The terms used to describe different states of myocardial health and disease are poorly defined. Imprecision and inconsistency in nomenclature can lead to difficulty in interpreting and applying trial outcomes to clinical practice. In particular, the terms ‘viable’ and ‘hibernating’ are commonly applied interchangeably and incorrectly to myocardium that exhibits chronic contractile dysfunction in patients with ischaemic heart disease. The range of inherent differences amongst imaging modalities used to define myocardial health and disease add further challenges to consistent definitions. The results of several large trials have led to renewed discussion about the classification of dysfunctional myocardial segments. This article aims to describe the diverse myocardial pathologies that may affect the myocardium in ischaemic heart disease and cardiomyopathy, and how they may be assessed with non-invasive imaging techniques in order to provide a taxonomy of myocardial dysfunction. While there are clear theoretical benefits in improving blood supply to large areas of dysfunctional ‘viable’ myocardium, several recent clinical trials have failed to demonstrate improved outcomes following revascularization.12Studies have demonstrated the benefits of pharmacologicalOne explanation for these results may be the terminology employed to describe myocardial health. In particular the terms ‘viable’ and ‘hibernating’ are often used interchangeably and sometimes incorrectly. ‘Viable’ is a summative term used to describe a range of myocardial states including both normal and diseased segments that nonetheless contain a substantial number of cardiac myocytes. Viable myocardial segments can thus include partial thickness scar with fairly normal cardiac myocyte function in the residual portion or myocytes that exhibit contractile dysfunction or failure. On the other hand, ‘hibernating’ myocardium refers only to the latter subgroup and can be narrowly defined as chronically dysfunctional, ischaemic myocardium that recovers contractile function following improvement in myocardial perfusion limitation. It follows that assessment of ‘viability’ can be made, to a large degree, prior to revascularization, but identification of ‘hibernation’ may only be retrospective. Furthermore, identifying myocardium as ‘viable’ does not necessarily imply ‘hibernation’ or functional recovery following revascularization, as is sometimes assumed.A second challenge in the taxonomy of myocardial dysfunction is that it may be assessed with a range of non-invasive imaging techniques. The available techniques differ fundamentally in methodology, the properties of acquired images and the tests' limitations. Therefore, discrepancies between the modalities are inevitable, making consistency in the definition of myocardial states across imaging fields challenging. Understanding these differences is imperative, especially in the design and interpretation of studies to determine the role of revascularization in patients with long-standing LVSD.This article creates a clinical taxonomy for the different states of myocardium that may exist and coexist in ischaemic heart disease and cardiomyopathy with reference to histology and non-invasive imaging techniques.Table 1).Non-invasive imaging techniques assess different aspects of myocardial health: function and morphology, perfusion, metabolism, and tissue characterization (14 Cardiac magnetic resonance (CMR) produces high-resolution morphological and cine images of the heart in unrestricted imaging planes and with high accuracy and reproducibility.16 In addition, cine CMR with tissue tagging or feature tracking analysis allows quantitative assessment of segmental contractile function. Both echocardiography and CMR can be combined with pharmacological (dobutamine) or physiological (treadmill/static bike) stress to detect ischaemia and viable, dysfunctional myocardium18 through demonstration of contractile reserve. Single photon emission computed tomography (SPECT) and positron emission tomography (PET) can provide information on global and regional contractile function, but at a lower resolution than echocardiography and CMR. Nuclear techniques are less suited than echocardiography and CMR to measure wall thickness. With all imaging techniques, assessment of segmental contractile reserve is significantly limited by adjacent wall motion abnormalities due to ‘tethering’.19Echocardiography provides real-time cine assessment of cardiac structure, myocardial wall thickness, and contractile function. Tissue Doppler imaging (TDI) adds quantification of myocardial motion and global longitudinal strain can be used to detect subtle systolic and diastolic abnormalities that may have greater prognostic value compared with LVEF.20 Myocardial perfusion CMR tracks the myocardial passage of predominantly extracellular paramagnetic contrast agents21 and allows estimation of absolute myocardial flow (MBF) and myocardial perfusion reserve (MPR).22 Single photon emission computed tomography and PET detect perfusion defects through a reduction of signal from radionucleotide bound perfusion tracers in the region of interest23; PET is considered the ‘gold-standard’ for quantitation of MBF and MPR .Myocardial contrast echocardiography is used to measure perfusion by observing the distribution of intravascular microbubbles in the myocardium and provides a surrogate of myocardial