTA defect that lead to its increased tissue stiffness. For example, both titin at a sarcomeric level and collagen in the extracellular matrix have been implicated as main contributors to passive ventricular stiffness . Further


Cardiovascular disease still remains the leading cause of deaths worldwide. Atherosclerosis, the most common type of cardiovascular disease, has continued to progress due to many factors, genetics, and lifestyles. All cells require adequate adenosine triphosphate (ATP) levels to maintain their integrity and function. Myocardial ischemia commonly found in atherosclerosis can produce lower levels of ATP, which affects not only cellular energy, but also alters normal function. D-ribose, a naturally occurring pentose carbohydrate, has been shown to increase cellular energy levels and improve function following ischemia in pre-clinical studies and have demonstrated potential benefits in clinical evaluations. This review paper presents an overview of ischemic cardiovascular disease and the potential role that D-ribose could play in improving myocardial energy levels and function in the area of ischemic cardiovascular diseases. Cardiovascular disease still remains the leading cause of deaths worldwide for both men and women. There are approximately 61 million individuals afflicted with heart disease in the United States according to the Centers for Disease Control and Prevention. The World Health Organization has reported that approximately 29% of all deaths worldwide are related to this disease state [Increasing plaque formation can ultimately limit the delivery of blood and thereby oxygen to viable tissues. Atherosclerosis is not confined to a sole anatomic region, for it is a systemic disease that can involve various arterial regions, such as the heart, cerebrovascular, and peripheral circulation. Clinically significant coronary arterial atherosclerotic disease can produce symptoms of angina or chest pain, commonly during and following stressful situations; however, some patients can even have symptoms at rest. Furthermore, with the progression of coronary artery disease with increasing atherosclerosis plaque formation, these patients are susceptible to sustaining an acute myocardial infarction or live with a chronic, debilitating condition, which over a prolonged period of time, can potentially advance into the development of congestive heart failure. Coupled with coronary artery ischemia and with longstanding hypertension, many patients develop myocardial diastolic dysfunction, an abnormality in ventricular relaxation. Ventricular dysfunction has continued to be a challenging clinical problem because, as of today, there is not yet an approved, solely directed therapy, both pharmaceutical and device-related, targeted at effectively treating this myocardial dysfunctional state .Medical investigations have found that left ventricular diastolic dysfunction is more prevalent than expected. Redfield et al. stated that “systolic dysfunction is frequently present in individuals without cognized congestive heart failure. Furthermore, diastolic dysfunction is common, often not accompanied by recognized congestive heart failure, and is associated with marked increases in all-cause mortality.” In 2003, Redfield et al. reported in randomly selected adults over the age of 45 that 21% had mild and 7% had at least moderate diastolic dysfunction. Six percent had moderate or severe diastolic dysfunction with a normal ejection fraction [Myocardial ischemia alters oxidative cellular metabolism, reflected in lower levels of adenosine triphosphate (ATP). Different states of ischemia, transient versus chronic, can reflect varying degrees of cellular reductions in ATP levels, as well as functional abnormalities and altered cellular homeostasis, and if severe enough, cellular viability. Myocardial ischemia is a common underlying cause in patients with congestive heart failure, and many of these patients also experience a degree of diastolic dysfunction. Clinically, at least 50% of patients diagnosed with congestive heart failure will have various degrees of diastolic dysfunction solely or potentially combined with systolic dysfunction. Within the last decade, Ingwall and Weiss proposed that the failing heart is energy starved [Cellular bioenergetics and functionEvery cell requires adequate levels of high-energy phosphates to maintain their integrity and function. This cellular supply of energy  usually meets demands. Adenosine triphosphate is produced by intracellular pathways, such as glycolysis and the tricarboxylic acid cycle, with glucose as the starting substrate. However, some cells can also rely on alternative pathways, such as the pentose phosphate pathway, for the production of ATP . There iWhen cells are subjected to ischemia or hypoxia, the normal production of energy compounds is reduced. Myocardial ischemia depletes ATP levels, which can affect intracellular reactions and the cells' function. There are degrees of ischemia, and if severe enough, the viability of the cell is jeopardized. Researchers have also demonstrated that this depletion in myocardial ATP levels following ischemia can last for a considerable time period due to a slow adenine nucleotide synthesis, which is reflected in an alteration in function . Zimmer Adenine nucleotide metabolism and D-riboseWard et al. reported that