In the following review we will discuss the basic aspects of fibrosis assessment with MR and its utility for diagnostic and prognostic evaluation. We will also address the topic of cardiovascular inflammation imaging with 19F as a potential new development that may broaden the indications for MR in the future.Late gadolinium enhancement is the technique of choice for detecting myocardial fibrosis. Although this technique is used in a wide range of cardiovascular pathologies, ischemic cardiomyopathy and the workup for myocarditis and other cardiomyopathies make up a significant proportion of the total indications. Multiple studies during the last decade have demonstrated its utility to adequately characterize myocardial tissue and offer diagnostic and prognostic information. Recent T1 mapping techniques aim to overcome the limitations of late gadolinium enhancement to assess diffuse fibrosis.  Late gadolinium-enhanced (LGE) magnetic resonance (MR) is the technique of choice for assessing fibrosis, as demonstrated by the vast amount of evidence arising from both animal and clinical studies , 2. Its The basic principle of late gadolinium enhancement imaging lies in the delayed washin and washout of gadolinium contrast media in tissue with an increased proportion of extracellular space. It is important to note that since LGE is based on differences in extracellular space in different areas of the myocardium, it is only useful if the disease is localized . While that is usually not a problem in ischemic heart disease, it may be an issue in other pathologies in which general fibrosis plays an important role .Although the indications for performing an MR exam with LGE cover multiple cardiovascular pathologies, a recent European survey  has poin19F) which, although currently mainly restricted to research purposes, may be used in the future in clinical practice.In this review article we discuss the basic aspects of fibrosis assessment with late gadolinium enhancement as well as its main applications in the field of ischemic heart disease, myocarditis, and other cardiomyopathies. Finally, we offer an insight into new promising techniques  is an ion with paramagnetic properties, which is toxic in its unbound state. Therefore, the contrast agents (CAs) consist of a large molecule which comprises a Gd ion and a carrier agent that keeps Gd bound during intravenous injection, while still retaining its imaging properties. Gadolinium CAs are relatively large in size which prevents them entering the intracellular space under normal conditions and are thus extracellular agents. Some CAs have a particularly large molecule , remain mainly intravascular with just a small degree of extravasation, and are considered vascular agents . Most of the CAs are renally excreted, have a half-life of 2 hours, and are almost completely cleared from the bloodstream after 24 hours. 2) or end-stage renal failure, which can be acute or chronic, and who received repeated high doses of Gd CA in a short period of time. Although liver transplantation was also considered to be a risk factor for the development of NSF, some reports seem to suggest otherwise [Adverse reactions to Gd-based CA are uncommon, although potentially severe. In addition to allergic reactions , a potential adverse effect of Gd CA is nephrogenic systemic sclerosis (NSF), a rare fibrosing disease involving the skin, subcutaneous tissue, and internal organs that can cause severe disability and even death. The reported cases of this disease involve patients with severe . The reasons for this increase in the distribution volume vary according to the underlying pathology: in the case of acute myocardial infarction, it is caused by myocardial edema and myocyte necrosis and lysis , while iGd reduces T1 time, which is a tissue-specific parameter. Since every tissue has its own T1 value, this parameter can be used to differentiate between tissues. The MR sequences in which most of the contrast between tissues is due to differences in T1 values are called T1 weighted and are the ones used to obtain images in the LGE technique. In particular, the inversion-recovery gradient-echo sequence used nowadays provides an excellent contrast between normal myocardium and scarring by nulling the signal from normal myocardium  .The LGE technique consists of an injection of a 0.1-0.2 mmol/kg bolus of Gd-based CA, followed by T1-weighted acquisition 10–20 minutes after administration of the contrast. The main determinant factor for obtaining good quality images is the correct selection of an adequate inversion time (TI). This parameter is highly variable among patients and physiological conditions, and its correct selection is essential to achieve an effective suppression of normal myocardium . The TI is selected either visually or by using a Look-Locker sequence, which offers a series of images with variable TI and allows the examiner to pick the one with the best contrast. Phase-sensitive inversion recovery (PSIR) techniques are an alternative to this approach.Hyperenhancement on LGE has a close correlation to histopathologically proven myocardial necrosis, as demonstrated by some studies. In an experimental study, Kim and colleagues  demonstrSome initial animal studies suggested the potential utility of LGE MR in acute myocardial infarction (MI). In a canine model of MI, an increase in the partition coefficient of Gd in the infarcted regions was observed, which was significantly different from noninfarcted regions. This increase in the partition coefficient started 1 min after reperfusion (following 2 hours of coronary occlusion) and persisted until 8 weeks , 13. LGEIn addition to the detection of the infarcted area, MR permits the detection of the ischemic area at risk by combining LGE MR with T2-weighted black blood imaging. Although this area does not demonstrate enhancement, it typically demonstrates a high intensity in T2-weighted imaging. In addition to its diagnostic utility, the extent of the enhanced myocardium seems to be related to functional parameters at followup. Acute MI mass was demonstrated to be correlated not only with peak troponine I but also with left ventricle (LV) ejection fraction (EF) at followup . FurtherAnother important determinant of prognosis in patients with acute MI is the presence of a microvascular obstruction (MVO), which can also be successfully visualized by MR as an subendocardial area of low signal intensity inside the enhanced region. The assessment of MVO can be performed during the contrast first pass, early (2–5 min) after its administration, or on late gadolinium-enhanced images. It has to be taken into account that the size of MVO decreases over time , but a lower variability on quantification has been obtained with LGE imaging . The preLately, there has been a growing interest in the presence of infarct hemorrhage as a strong marker of adverse cardiovascular events and LV remodelling . AlthougFinally, the infarct peripheral zone has also been shown to provide prognostic information and can also be detected by LGE MR. In the peripheral zone both viable and nonviable myocytes are present and constitute an arrhythmogenic substrate, whereby the extent of the peripheral zone is a predictor of cardiovascular and all-cause mortality . The perAlthough both acute and chronic MI scars show LGE, the presence of wall thinning and the absence of hyperintensity in T2-weighted imaging suggest chronic MI . In addiSimilar to acute MI, in chronic ischemic heart disease (IHD) MR can be useful to predict the probability of functional recovery with an inverse relationship between the transmural extent of LGE and the likelihood of functional improvement after revascularization . The perOn the other hand, the concomitant use of low-dose dobutamine stress MR may offer additional information to that of LGE MR alone, both in terms of functional recovery  and to pIn Takayasu arteritis, which usually affects the aorta and its main branches, the presence of delayed enhancement of the artery wall seems to be correlated with inflammatory markers and disease activity , 32.Detection of LGE in the coronary artery wall is also feasible. In a study by our working group, the presence of LGE in the coronary artery wall of all coronary artery disease (CAD) patients could be observed, but it was not seen in any of the healthy subjects . In addiHowever, the exact significance of the presence of enhancement on the coronary wall remains unclear, as demonstrated by the fact that LGE of the coronary artery wall has also been found in patients with Takayasu arteritis, with a similar proportion to that of CAD patients . The LGEFinally, the potential utility of Gd-enhanced MR for differentiating between atherosclerotic coronary plaque types has also been demonstrated . In addiThe assessment of LGE in the coronary wall currently remains limited to research studies and is not yet used in daily clinical practice. MR is a useful technique for the diagnosis of myocarditis. The typical pattern of LGE in myocarditis is the presence of patchy enhancement with a subepicardial localization, usually affecting the inferolateral segments and, less frequently, the anteroseptal region  Figure . The hyperenhanced areas correlate also with histologic active inflammation. In a study with both MR and biopsy, histologically active myocarditis was found in 19 out of 21 patients with biopsy coincident with the area of LGE, but in only one patient in which the biopsy region did not coincide . In addiLGE MR can also offer prognostic information in patients with myocarditis. In a recent work including more than 200 patients with biopsy-proven myocarditis and MR, LGE was the best independent predictor of both all-cause and cardiac mortality, with a hazard ratio superior to that of functional class, EF, or LV volumes .The LGE method is also useful for the evaluation of other nonischemic cardiomyopathies. Although different patterns of LGE have been described for various nonischemic pathologies, the key characteristic is that, in contrast to ischemic cardiomyopathy, the subendocardial region is usually