blood flow.The principal method for metabolic myocardial imaging is currently PET, which allows myocardial metabolic substrate utilization to be characterized and quantified. Magnetic resonance spectroscopy is a less widely used method to interrogate myocardial energetics.25 while T2-weighted CMR provides assessment of myocardial oedema. Integrated back-scatter echocardiography, which provides assessment of tissue fibrosis might also be applied in this context.Non-invasive tissue characterization is predominantly performed with CMR. Late gadolinium enhancement (LGE) CMR allows identification of scar and focal fibrosis. T1 and extracellular volume (ECV) measurement appears a useful and reproducible surrogate for diffuse myocardial fibrosis,Hybrid systems that combine anatomical with perfusion or metabolic imaging (e.g. PET/MR) are becoming available whilst molecular imaging may soon allow identification of specific biological processes.Normal    (a) Acute prolonged ischaemia    (b) Chronic intermittent ischaemiaReversible ischaemiaStunningHibernationInfarctionIschaemicMyopathicDefinition: Normal myocardium is by definition viable and metabolically active with normal contractile function and exhibiting contractile reserve in response to increased demand.Metabolism: Normal cardiac function, including contraction, relaxation, and ionic regulation, is dependent upon adenosine triphosphate (ATP) metabolism. The majority of ATP consumption occurs in myo-fibrils throughout the cardiac cycle. Further ATP is used to regulate sarcolemmal calcium and, at the membrane, Na+/K+ ATPase transporter.27 The heart consumes ATP rapidly and is dependent upon constant renewal of ATP, which in turn is dependent upon creatine phosphate levels. Were ATP production to cease and consumption to continue unchecked, cardiac stores would be depleted in ∼10–15 s.26 There are three main pathways by which ATP is synthesised: fatty acid oxidation, ketone body, and carbohydrate metabolism. Fatty acid oxidation yields the most ATP, though all pathways share a common endpoint of mitochondrial ATP synthesis.28 In situations of increased metabolic demands, the proportion of ATP derived from carbohydrate metabolism increases .27Histology: More than 70% of left ventricle (LV) myocardial tissue volume is cardiac myocytes; the rest is vasculature and extra cellular matrix (ECM).29 Predominantly containing collagen types I and III, ECM composition is regulated by a number of factors, including circulating neuro-hormones and mechanical strain.31Imaging, morphology, and function: The LV is a conical structure that tapers from base to apex. The normal LV wall has a thickness of between 6 and 10 mm in men, and 6 and 9 mm in women,32 in diastole and thickens uniformly by at least 50% in systole. In response to increasing demand, contraction becomes increasingly dynamic.33 Quantitative measurement of the T1 signal, by T1 mapping, shows normal values in narrowly defined ranges,34 but depend on scanner field strength and pulse-sequence used.34Extracellular volume, calculated using pre- and post-contrast T1 mapping, is less method dependent and is 26 ± 3% in healthy myocardium.24As well as function, it is also possible to assess the constituents of myocardium and tissue homogeneity. By CMR the signal in healthy myocardium is uniform on T1 and T2 weighted and contrast enhanced images. Semi-quantitative assessment of the ratio of T2 signal in healthy heart to skeletal muscle is <1.9.Figure 5). Myocardial perfusion may be quantified both at rest and hyperaemia, allowing calculation of MPR. By PET normal resting MBF is ∼0.7 mL/min/g, increasing to 2.75 mL/min/g on stress, with a flow reserve of >4.35 ‘Gold-standard’ PET flow quantification is not without limitation, especially when the flow reduction is only mild.36 Estimates of absolute MBF with CMR show limited agreement with PET,37 though MPR correlates well with PET in health and disease,37 with normal MPR by CMR being ∼2.2.38Nuclear techniques of perfusion and metabolism display uniform signal throughout the myocardium .Exercise or dobutamine stress echocardiography allows detection of ischaemia as well as determining its location and extent.Figure 7). Quantitative assessment of perfusion with CMR has limited agreement with PET imaging44 and is less commonly used in clinical practice than qualitative assessment.Cardiac magnetic resonance also allows detection of ischaemia through assessment of regional systolic function. Tissue perfusion can be assessed using first pass adenosine stress CMR  may be appreciated on stress SPECT imaging, marking adverse prognosis.48 Transient ischaemic dilation may either represent true dilation as a result of severe coronary disease and stunning, or rather may reflect sub-endocardial defects not appreciated on perfusion imaging.49Single photon emission computed tomography is commonly used in the investigation of chronic intermittent ischaemia, and while image quality on PET is superior to SPECT, availability of PET limits utility. The sensitivity and specificity of SPECT compare well with other non-invasive imaging techniques50 As well as detection of ischaemia it is also possible to measure myocardial blood flow with PET,51 enabling quantitative assessment of myocardial blood flow reserve, which correlates strongly with coronary artery stenosis severity.52In head-to-head studies, the theoretical advantages of PET over