myocardial precursor availability is an important limiting factor in the recovery of myocardial ATP molecules following ischemia . AdenineThe ultimate repletion of myocyte ATP levels following ischemia depends on the availability of the precursor phosphoribosyl-pyrophosphate (PRPP), and D-ribose has shown to accelerate this nucleotide synthesis by directly increasing PRPP levels . VariousMetabolism of D-riboseD-ribose can produce nucleotides and metabolic intermediates, such as ribose-5-phosphate. Ribose-5-phosphate is an important intermediate of the pentose phosphate pathway, also known as the hexose monophosphate shunt or phosphogluconate pathway Figure .de novo synthesis of ATP , improve their ventilatory efficiency, and experience a positive trend in their quality of life measurements . Vijay et al. concurred with these reported D-ribose benefits in a separate clinical study involving Class II-IV CHF patients when taking D-ribose supplementation. Clinically, significant improvements were observed in ventilator efficiency in the Class III-IV patients. The Class II patients were observed to have a positive, but not statistically significant, trend in improved ventilator efficiency .Long-term myocardial ischemia does play a factor in the development of congestive heart failure and further reports have proposed that the failing heart is energy starved . Since pThe use of D-ribose supplementation in cardiovascular surgery has revealed alterations in myocardial function in the post-revascularization period. Wyatt et al. found that the use of a cardioplegic solution of adenosine, hypoxanthine, and D-ribose supplementation intraoperatively maintained myocardial energy levels during ischemia and, with reperfusion, resulted in enhanced functional recovery post-cardiopulmonary bypass . Vance eCardiovascular disease still ranks as the leading cause of deaths worldwide, even with continued advances in cardiovascular therapeutic technologies. Myocardial ischemia, commonly found in cardiovascular disease, plays a major role a majority of these deaths. There continues to be strong efforts to educate the population in addressing atherosclerotic risk factors, such as refinements in a more healthy diet, regular exercise, smoking cessation, blood pressure control, and stress reduction.All cells require adequate levels of high-energy phosphates to maintain their integrity and function. Numerous studies have demonstrated that myocardial ischemia lowers ATP levels, which can be reflected in alterations in diastolic function. Myocardial ischemia, which lowers ATP levels and causes a dysfunctional state, is a main category in cardiovascular disease. Myocardial adenine nucleotide precursor availability is an important limiting factor in the recovery of myocardial ATP molecules following ischemia, for which various substrates have been investigated. D-ribose, a naturally occurring pentose carbohydrate, has been shown in both pre-clinical and in pilot clinical studies to enhance the recovery of ATP levels and also to aid in improving left ventricular diastolic dysfunction following ischemia. These studies have shown its potential clinical benefits in acute and chronic myocardial ischemic conditions, enhancing the identification of hibernating myocardium, aiding congestive heart failure patients, and its perioperative use in cardiovascular surgery. Future, larger cohort, multicenter clinical investigations are mandatory to further substantiate these initially observed benefits in patients afflicted with ischemic cardiovascular disease.


The European Society of Cardiology recognizes different hypertensive heart disease (HHD) phenotypes. HHD can be classified into 4 left ventricular (LV) phenotypes by indexed LV mass, mass to volume ratio (M:V) and indexed end diastolic volume (EDV) Table . All rem88 treated hypertensive patients  underwent 1.5T CMR and were compared with 29 age- and sex-matched normotensive controls .Native and post-contrast T1 myocardial values were measured with a modified look-locker inversion-recovery sequence. Extracellular volume (ECV) and myocardial cell volume fractions were calculated. Circumferential strain values were estimated by voxel-tracking.2 vs 75 ± 10 g/m2 vs 108 ± 24 g/m2 vs 122 ± 30 g/m2, p < 0.05 respectively). This was due to step-wise increases in both: 1) indexed myocardial cell volume  and indexed interstitial volume .There was a gradient of increasing LV mass from normal, to remodeling, concentric LVH and eccentric LVH , with evidence of both peak systolic  and peak diastolic strain rate impairment .Despite similar BP severity as LVH, LV remodeling was associated with neither significant intracellular/interstitial expansion , nor myocardial dysfunction compared to normotensive controls.We comprehensively characterize, at the intra/extracellular myocardial level, structural differences between hypertensive phenotypes that are associated with functional consequences. We show that:1) LVH, in particular eccentric LVH, is associated with significantly elevated myocardial cell volume, interstitial volume as well as myocardial systolic and diastolic strain impairment.2) LV remodeling is associated with both normal myocardial structure and function.Our results may help explain why eccentric LVH has poor prognosis. Our findings may have implications for future anti-hypertensive treatments.