not affected. The hyperenhancement regions are usually subepicardial or midventricular and do not correspond to any known coronary territory. In the case of amyloid, the main distinct feature is the difficulty of choosing an optimal TI value to null the myocardium .In addition to its diagnostic utility, the presence of LGE can also offer prognostic information in some entities. In the case of hypertrophic cardiomyopathy, the presence of hyperenhancement has been shown to be an independent predictor of both cardiovascular and global mortality, and of ventricular arrhythmias , 46.As it has been described before, although LGE reliably detects localized fibrosis, it is limited in the assessment of diffuse fibrosis. The main reason for this limitation lies in the fact that the LGE technique detects fibrosis on the basis of the difference in signal intensity between an enhanced area and the normal myocardium. As a consequence, no signal intensity difference will be detected if there is a pathology which causes diffuse fibrosis. In order to overcome this limitation of LGE, T1-mapping techniques have been developed which permit the assessment of diffuse fibrosis. This new method allows for evaluation of pathologies which, although associated with a high fibrosis content, cannot be studied with LGE. These T1-mapping techniques permit the direct quantification of the myocardial T1 time. In the setting of an increase in collagen fibers (and thus extracellular space), T1 time decreases after contrast administration. In a recent study with cardiomyopathy patients with endomyocardial biopsy, postcontrast T1 times correlated histologically with fibrosis  and wereThe modified Look-Locker inversion recovery (MOLLI) sequence is frequently used to measure T1 times, and its reproducibility has been demonstrated . MOLLI TDespite promising results, T1 mapping is currently still limited to research purposes and is not yet widely used in clinical practice.19F to detect inflammation. Because fluorine is only found in the body at very low levels, there is no background signal and it offers excellent specificity [19F, have the advantage of being taken up by the reticuloendothelial cells and, as a consequence, can be used to track these cells. Once they are administered intravenously, PFCs are taken up predominantly by monocytes [This technique is based on the utilization of cificity . Perfluoonocytes  and tranIn a study with a murine model of MI, the authors demonstrated the feasibility of visualizing with fluorine MR a infiltration of PFCs in the border zone of the infarcted areas, which corresponded to cells of the monocyte/macrophage system in the histologic analysis . Another19F MRI is a promising method for imaging cardiovascular inflammation although it is currently still limited to research purposes. The further development of these promising new techniques will expand the application of MR in the future.Late gadolinium-enhanced MR is an essential technique for assessing cardiovascular localized fibrosis. In the field of myocarditis and ischemic cardiomyopathy, LGE MRI is a valuable tool that offers diagnostic and prognostic information and can guide therapeutic decision. Although still not widely available in clinical practice, T1 mapping offers the possibility of overcoming the limitations of late gadolinium enhancement by visualizing diffuse fibrosis. Finally,


Pulmonary atresia with intact ventricular septum (PAIVS) is a rare type of congenital heart disease. Biventricular surgical repair is considered to be the optimal treatment option as it provides satisfactory results in terms of survival and clinical outcome during the early follow up period. However the long term clinical fellow-up studies are limited. In the present study we evaluated the cardiac response to the physical and pharmacological stress using dobutamine stress MRI in children and young adults with PAIVS after biventricular repair.In patients with pulmonary atresia with intact ventricular septum (PAIVS) biventricular repair is considered to be the optimal treatment option in the absence of significant right ventricular (RV) hypoplasia. However, long term clinical outcome studies are limited. We evaluated exercise capacity and cardiac function during pharmacological stress in children and young adults with PAIVS after biventricular repair.Ten PAIVS patients after biventricular repair, median age 12 years (range 9 - 42 years), underwent a cardiopulmonary exercise test, dobutamine stress magnetic resonance imaging (MRI) and delayed contrast enhancement (DCE) MRI.The patients' age negatively correlated with exercise capacity  as well as left and right ventricular stroke volume (SV) response to pharmacological stress (r = -0.69, p = 0.02; r = -0.73, p = 0.01, respectively- Figure In PAIVS patients after biventricular repair exercise capacity and cardiac reserve decrease with age. These findings appear to be related to impaired diastolic RV function and decreased RV filling, indicating that the function of the relatively small RV deteriorates with time.Financial disclosure: none.


Sudden cardiac death (SCD) due ventricular tachyarrhythmias is an important cause of mortality world wide. While the majority of these deaths occur in those with structural heart disease, a small percentage (about 4%) can occur in those with structurally normal heart as well . Such prIn this issue of the journal, Madhavan SR et al  present Sudden cardiac death can be an initial presentation or preceded by symptoms related to arrhythmias or hemodynamically significant cardiovascular disorders. Sometimes evaluation is called for due to family history of sudden cardiac death. In any case, the evaluation begins with a detailed history of clinical details, family history if present and a clinical evaluation to look for potential conditions which can cause SCD. This will be followed by the assessment of a baseline electrocardiogram and other investigations as deemed necessary. An echocardiogram is useful in documenting structural heart diseases prone for SCD like severe aortic stenosis and hypertrophic cardiomyopathy. Stress testing for myocardial ischemia or inducible arrhythmia; Holter monitoring, loop monitoring and implantable loop recorders for documenting siginificant arrhythmia and finally genetic testing in case of suspected inherited arrhythmias would be other important investigations to be undertaken in this setting.Prevention of SCD in heart failure and left ventricular dysfunction assumes great importance as this is one of the largest groups in the whole arena of sudden cardiac death. Rather than pump failure, sudden cardiac death is the most common mode of death in persons with left ventricular dysfunction, more so in those with mild and moderate left ventricular dysfunction. Pump failure deaths definitely increase in those with severe left ventricular failure. Implantable defibrillators have been shown to be the most important way of prevention of SCD in this subset of patients by various large clinical trials like Multicenter Automatic Defibrillator Implantation Trial (MADIT), Multicenter Unsustained Tachycardia Trial (MUSTT), and MADIT-II . OptimalAt the community level, measures to improve the coronary risk factors can bring down the incidence of coronary artery disease as it is a major contributor to SCD. Another important aspect at the community level is the implementation of emergency medical services which can provide immediate medical care at the onset of symptoms of diseases which can lead to sudden cardiac death.Even though implantation of cardioverter-defibrillator is finally the answer in prevention of SCD in most inherited arrhythmias, several other interventions have been found useful. These include beta blockers in catecholaminergic polymorphic ventricular tachycardia and many subtypes of congenital long QT syndromes, quinidine in Brugada syndrome  and left


Speckle-tracking echocardiography (STE) has emerged as an ultrasound technique for accurately evaluating myocardial function also in critically ill patients. By tracking the displacement of the speckles during the cardiac cycle, the strain rate can be measured offline after adequate image acquisition. The aim of the study was to evaluate the effects of the positive end-expiratory pressure (PEEP) on four-chamber longitudinal strain (LS) analysis in critically ill patients.2O . Blood gas analysis, respiratory, and hemodynamic parameters provided by a pulse contour method were also recorded. STE analysis was performed offline .We enrolled 20 consecutive patients (mean age 64 ± 18) who needed mechanical ventilation and were admitted to the ICU due to heterogeneous causes. Inclusion criteria were: hypoxia requiring PEEP titration, invasive arterial pressure monitoring, age >18. Exclusion criteria were: myocardial dysfunction, cardiac arrhythmias and valvular pathologies. The same operator performed three standard echocardiography measurements , each of them after having increased PEEP at 5, 10, and 15 cmHP <0.05). Right peak atrial LS (RA-PALS) and right ventricular (RV)-LS showed a significant reduction only at T3 . Left ventricular (LV)-LS did not change significantly during titration of PEEP. Cardiac chambers' volumes and cardiac output (CO) showed a significant reduction at higher levels of PEEP. Pulse pressure variation was significantly affected by higher levels of PEEP (P <0.05).Left peak atrial LS (LA-PALS) was significantly reduced from T1 to T2, and from T2 to T3 (40.2 ± 12%, 35.9 ± 9%, 28.4 ± 8%, T1, T2, T3, respectively; In hypoxic patients with normal cardiac function, PEEP titration determined a reduction of LA-LS, RA-LS and RV-LS values. LV-LS values were not influenced by PEEP changes. The fall in CO, observed with higher values of PEEP, seemed to be related to the impairment of preload and not of myocardial contractility. Whenever interpreting data on cardiac function obtained with longitudinal strain analysis, attention of the clinician should be drawn to different levels of PEEP. The higher the PEEP, the more the probability of misleading interpretation of STE data.


Right ventricular apical pacing may cause or worsen mitral regurgitation (MR). Potential mechanisms for this adverse sequelae include intraventricular dyssynchrony, altered papillary muscle function, pacing-induced cardiomyopathy with left ventricular dilation, and annular dilation. In contrast, biventricular (BiV) pacing may improve MR presumably by opposing the negative effects. Whether or not left ventricular lead location is important in treating mitral regurgitation in patients with pacemakers is unknown.We report a case of severe MR and left ventricular (LV) systolic failure in a patient with right ventricular pacing. Multiple potential etiologies for the worsening valve function were noted, and a stepwise iterative optimizing scheme that included basal lateral LV pacing improved mitral valve function and ameliorated heart failure symptoms. Mitral regurgitation (MR) can worsen as a result of acute or chronic right ventricular apical pacing ,2. The mWe report a case of worsening mitral regurgitation and systolic heart failure caused by right ventricular apical pacing. A cardiac resynchronization device was ultimately placed for biventricular pacing and improved severe MR, systolic function, and heart failure symptoms.This case illustrates that even after optimization of pacemaker function for improved contractility and valve function; a real incremental benefit can be seen with a very basal positioning of the LV lead.An 85-year-old female with a history of hypertension developed symptomatic paroxysmal atrial fibrillation manifesting as palpitations associated with dyspnea, weakness, and presyncope. Holter monitoring confirmed paroxysmal atrial fibrillation (PAF) with rapid ventricular response and echocardiography showed a mild reduction in left ventricular systolic function with an ejection fraction of 49%, diastolic dysfunction, and mild to moderate mitral regurgitation (MR)  and 1B. Ablation and pacemaker implantation was successful. The pacemaker was initially programmed to DDDR but due to a large amount of pacing energy required was programmed to VVIR. At 3 month device follow up, her atrial lead thresholds improved and the pacemaker mode was changed to DDDR.Approximately two weeks after pacemaker settings were changed, she presented in decompensated heart failure. A transthoracic echocardiography showed worsening left ventricular systolic function with ejection fraction decreasing to 30%, moderate to severe decreased right ventricular function and RV enlargement, and development of severe MR  and 2B. Pacemaker reprogramming resulted in only slight improvement in overall LVEF to 35% at one month follow up, but left ventricular contraction was dyssynchronous and severe MR persisted. The patient continued to have refractory brittle congestive heart failure. A potential cause of MR such as coronary ischemia was evaluated with angiography but only showed mild coronary artery disease. She was on optimal medical management with beta-blocker, two diuretics, and an ACE inhibitor. However, because of left ventricular dyssynchrony and severe MR on repeat echo at 3 months, the decision was made to upgrade the pacemaker to a biventricular pacing system. The left ventricular lead was placed in the coronary sinus at the mid-basal position. Two months later, echocardiography revealed improved left ventricular synchrony, contractility, and left ventricular ejection fraction increased to 40%, RV systolic function improved back to baseline, and there was significant improvement of MR back to baseline mild to moderate  and 3B. Pacemaker-induced worsening MR and the subsequent improvement in valvular function by altering pacing has been highlighted in the literature. The improvements in valvular regurgitation have come about through altering the site of right ventricular lead pacing to the interventricular septum , or placSeveral key points are illustrated by our case. First, this case highlights the importance of pacing mode post nodal ablation in patients with baseline valvular disease and decreased cardiac function . Second,


Left ventricular (LV) dysfunction is common in septic shock. Its association with the clinical outcome is still controversial. Tissue Doppler imaging (TDI) is a useful tool to quantify LV function; however, little knowledge is available about the prognostic value of these TDI variables in septic shock. Therefore, we performed this prospective study to determine the role of TDI variables in septic shock.Patients with septic shock in a medical intensive care unit were studied with transthoracic echocardiography with TDI within 24 hours after the onset of septic shock. Baseline clinical, laboratory, and echocardiographic variables were prospectively collected. Independent predictors of 90-day mortality were analyzed with the Cox regression model.P < 0.0001), lower PaO2/FiO2 (123 (83 to 187) versus 186 (142 to 269) mm Hg; P = 0.002], higher heart rate (120 (90 to 140) versus 103 (90 to 114) beats/min; P = 0.004], and ahigher dose of norepinephrine (0.6 (0.2 to 1.0) versus 0.3 (0.2 to 0.5) μg/kg/min; P = 0.007]. In the multivariate analysis, Sa > 9 cm/sec (hazard ratio (HR), 5.559; 95% confidence interval (CI), 2.160 to 14.305; P < 0.0001), dose of norepinephrine , and PaO2/FiO2  remain independent predictors of 90-day mortality in septic-shock patients.During a 20-month period, 61 patients were enrolled in the study. The 90-day mortality rate was 39%; the mean APACHE IV score was 84 (68 to 97). Compared with survivors, nonsurvivors exhibited significantly higher peak systolic velocity measured at the mitral annulus (Sa) (11.0 (9.1 to 12.5) versus 7.8 (5.5 to 9.0) cm/sec; Our study demonstrated that LV systolic function as determined by TDI, in particular, Sa, might be associated with mortality in patients with septic shock. Although left ventricular (LV) depression in sepsis was first reported decades ago , it has Tissue Doppler imaging (TDI) has been shown to be useful for quantifying global systolic and diastolic LV function -6. The pTherefore, we performed a prospective, observational study to evaluate the prognostic significance of TDI variables in septic shock.The study was performed in a nine-bed medical ICU of a university teaching hospital. Between January 2010 and August 2011, all patients admitted for septic shock that developed within 24 hours before ICU admission were prospectively screened for eligibility. Sepsis, severe sepsis, and septic shock were defined according to consensus definition   were collected prospectively, including age, gender, comorbidities, hemodynamic parameters, vasopressor or inotropic dose, Acute Physiology and Chronic Health Evaluation (APACHE) IV score , and SeqTwo-dimensional conventional Doppler echocardiography and TDI studies were performed with commercially available equipment . All studies were performed and reviewed by cardiologists with advanced training in echocardiography.The transthoracic echocardiographic examination was performed within 24 hours after the onset of septic shock at the first day of ICU stay (day 1). LV end-diastolic volume (LVEDV), LV end-systolic volume (LVESV), and LV ejection fraction (LVEF) were assessed by using the modified biplane Simpson equation in the apical four- and two-chamber views, according to the American Society of Echocardiography Guidelines . Mitral TDI was performed at the apical four-chamber view for the long-axis motion of the heart ,14. Two-The intraobserver and interobserver variability in the measurements of Sa were 1.8% and 4.2%, respectively.Follow-up was performed for 90 days after the onset of septic shock. The primary end point was 90-day all-cause mortality, defined as death within 90 days after onset of septic shock. Death was identified from hospital records or telephone interviews with relatives.The Institutional Review Board of Peking Union Medical College Hospital approved this study protocol. Written informed consent was obtained from either the patients or their authorized relatives.t test or Mann-Whitney test. Categoric variables were compared with the χ2 test or Fisher Exact test. Linear regression was used to investigate the correlation between EF and Sa. A receiver-operating characteristic (ROC) curve analysis was performed to determine the cutoff value of Sa for the prediction of 90-day mortality. The optimal cut-off value was defined as the point at which the value of "sensitivity + specificity - 1" was maximum (Youden index . Forty-nine (80%) patients received norepinephrine infusion at a median dose of 0.5 (0.2 to 0.7) μg/kg/min. The dose of norepinephrine was significantly higher in nonsurvivors (0.6 (0.2 to 1.0) versus 0.3 (0.2 to 0.5) μg/kg/min; P = 0.007]. Twenty-seven (44%) patients were treated with dopamine, the median dose being 6.0 (5.0 to 10.0) μg/kg/min. During the study periods, one patient was treated with dobutamine (5 μg/kg/min), and another, with epinephrine (0.5 μg/kg/min).Table P < 0.0001), with a mean value of 9.0 (6.6 to 11.0) cm/sec for the whole cohort. Sixteen (27%) patients had an LVEF < 50%. LVEF values for survivors and nonsurvivors were 56% (36% to 65%) and 63% (52% to 66%), respectively. Other parameters, including those evaluating diastolic function, did not show any statistical difference between survivors and nonsurvivors  versus 11.0 9.1 to 12.5) cm/sec; .5 cm/secP < 0.0001; log-rank = 24.03; P < 0.0001) . Moreover, norepinephrine dose and PaO2/FiO2 were also independent predictors, whereas heart rate did not exhibit any predictive value. Subgroup analysis showed that, in patients without a history of coronary heart disease, a Sa value of > 9 cm/sec was still an independent predictor of 90-day mortality  . However, similar to our study, the difference in LVEF between survivors and nonsurvivors was not significantly different.In the landmark study of Parker et al. , 10 of tet al. ,18 demonet al.  observedet al. . In anotThe linear correlation between Sa and ejection in our study was similar to that of a previous study . Unlike et al. [Many hypotheses have been proposed for myocardial depression in septic shock ,22. Howeet al.  demonstret al. , was notet al. [Persistent vasoplegia might be another explanation for our finding. Although the Sa has advantages over previously used measures of LV systolic function, such as LVEF, it still is load dependent, afterload especially ,26. In tet al. [n = 21) and high prevalence of cardiac diseases (43%) in the study population. Myocardial infarction may influence systolic and diastolic TDI values, as previously described by Alam et al. [et al. [P = 0.012), precluded direct comparison between their study result and that of our study.Sturgess et al.  also repm et al. . We alsom et al. , Landesb [et al.  did not et al. [et al. [In our cohort of patients, MAP was maintained at a higher level than that recommended by the guideline . This caet al.  reportedet al. . Accordi [et al.  suggesteFirst, the sample size in our study was relatively small, but the robust association between Sa and mortality rate suggests that this was not just an accidental finding. Possible selection biases might exist because more patients were excluded than were studied. However, the baseline characteristics, except for coronary heart disease, did not show significant differences between the patients excluded and included. Second, this study is a single-center study. Our local management strategy may influence the patient's outcome, which might preclude the generalization of the study findings. Third, the potential confounding factors for TDI variables were not explored in this study. A more-detailed study focusing on these confounding factors is highly desirable. Fourth, correlation between TDI variables and blood flow-derived parameters was not performed because pulmonary artery catheters were inserted in only half of the study population.Our study demonstrated that LV systolic function, as determined by TDI, in particular, by Sa, might be associated with mortality in patients with septic shock. Concerning the limitations as discussed earlier, further studies are warranted to confirm our findings.• In patients with septic shock, compared with nonsurvivors, survivors exhibited more marked myocardial depression.• Evaluation of LV function by TDI, in particular, by Sa, might be associated with mortality in patients with septic shock.APACHE: Acute Physiology And Chronic Health Evaluation; E: peak velocity of early diastolic transmitral flow; Ea: early diastolic velocity measured at the mitral annulus; EF: ejection fraction; ICU: intensive care unit; LV: left ventricular; LVEDV: LV end-diastolic volume; LVESV: LV end-systolic volume; PCWP: pulmonary capillary wedge pressure; ROC: receiver-operating characteristic; SIRS: systemic inflammatory response syndrome; SOFA: Sequential Organ Failure Assessment; TDI: tissue Doppler imaging; Sa: peak systolic velocity measured at the mitral annulus.The authors declare that they have no competing interests. All authors report no funding for support of this work.YL, LW, BD, JZ, XG, JP, XH, SZ, QF, and WZ participated in the design of the study and performed the statistical analysis. YL, LW, and BD conceived of the study and participated in its design and coordination. All authors read and approved the final manuscript.Supplement. Supplement to Methods Results.Click here for file


Pan troglodytes) assigned to a life-long sign language communication project presented for sudden death. No other clinical or clinical pathological abnormalities were noted and given the signalment, death due to cardiac failure was suspected. Necropsy findings revealed moderate cardiomegaly and other chronic age-related findings including focal renal tubular cystic dilation and gingival hyperplasia. Histologic evaluation of the heart revealed interstitial fibrosing cardiomyopathy characterized by severe interstitial myocardial fibrosis replacing and separating myofibers within all chambers of the heart, especially the left ventricle, interventricular septum and subvalvular areas. This case report represents an additional case of sudden death associated with interstitial myocardial fibrosis in a chimpanzee. This process has been previously cited as the most common cause of sudden death in aged chimpanzees.A 36-year-old male chimpanzee ( Sudden death associated with heart failure is described as the most common cause of death in captive populations of chimpanzees and has been described in other great apes including gorillas and orangutans –4. The mSeveral mechanisms may contribute to age-related cardiac fibrosis, including recruitment and activation of resident fibroblasts and fibroblast precursors influenced by various molecular signaling pathways such as the endothelial-mesenchymal transition mediated by TGF-β or bone marrow-derived circulating stem cells and monocytes , 6, and Due to the genetic similarities, cardiac disease in aging humans has been compared to heart failure in great apes, especially the chimpanzee. The differences in presentation and lesion characteristics between non-human primates and human cardiac disease are striking in that aging chimpanzees develop a network of interstitial collagen without apparent vascular disease or myofiber injury, whereas humans typically acquire vascular occlusive disease over the course of their lives which leads to ischemic injury to myocardial fibers . Other nPan troglodytes) presented to the Washington National Primate Research Center for postmortem examination following sudden and unexpected death. For the past 31 years, the animal had been housed in an indoor/outdoor facility at the Central Washington University Chimpanzee and Human Communication Institute. The animal was maintained in accordance with the Animal Welfare Act and the Guide for the Care and Use of Laboratory Animals  predominantly within the left ventricular free wall, interventricular septum, and apex of the heart, with similar though less prominent lesions seen in all chambers . There was moderate postmortem autolysis. Externally, there was marked, multifocal gingival hyperplasia and dorsal displacement of the right maxillary canine tooth. Multifocal, postmortem skin abrasions and lacerations were present ventrally, focused on the perioral and scrotal areas. The heart was diffusely, moderately enlarged A, with achambers B. The riTissues were fixed in 10% neutral buffered formalin, processed routinely, embedded in paraffin and stained with hematoxylin and eosin (H&E). Histologic examination of the heart revealed multifocal, moderate to severe, mostly mature fibrosis separating and replacing myofibers in all chambers C and D. Sudden cardiac death has been previously described in great apes and the prevalence of sudden death associated with heart disease in chimpanzees has been reported to be as high as 68% in captive adult populations, with males more often affected than females –13. ThisTrypanosoma cruzi or viral disease was considered unlikely because no histological evidence was present and the chimpanzee did not have a compatible travel history. Amyloidosis has been described concurrently with cardiac fibrosis in one chimpanzee and was thought to be associated with chronic inflammation although no histologic examination was described in that retrospective report , do not develop atherosclerosis naturally, they do form atherosclerotic plaques if fed an atherogenic diet resulting in hypercholesterolemia (Macaca fascicularis) have been shown to display a marked difference in development of atherosclerotic lesions related to age, with young animals (2.5–3.5 years of age) showing less coronary artery lesions despite similar serum lipid concentrations as compared to adults (6–12 years of age)  and supplemented with fruits and vegetables. The average LDL of Americans is 130 mg/dl, while free ranging baboons on a foraging diet have reported values of 40–80 mg/dl . Howevererolemia , 18. Cyn of age) , 20. Oth of age) , 19 but Early diagnosis of heart disease may assist in clinical management. In human medicine, investigation into the potential uses of biomarkers of inflammation, oxidative stress, myocyte injury, and collagen metabolism has been investigated . In one


N = 36) or to sham operation (N = 12). One week after the surgery, rats with heart failure received daily treatment of double-distilled water, captopril or VAD by gavage for consecutively four weeks, while sham-operated animals were given double-distilled water. Ultrasonic echocardiography was adopted to examine cardiac structural and functional parameters and serum brain natriuretic peptide (BNP) concentration was measured using radioimmunoassay. We found that VAD partially reversed changes in cardiac functional parameters and serum BNP levels in rats with heart failure. These results provide further evidence for the heart-kidney-related theory and suggest that VAD might be a potentially alternative and complementary medicine for the treatment of heart failure.Velvet antler of deer (VAD) is a commonly-used kidney-Yang supplementing traditional Chinese medication. According to the heart-kidney-related theory, heart Yang originates in kidney Yang and heart failure due to heart Yang deficiency can be treated by tonifying kidney Yang. In this study, we investigated therapeutic effects of VAD on cardiac functions in rats with heart failure following myocardial infarction. Forty-eight male Wistar rats were subjected either to left coronary artery ligation ( Velvet antler of deer (VAD) is a precious traditional Chinese medication, warm in nature and sweet and salty in flavor, and is commonly used to treat various diseases by supplementing kidney Yang. According to TCM theories, kidney Yang deficiency can be presented in the symptoms including declining libido, soreness, or cold sensation in the knees and lumbar regions, spiritual fatigue, and so forth. Both clinical and animal studies have shown that VAD can promote the development of reproduction systems, relieve the pain of arthritis, nourish the neural cells, and so on . These pHeart failure (HF) is a clinical syndrome which all types of heart diseases will eventually develop into. Evidence from epidemiological studies has demonstrated that the incidence of HF in Chinese adults was 0.9%: it reached 0.7% in males and 1.0% in females . From thLeft coronary artery ligation is one of the widely used animal models to mimic myocardial infarction and heart failure in patients . EchocarN = 48, age 8 weeks, weighing 230 ± 20 g) were purchased from the Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences, Beijing, China. They were housed four/cage in a controlled environment  with food and water ad libitum. All procedures were performed in accordance with the National Institute of Health's Guide for the Use and Care of Laboratory Animals and were approved by the Committee on Animal Care and Use of the China-Japan Friendship Hospital.Male Wistar rats  with a pressure-controlled respirator for small animals . An incision of the skin and intercostal muscles was made between the third and fourth ribs. Under the monitor of a lead 2 electrocardiogram , a thoracotomy was performed and the pericardium was opened, which left the heart adequately exposed. To induce myocardial infarction, the left coronary artery was ligated 1.5–2 mm from the aortic root between the pulmonary cone and the left auricular appendage with silk sutures. Then the muscles and skins were sutured and the ventilation was stopped when rats' heart rate and respiration went steady. The sham-operated animals underwent the same procedure except that the silk suture was placed around the left coronary artery without being tied. After the surgery, all animals were injected with penicillin for three days to prevent infection. Six rats with induced myocardial infarction died during the operation whereas two rats in the sham group died of infection. The operative mortality was 16.7%. The powder of velvet antler of deer  and captopril  were triturated and then well suspended in double-distilled water at the doses of 20 mg/mL and 1 mg/mL respectively. These doses were calculated according to the conversion table of animal doses to human equivalent doses based on body surface area . Provide3- LVDs3)/ LVDd3. Echocardiography  was performed before rats were sacrificed. Under anesthesia by intraperitoneal injection of 40 mg/kg pentobarbital sodium, rats were fixed on their backs with their fur shaved and skin cleaned. Using a high-frequency linear-array transducer (CL15-7), the structural parameters of the heart included left atrial diameter (LAD), left ventricular end-diastolic diameter (LVDd), left ventricular end-systolic diameter (LVDs), end-systolic interventricular septal thickness (IVSTs), end-diastolic interventricular septal thickness (IVSTd), left ventricular end-systolic posterior wall thickness (LVPWTs), and left ventricular end-diastolic posterior wall thickness (LVPWTd). Besides, two functional parameters were calculated by the following formulas: left ventricular short-axis fractional shortening (LVFS) = (LVDd-LVDs)/LVDd, left ventricular ejection fraction (LVEF) = (LVDd125I-BNP (10 000 cpm) was then added, followed by additional incubation for 24 hours at 4°C. Then after 90 min of incubation with a secondary antibody, free and bound fractions were separated, and the radioactivity of the bound fraction was measured by a gamma counter .Blood samples were collected in EDTA tubes, which was then placed on ice and centrifuged within 30 min at 4°C. The plasma was stored at −80°C until assay. Radioimmunoassays for rat BNP were performed as previously reported . BrieflyP < 0.05 was considered to be statistically significant.All data were expressed as means ± standard deviation. Group differences were evaluated using one-way analysis of variance (ANOVA). If the variance of the data was heterogeneous, the Kruskal-Wallis test was adopted, which was followed by the Nemenyi multiple comparison test. P < 0.001) whereas no group differences were found with respect to LVPWTd and LVPWTs (P > 0.05). VAD and CAP treatment did fail to reverse the effects of myocardial infarction on cardiac structural parameters (P > 0.05). Compared to the SHAM group, the diameters of left atrium and left ventricle  of animals in the heart failure groups were significantly increased, the interventricular septal thickness (IVSTd and IVSTs) was decreased (P < 0.001), indicating that cardiac function was severely impaired by myocardial infarction. Further comparisons with the heart failure groups showed that the LVFS of the VAD group was significantly elevated than that of the HF group (P < 0.05) whereas the similar trend in the CAP group did not reach significance (P = 0.377). The LVEFs of both treatment groups were higher than that of the AMI group (Ps < 0.05 for the VAD group and the CAP group). These results indicated that both VAD and CAP partially reversed the functional damage induced by myocardial infarction. No differences were found between the two treatment groups (P > 0.05). Compared to the SHAM group, animals in the heart failure groups had significantly lower LVFS and LVEF (P < 0.001), a change that was reversed by both VAD and CAP treatments (P < 0.05). No differences were found between the two treatment groups (P > 0.05).The serum BNP levels of the HF group were significantly higher than the sham group  in traditional Chinese medicine (TCM), its symptoms can be classified into the categories of dyspnea, palpitation, and edema. This disease is a condition of heart Qi deficiency and heart Yang devitalization due to Zang-Fu dysfunction that could be resulted from various factors such as improper diet, overstrain, and repeated invasion of exterior pathogens. The heart belongs to fire, governs blood and vessels, and controls spirit. It is a vital organ of the body just like a monarch to a country and plays a leading role in physical activities. The kidney belongs to water and is the organ which stores essence as well as true Yin and true Yang. It is the congenital origin and the root of life. Heart Yang originates in kidney Yang. Normal physical activities of the human body must rely on mutual coordination and constraints of these two organs. The outflow of heart Yang is the primary force that warms kidney Yang. The deficiency of Yang in the heart and kidney leads to weak contraction, which causes vascular obstruction and blood stasis, and hence the symptoms of heart failure appear. Just as Previous studies have shown that the TCM syndrome-type of rats with heart failure following myocardial infarction in the current study may belong to the syndrome of deficiency of Qi and blood stasis . The patBased on the heart-kidney-related theory of TCM, in this study we investigated the therapeutic effects of VAD, a precious kidney Yang supplementing medicine, on cardiac structure and function as measured in echocardiography and serum BNP levels in rats with HF induced by myocardial infarction. BNP is a 32-amino-acid polypeptide secreted by the ventricles of the heart in response to excessive stretching of heart muscle cells and therefore has been used as an objective index reflecting the immediate condition of cardiac function and clinical severity of HF . The finWe did not observe the therapeutic effects of VAD in cardiac structural parameters, a finding in contrast to a study showing that chronic treatment with VAD could significantly reverse the enlargement of left ventricle caused by myocardial infarction . The incIn the current study, we used captopril as a positive control and found that VAD and captopril showed comparable effects in reversing changes in functional parameters and BNP levels in rats with heart failure. Although VAD is more expensive than captopril, it has edges over captopril for patients with heart failure accompanied with lower blood pressure given the hypotensive side effect of captopril.In conclusion, the kidney Yang supplementing drug, VAD, shows comparable therapeutic effects with captopril for heart failure induced by myocardial infarction as revealed by functional parameter changes in echocardiography and serum BNP levels. These results provide evidence for the heart-kidney-related theory of TCM and demonstrate that heart failure due to heart Yang deficiency can be treated by strengthening kidney Yang. Therefore, VAD might be a potentially alternative and complementary medicine used in the treatment of heart failure.


The widely used MOdified Look-Locker Inversion-recovery (MOLLI) [1 at higher heart rates, but its dependence on T2 has not been explored. We investigate MOLLI’s T1 accuracy in phantoms and confirm with simulations and in-vivo studies. T1 values are further compared with a saturation-recovery T1 mapping sequence [Diffuse myocardial fibrosis occurs in various cardiomyopathies and can be indirectly assessed with blood and myocardial T2 agarose phantoms with a broad range of T1 and T2 values were imaged with a gold-standard inversion-recovery spin-echo (IR-SE) sequence, MOLLI, and a new SAturation-recovery single-SHot Acquisition (SASHA) technique (Siemens Avanto 1.5T). IR-SE: 16 TIs 100-5000ms, TE=11ms, TR>5s, 90° flip. MOLLI: 2 inversion sets of 3 and 5 images, 75% partial Fourier, TImin=110ms with 80ms increment, 35° flip, TE/TR=1.3/2.9ms, simulated HR=60bpm. SASHA: single-shot SSFP images from 10 consecutive heartbeats with incremented TI spanning the RR interval in the last 9 images (no saturation in the first image), 70° flip, TE/TR=1.3/2.6ms, full k-space, simulated HR=60bpm. T2: spin-echo (SE) with 7 TEs 11-200ms. Simulations: Bloch equation simulations of MOLLI and SASHA were performed in MATLAB using actual acquisition and physiology parameters and SE measured T1 and T2 values.14 NiCl1s were measured using MOLLI and SASHA (parameters as above) in a mid-ventricular short-axis slice at baseline and 20 minutes following 0.1mmol/kg Magnevist.For 10 healthy volunteers , blood and myocardial T2 (179-196ms), SASHA and MOLLI T1s agree well with IR-SE (0.7±0.5% and 2.2±1.8% absolute difference respectively), while shorter T2 (46-76ms) tissue-like phantoms have greater underestimation with MOLLI (8.4±3.5%) than SASHA (0.9±0.6%)  than predicted. SASHA had good agreement with IR-SE T1 phantom measurements and simulations and can be acquired in less time than MOLLI.MOLLI significantly underestimates TN/A


Valvuloarterial impedance (Zva) is a measure of global  load opposing left ventricular (LV) ejection in aortic stenosis (AS). The present study identified covariates and tested the prognostic significance of global LV load in patients with asymptomatic AS.2. The impact of baseline global LV load on rate of major cardiovascular (CV) events, aortic valve events and total mortality was assessed in Cox regression models reporting hazard ratio (HR) and 95% Confidence Intervals (CI).1418 patients with mild-moderate, asymptomatic AS in the Simvastatin Ezetimibe in Aortic Stenosis (SEAS) study were followed for a mean of 43±14 months during randomized, placebo-controlled treatment with combined simvastatin 40 mg and ezetimibe 10 mg daily. High global LV load was defined as Zva >5 mm Hg/ml/mHigh global LV load was found in 18% (n=252) of patients and associated with female gender, higher age, hypertension, more severe AS and lower ejection fraction . A total of 476 major CV events, 444 aortic valve events and 132 deaths occurred during follow-up. In multivariate Cox regression analyses, high global LV load predicted higher rate of major CV events  and aortic valve events  independent of hypertension, LV ejection fraction, female gender, age, abnormal LV geometry and AS severity, but failed to predict mortality.In asymptomatic AS, assessment of global LV load adds complementary information on prognosis to that provided by hypertension or established prognosticators like AS severity and LV ejection fraction. Patients with aortic stenosis (AS) often have hypertension,-5 which The aim of the present study was to further characterize the phenotype associated with high global LV load and prospectively evaluate if high global LV load predicted increased rate of CV events also in patients with milder AS beyond the increased risk associated with concomitant hypertension and other known prognosticators in AS like AS severity and LV ejection fraction,10.The methods and results of the prospective Simvastatin Ezetimibe in Aortic Stenosis (SEAS) study which tested the effect of randomized, double-blind, placebo-controlled treatment with combined simvastatin and ezetimibe on AS progression and CV morbidity and mortality in 1873 patients with initially asymptomatic, mild-to-moderate AS, have been reported. All of Study echocardiograms were recorded at 173 SEAS study sites following a standardized protocol and sent for expert interpretation at the SEAS echocardiography core laboratory at Haukeland University Hospital. The echocardiographic protocol has been previously published,16. All 2.7 exceeded 46.7 g/m2.7 in females and 49.2 g/m2.7 in men, respectively, where v is the mean aortic jet velocity, AVA is calculated by the continuity equation and Aa is the aortic area[Severity of AS was assessed following current guidelines. Energy tic area. Stroke tic area.The primary endpoint of the prospective SEAS study was major CV events, including hospitalization for heart failure due to progression of AS, death from CV causes, aortic valve replacement, non-fatal myocardial infarction, hospitalization for unstable angina, coronary revascularization and non-hemorrhagic stroke. Seconda2[IBM SPSS 20.0  software was used for data management and analysis. The study had a statistical power of 95% to detect a 30% difference in incidence of major CV events, the primary study end-point, with a significance level of 0.01. Data are expressed as mean ± standard deviation for continuous variables and as percentages for categorical variables. High global left ventricular load was defined as Zva > 5.00 mm Hg/ml/mKaplan-Meier curves were used to compare cumulative hazard of CV events in groups of patients who had lower vs. higher global LV load at baseline. Uni- and multivariate Cox regression analyses were used to assess the relation of baseline global LV load to major CV events, aortic valve events, ischemic CV events and total mortality. In the primary multivariate model, global LV load, randomized study treatment, hypertension, LV ejection fraction, female gender, age and abnormal LV geometry were included as covariates. In further models, conventional indices of AS severity, like aortic valve area, mean transaortic gradient and peak aortic jet velocity, were added as covariates. Results are reported as hazard ratio (HR) and 95% confidence interval (CI). A two-tailed p <0.05 was considered statistically significant both in univariate and multivariate analyses.The main clinical and echocardiographic features of the study population are shown in TableIn multivariate linear regression analysis higher global LV load at baseline was independently associated with hypertension, female gender, higher age, lower LV ejection fraction and more severe AS Table.During a mean follow-up of 43±14 months, a total of 476 major CV events, 444 aortic valve events , 226 ischemic CV events and 132 deaths occurred (TableConcomitant hypertension is common among patients with AS, being found in up to 86% of patients in previous studies-5. As reThe present results add to previous knowledge by demonstrating that also in milder, asymptomatic AS, high global LV load is associated with a high risk phenotype including female gender, older age, concomitant hypertension and reduced LV systolic function, independent of an association with more severe AS by conventional measures like peak aortic jet velocity, mean aortic gradient or aortic valve area. Our finding that older age was associated with higher global LV load is consistent with the consequences of vascular aging. PhysiolConsistent with previous reports, hypertenThe negative association between global LV load and LV ejection fraction is in line with previous studies reporting increased global LV load to be associated with reduced LV systolic function assessed by midwall shortening or longitudinal strain-35. In tConfirming our hypothesis, global LV load predicted an increased rate of major CV events, in particular aortic valve events, independent of hypertension. As previously reported from the SEAS study, concomitant hypertension primarily predicted increased risk of ischemic CV events and mortality. Of note2 predicted increased 4-year mortality, while the present study defined high global LV load as valvuloarterial impedance >5.00 mmHg/ml/m2. Of note, the present results add to the finding by Lancellotti et al. from a prospective study in 163 patients with asymptomatic, moderate to severe AS, that higher global LV load predict rate of major CV events independent of peak aortic jet velocity, while longitudinal deformation and left atrial area index were not assessed in the present study[Our findings expand observations from a retrospective study by Hachicha et al. in 544 patients with asymptomatic moderate AS. In theint study. Furthernt study. In contnt study,37.It has been suggested that calculating global LV load using central systolic blood pressure might yield better prediction of adverse outcome. Central blood pressure was not recorded in the SEAS trial. However, the use of central instead of brachial aortic blood pressure did not increment the predictive ability of global LV load in a recent publication.The present study was not designed to assess the effect of different types of medication on the progression of global LV load. 68% of hypertensive SEAS patients were on blood pressure-lowering medication. However, at baseline, no difference in use of different classes of antihypertensive agents was found between patients with lower vs. higher global LV load. Although the study had high power to detect a difference in incidence of major CV events, including total mortality, the study did not have statistical power to detect the observed 20% difference in ischemic CV event incidence between the groups. Thus, a type 2 error cannot be excluded for the lack of association between high global LV load and rate of ischemic CV events in the present study.AS: Aortic valve stenosis; CV: Cardiovascular; LV: Left ventricle; SEAS: Simvastatin and Ezetimibe in Aortic Stenosis; Zva: Valvulo-arterial impedance; CI: Confidence Interval.The authors declare that they have no competing interests.ÅER, EG and DC designed the study, participated in data collection, performed the statistical analysis and drafted the manuscript. EB participated in the data collection. EB MTL CGB GC and SR participated in revisions of the manuscript. All authors read and approved the final manuscript.


The complexity of cardiopulmonary exercise testing data and their displays tends to make assessment of patients, including those with heart failure, time consuming.2 and CO2 content differences, and ventilation  Only 16 were classified as having NYHA Class IV heart failure and 52 as having NYHA Class II heart failure. Ten of the 16 patients with Class IV heart failure were randomly selected for comparison with an equal number (n=10) of the 52 patients with Class II heart failure of similar sex, age, and size. For the patients with heart failure, ejection fractions had been obtained by echocardiography and resting hemodynamics by cardiac catheterization within 3 weeks of exercise tests. All patients were considered to be optimally medicated by their physicians; most were receiving β-blockers, diuretics, and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers.All of the patients with heart failure were participants in St. Jude Medical device studies and were carefully seen, screened, classified, treated, and managed by cardiologists at other institutions. All had systolic dysfunction with left ventricular ejection fractions <35%. None were considered to have significant anemia or pulmonary, neuromuscular, or skeletal disorders.17 Peak 2 pulse were measured over that same time period. The anaerobic threshold was measured by the V-slope method.17With a physician in attendance, gas exchange and ECG measurements of subjects or patients were made with well-maintained commercial equipment systems  that were properly calibrated just before each test. The protocols required measurements during 3 minutes of rest and 3 minutes of unloaded cycling or comparable warm-up on the treadmill, followed by a progressively increasing work rate in ramp pattern or 1-minute intervals to maximum tolerance, followed by 2 to 3 minutes of recovery. The schedule for increasing the work rate was designed to have the subjects smoothly reach their maximum tolerated work rate in 6 to 15 minutes of exercise, whether on the cycle or treadmill. Whether a cycle or treadmill was used, work rate was increased at 10 to 30 Watts/min for healthy subjects and 5 to 15 Watts/min for patients according to their size, sex, and perceived health. Breath-by-breath data were interpolated to second-by-second values, sequentially averaged in 10-second bins, and plotted traditionally with heart rate data in 9 panels.For each exercise test, time, activity level, 19 Data from these same subjects20 were used to calculate normal reference 90-second values for highest mean±SD 21 and mean±SD values of relevant gas exchange variables and parameters were calculated for the 3 previously identified groups. Analyses of variance (with Tukey tests) or unpaired 2-tailed t tests were used to compare variables. P values <0.05 were considered statistically significant.Reference mean ± standard deviation (mean±SD) values for 90-second averages of highest P value differences between groups are indicated by single or multiple asterisks (*) or daggers (†). Demographics do not differ significantly except for lower ages in the healthy subjects, but the patients with Class IV heart failure show a trend (P>.05) toward lower ejection fractions and lower stroke volumes than those seen in the patients with Class II heart failure. The upper half of P<0.05 or 0.01). The lower half of 2 pulse, or P<0.001 and P<0.01, respectively). In a comparison of the patients with Class II heart failure versus those with Class IV heart failure, the P>.05) higher (23.9 versus 21.8 L/min and 26.7 versus 23.9 L/min). Given the numerators, C(a−v)O2 and C(v−a)CO2 should not be larger in Class II than Class IV heart failure,22 so the dominant difference between the groups must be cardiac output. Because In 23 with heart failure before and after a change in treatment  before and 3 months after adjustment of his drug therapy.23 Note the changes in resting and exercise values and the changes in pattern of Six studies of successive 90-second averages of subjects , 2 patiesubjects , and 1 preatment . These dThus, in groups and individuals, both highest 19 The new display plus the data and analyses of this study CO2 differences progressively widen soon after the onset of exercise.24 In healthy subjects, after considerable variability of 2 and C(v−a)CO2 differences increase proportionally considerably more than 2 and 2 and 2 decline more than 2; and finally (6) although not recorded, predominantly easterly to eventually return to resting values when O2 debt is gradually repaid.Increases or decreases in the numerators (cardiac output times blood differences) or denominators CO2, so that further increases in the numerators during exercise are limited.A high Optimally, during exercise, both perfusion and ventilation are not only “matched” but are adequate without being “wasteful.” From our perspective, perfusion and ventilation are least wasteful and best matched during moderate-intensity exercise—ie, near the anaerobic threshold CO2. Despite that, the absolute values and changing patterns of (1)


Renal artery stenosis (RAS) promotes hypertension and cardiac dysfunction. The 2-kidney, 1-clip mouse model in many ways resembles RAS in humans and is amenable for genetic manipulation, but difficult to evaluate noninvasively. We hypothesized that cardiovascular magnetic resonance (CMR) is capable of detecting progressive cardiac and renal dysfunction in mice with RAS and monitoring the progression of the disease longitudinally.RAS was induced at baseline in eighteen mice by constricting the renal artery. Nine additional animals served as normal controls. CMR scans (16.4 T) were performed in all mice one week before and 2 and 4 weeks after baseline. Renal volumes and hemodynamics were assessed using 3D fast imaging with steady-state precession and arterial spin labelling, and cardiac function using CMR cine. Renal hypoxia was investigated using blood oxygen-level dependent (BOLD) MR.Two weeks after surgery, mean arterial pressure was elevated in RAS mice. The stenotic kidney (STK) showed atrophy, while the contra-lateral kidney (CLK) showed hypertrophy. Renal blood flow (RBF) and cortical oxygenation level declined in the STK but remained unchanged in CLK. Moreover, cardiac end-diastolic and stroke volumes decreased and myocardial mass increased. At 4 weeks, STK RBF remained declined and the STK cortex and medulla showed development of hypoxia. Additionally, BOLD detected a mild hypoxia in CLK cortex. Cardiac end-diastolic and stroke volumes remained reduced and left ventricular hypertrophy worsened. Left ventricular filling velocities (E/A) indicated progression of cardiac dysfunction towards restrictive filling.CMR detected longitudinal progression of cardiac and renal dysfunction in 2K, 1C mice. These observations support the use of high-field CMR to obtain useful information regarding chronic cardiac and renal dysfunction in small animals. Cardiovascular disease (CVD) associated with renovascular disease is a major cause of morbidity and mortality among patients with chronic kidney disease (CKD)-3. RenalSeveral imaging modalities can provide important diagnostic and prognostic insights into cardiac and renal dysfunction in RAS. In the Echocardiography has been extensively used for quantitative LV characterization using imUltra-high field (UHF) MRI has surpassed some limitations of small animal CMR imaging and improved cardiac imaging in mice. The modThe aim of this study was to determine if UHF-CMR can non-invasively quantify crucial parameters of cardio-renal dysfunction and the progression of LV dysfunction secondary to RAS in 2K, 1C mice model.All animal procedures were performed in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals, and approved by the Mayo Clinic Institutional Animal Care and Use Committee.The study was performed on 27 male 129S1 mice . Animals arrived to the lab at 6 weeks of age, were acclimatized to blood pressure measurements, and underwent a baseline CMR scan a week later. Then mice were randomly divided into two groups. RAS was induced in the first group (n = 18) one week after the baseline scan by surgical placement of an arterial cuff. The second group (n = 9) served as the control Normal. All the animals underwent additional scanning 2 and 4 weeks later.Animals in the RAS group were anesthetized with Isoflurane (1.5-2.0%). The right lateral area between the margin of the rib cage and thigh was shaved and scrubbed with povidone-iodine solution. The right kidney was exposed by a flank incision (~1 cm) and reflected midline. The right renal artery was then bluntly dissected from the renal vein between the renal bifurcation and the bifurcation of the testicular artery. A 0.2 mm ID × 0.5 mm length cuff  was cut longitudinally, placed around the renal artery, and secured with 10-0 nylon suture. Kidney was returned to its native position and the incisions were sutured as described,27.Mice were recovered on a warm (37°C) pad until ambulatory, and then returned to normal housing with ad libitum access to standard chow and water. Blood pressure and heart rate were measured before, at 2 weeks and at 4 weeks after baseline by tail-cuff, using a XBP1000 system . Animals were euthanized within a day after the 4-weeks scan. The kidneys and the heart were harvested and fixed for immunohistochemical staining.Imaging was performed on an Avance DRX 700WB  spectrometer with a vertical 16.4 T wide bore magnet equipped with mini imaging accessories. A 38 mm volume RF coil was used for the kidney and cardiac imaging. Mice were mounted vertically along the magnetic field in a home-made animal holder. Cardiac and respiratory monitoring and gating were performed using the Control/Gating Module of Model 1030 Monitoring and Gating System . Body temperature was measured through a rectal sensor, using temperature module and maintained at 37°C throughout the course of experiment. Respiration was measured through a balloon sensor attached to Respiration Module and monitored using the software provided by SA Instruments. Using 3 planes , scout images were collected to locate the heart and kidneys and prescribe the geometry for anatomical and functional imaging.Renal perfusion and volume were measured in all animals. Renal blood oxygenation level and cardiac function were measured in all control animals (n = 9) as well as in 12 of the 18 RAS animals.The kidney volumes were estimated from images collected using respiratory-gated 3D Fast Imaging with Steady Precession (3D-FISP)  method using a BOLD CMR was applied using respiratory-gated conventional 2-dimensional Multi-Gradient Echo (MGE) sequence  BOLD CMR images were also collected using 3-dimensional MGE to investigate the feasibility of reducing the effect of the external field inhomogeneity and susceptibility artefact. The samThe cardiac cine images were acquired using IntraGateFast Low-Angle Shot (ig-FLASH) sequence . Corticomedullary borders were evident in the MR images and used to differentiate cortical and medullary regions of interest (ROI).ASL Tool Module (Bruker-ParaVision) was used to calculate cortical and medullary perfusion in both the stenotic and contra-lateral kidneys. Blood flow for each compartment was calculated by multiplying its perfusion and corresponding volume, and RBF calculated as their sum.2* (1/T2*), we took advantage of the high contrast of cortex and medulla in ASL images to differentiate the two compartments. ROIs were drawn on ASL images and then transferred to all BOLD images corresponding to the 8 echo times. Voxel-based R2* values were calculated by fitting the decaying signal of each ROI to a mono-exponential curve vs. echo times, and cortical and medullary R2* values by averaging the R2* values for all voxels within the corresponding ROIs.To calculate the BOLD index, RCardiac function was calculated from cine images, reconstructed by Paravision-IntraGate Module. LV myocardial volume was estimated by drawing ROIs around the outer and inner segments of the myocardium, calculating the difference, and multiplying by the slice thickness (Simpson’s rule). The strHIF-1α and trichrome were stained on 5-μm axial slides of tissue using Rabbit polyclonal antigen  with working dilution of 1:100. EDTA was used for antigen retrieval.Minimum sample size was calculated using power analysis for the power value of 0.8. Non-parametric Wilcoxon signed-rank test was used for comparisons within groups and Mann-Whitney for comparison among groups. For p values smaller than 0.05, differences were considered significant.Blood pressure measurements at 2-weeks demonstrated development of renovascular hypertension in RAS. Mean, systolic, and diastolic blood pressures were significantly increased in RAS and remained elevated throughout the study, while control blood pressure remained unchangedTable . Two weeTwo weeks after inducing RAS, the STK cortical and medullary volumes significantly decreased, and by the fourth week were on average reduced to 39% and 61% of their baseline values, respectively (p < 0.001). At 2 weeks, the CLK cortical volume tended to increase (p = 0.06 vs. Baseline) and at 4-weeks was significantly elevated compared to both baseline and the control 4-weeks. Medullary volume remained unchanged during the first 2 weeks, but at 4 weeks was subsequently diminished compared to the control group . In the CLK, however, cortical blood flow was preserved, although CLK medullary blood flow decreased by the fourth week compared to the control. Control RBF remained unaltered at all time points.Both medullary and cortical perfusions in the STK were impaired at two and four weeks (p < 0.001 vs. baselines and Control), whereas CLK cortical perfusion was not significantly changed, but showed strong tendency to decline during the entire 4 weeks of RAS.In all the groups BOLD images, acquired using the conventional method, were highly affected by susceptibility artefacts, particularly in regions adjacent to the bowel.2* in the STK significantly increased  at 2-weeks and further elevated at 4-weeks  . In the CLK, at 4-weeks cortical oxygenation significantly diminished (p < 0.015 vs. Baselines and 4-weeks Control) although it was significantly higher than in STK. R2* values in the control group were unchanged.In BOLD acquired with the improved method, cortical RIn RAS stroke volume and cardiac output decreased at 2 weeks Table C.The quality of images deteriorated as the number of reconstructed phases per cardiac cycle increased. End-diastolic, end-systolic, and stroke volumes, calculated from images reconstructed at 25 and 40 phases per cycle were slightly (7-11%) albeit not significantly, higher than those calculated from the set acquired with 10 phases per cycle Figure B, while 2 = 0.32, p < 0.0001). Additionally, in the STK cortex volume and oxygenation level correlated with its perfusion .Linear regression Figure  revealedRenal staining for HIF1-α and trichrome, indices of tissue hypoxia and fibrosis, demonstrated significantly higher values in STK vs. CLK at the end of fourth week Figure .This study demonstrated the feasibility of using UHF-CMR to longitudinally derive quantitative measures of both renal and cardiac function and structure in mice with RAS. The sequential changes in renal and cardiac function were significant compared to matched controls, and corresponded to the pathophysiology of the disease.Two weeks after unilateral RAS, MAP showed significant elevation and hemodynamic and morphological changes were evident. Main renal artery stenosis reduces the intra-renal perfusion pressure, which activates renin-angiotensin-aldosterone system (RAAS). RAAS acIn the CLK, hypertrophy in the face of unchanged RBF slightly reduced cortical perfusion. In contrast to the STK, no correlation was found between cortical perfusion and volume, suggesting that the perfusion decline in CLK is regulated by factor(s) other than hypertrophy alone. Previous studies have demonstrated significantly higher renal vascular resistance in CLK of 2K, 1C rats as a result of elevated oxidative stress or reduced bioavailability of nitric oxide. In addiLV dysfunction driven by hypertension was also observed two weeks after RAS induction. Myocardial hypertrophy, initially an adaptive mechanism in response to the increased afterload, subsequently evolves into pathological cardiac remodelling, reducing stroke volume and cardiac output. Our res2* values in CLK were significantly lower than those in the STK. Histological markers of tissue hypoxia and fibrosis were greater in the STK compared to the CLK, confirming BOLD-MRI results and implying deterioration of the STK structure. In the heart, despite further hypertrophy of the myocardium, functional parameters at 4 weeks did not change any further. Nevertheless, high values of E/A became more common, suggesting further progression towards LV restrictive diastolic dysfunction, concordant with aggravated LVH.By 4 weeks of RAS MAP remained elevated, STK RBF, perfusion and volume remained impaired, and hypoxia exacerbated. Conversely, the CLK cortex underwent further hypertrophy and a mild hypoxia, likely due to over-functioning as a compensatory mechanism in the face of slightly declined perfusion that was correlated to the cardiac output. Yet, RThese observations indicate that UHF-CMR allows a detailed characterization of the evolution of cardiac dysfunction following RAS. In large animal models and clinical studies, CMR is the reference standard for diagnosis of cardiac and renal dysfunction. Several studies have demonstrated the accuracy of this modality compared to ultrasound-based methods,39. NeveIn addition to cardiac imaging, UHF-CMR was found to be useful for functional renal MRI. Kidney perfusion measurement using ASL is rapidly gaining popularity due to its non-invasive nature. ASL relies on endogenous spin labelled plasma, which carries no physiological hazard, while an alternative perfusion measurement method, dynamic contrast-enhanced CMR, requires administration of potentially nephrotoxicity contrast-media, particularly in functionally compromised kidneys. To the best of our knowledge, this is the first study utilizing ASL with UHF in the kidney. However, previous studies in other organs have suggested that ASL benefits from high fields,44. Prol2* values calculated from conventional BOLD maps were highly influenced by the susceptibility artefact. Therefore, improved BOLD was employed under the assumption that reducing the thickness and utilizing isotropic voxels would reduce the phase dispersion caused by the macroscopic external field inhomogeneity, while the microscopic field inhomogeneity caused by deoxyhemoglobin would remain unaffected[2* values generally observed in the improved compared to the conventional BOLD. Nevertheless, because R2* values are scaled by magnetic field strength, and the values in this study are considerably higher than those acquired using clinical MR systems (1.5 and 3 T)[Yet, the high signal-to-noise ratio in UHF-CMR comes at the cost of amplified susceptibility artefact, which particularly affects BOLD images corresponding to later echoes with longer TE values. Perfectaffected. Theoretand 3 T), or evenand 3 T).Our study involved several limitations. Mice reach sexual maturity between 5-8 weeks of age. Body weight, renal, and myocardial volumes in the control group showed slight growth during the course the study. Physiological parameters in the RAS group were compared not only to their baseline, but also to those in the control group, yet we cannot rule out the influence of age on the longitudinal assessments. Furthermore, despite using a similar cuff, the severity of RAS and the rate of progression of the disease might not have been identical in all animals, due to intrinsic variability. This might have introduced variations in some of the physiological markers and influenced their statistical significance. In addition, renal cortical and medullary volumes were quantified from 3D images with relatively short echo time, and especially in the STK were at times difficult to differentiate. Similarly, ASL images were also less clear in STKs. In the heart, dark regions caused by ventricular blood vortex, particularly in slices in the vicinity of the mitral and aortic valves, could have been mistaken for myocardium and introduced some error into myocardial mass quantifications. Nevertheless, our measurements were consistent.Despite potential limitations, UHF-CMR detected measurable changes in functional and morphological biomarkers of cardio-renal dysfunction, and afforded a comprehensive depiction of longitudinal progression of the disease. Importantly, UHF-MRI, non-invasively, provided useful information on a broad range of markers of cardiac and renal dysfunction at higher spatial and temporal resolution than typically achieved using alternative modalities. These observations support the application and further development of UHF-MRI for studies of renal and cardiac function.2 K: 1C, 2-kidney, 1-clip; STK: Stenotic kidney; CLK: Contra-lateral kidney; BOLD: Blood oxygen-level dependent; CKD: Chronic kidney disease; CVD: Cardiovascular disease; E/A: Early to late ventricular filling velocity ratio; LV: Left ventricular; LVH: Left ventricular hypotrophy; RBF: Renal blood flow; RAS: Renal artery stenosis; UHF-MRI: Ultra-high field magnetic resonance imaging.The authors declare that they have no competing interests.BE made substantial contributions to the conception, design, acquisition of data, analysis and interpretation of data, drafting the manuscript and has given final approval of the version to be published. JAC has made substantial contributions to the analysis and interpretation of data, drafting the manuscript and has given final approval of the version to be published. BEK has made substantial contributions to design, surgical procedures, acquisition of data, drafting the manuscript, revising it critically, and has given final approval of the version to be published. SIM has made substantial contributions to the conception, design, acquisition of imaging data, analysis and interpretation of data, revising it critically for important intellectual content and has given final approval of the version to be published. JPG made substantial contributions to the conception, design, interpretation of physiological data, revising it critically for important intellectual content and has given final approval of the version to be published. LOL made substantial contributions to the conception, design, interpretation of data, drafting the manuscript and revising it critically for important intellectual content and have given final approval of the version to be published. All authors read and approved the final manuscript.