SPECT have been demonstrated.Definition: Myocardium is ‘stunned’ when contractile function is depressed following transient ischaemia, prior to a full recovery, and having sustained no irreversible myocyte damage. The mechanism of sustained systolic dysfunction in stunning is incompletely understood. However, it is believed that oxygen free radical formation and elevated myocardial calcium levels may lead to damage of myocardial proteins or sarcoplasmic reticulum.53Metabolism: Sub-epicardial and sub-endocardial myocardial blood flow normalises quickly following restoration of normal coronary flow, however normal myocardial metabolism takes time to recover. Metabolic changes in transient ischaemia, including fall in myocyte ATP, phosphocreatine and pH, take several hours to reverse.54 Post-ischaemic myocardial oxidative and glucose metabolism remain depressed by ∼20% of normal levels for several hours after an ischaemic insult, and take up to 1 week to recover to near normal levels.55Histology: Histological changes reflect sustained ischaemia. In common with metabolic changes, resolving myocardial oedema, myocardial glycogen, and ATP depletion40 may be detected several days later.Imaging, morphology, and function: Systolic function of affected segments is impaired in stunning. The speed of recovery of systolic function is variable and may be related to the duration and severity of the ischaemic insult,57 Abnormalities of diastolic function, whether assessed by CMR, conventional or tissue Doppler persist beyond systolic abnormalities.59 It is likely that stunning is an under-appreciated phenomenon as functional abnormalities associated with acute ischaemia will often have recovered.60Dobutamine stress echocardiography in reperfused acute MI has been shown to predict recovery of dysfunctional segments with sensitivity and specificity of 86 and 90%, respectively.Cardiac magnetic resonance demonstrates changes in keeping with ischaemia including high signal on T2-weighted images indicative of oedema, as well as regional systolic and diastolic wall motion abnormalities.58Positron emission tomography FDG metabolism assessment may demonstrate depressed levels of glucose metabolism, but no significant metabolism perfusion mismatch, as in hibernation, is seen.Definition: Chronically dysfunctional viable myocardium of ischaemic origin that recovers systolic function following revascularization.61 This leads to repeated episodes of ischaemia and repetitive myocardial stunning, causing a complex series of physiological and structural changes characteristic of hibernation.62 The abnormalities seen in hibernating myocardium become more pronounced as the duration of hibernation increases.64 The time course of recovery of LV systolic function following revascularization is dependent upon the severity of myocardial change, with some studies suggesting that irreversible remodelling may occur with extended hibernation despite successful revascularization.65 However, it is not known if delayed recovery may occur beyond study duration.66The processes underlying the development of hibernation remain unclear, although several mechanisms have been proposed. It is thought that although resting blood flow is normal, coronary flow reserves are low.Metabolism: There remains debate regarding the metabolic changes present in hibernation. However, there is evidence to suggest that glucose uptake and utilization are increased and fatty acid metabolism is decreased in hibernating myocardium.68Histology: Hibernating myocardium is macroscopically similar to normal myocardium. However, at a microscopic level, there are diffuse changes within the myocyte and extracellular ultrastructure.62 Structural changes in the ECM become more pronounced as duration of hibernation increases.69 Furthermore, there is down-regulation of myocyte mitochondria and increased glycogen storage when compared with both normal and remote myocardium.68 These changes reflect alteration of mRNA expression and disorganization of cytoskeletal proteins as a result of cellular de-differentiation.All types of collagen increase in the ECM of hibernating segments, and are more than twice that found in normal myocardium when de-differentiation is severe.Imaging, morphology, and function: On functional imaging, hibernating myocardium has impaired resting systolic function, and will typically be hypo- or akinetic. Diastolic wall thickness is >6 mm by CMR70 or 7 mm on trans-thoracic echocardiography,65 though recent studies have demonstrated that thinning below these thresholds, in the absence of extensive scar, does not preclude recovery.71 With inotropic stimulation, hibernating myocardium shows ‘contractile reserve’ or a ‘biphasic response’, with an improvement in contractile function on low-dose/effort stress prior to deteriorating at higher workloads.72 Low dose stress TDI allows quantification of systolic function: Doppler tissue velocities increase more in hibernating myocardium than in dysfunctional tissue that does not show improvement in systolic function following revascularization .74. Late gadolinium enhancement CMR contributes only indirectly to the diagnosis of hibernation. On LGE CMR, hibernating myocardium has the same signal characteristics as normal myocardium, with signal uniformly nulled. Late gadolinium enhancement CMR therefore only excludes the presence of myocardial infarction as the cause of contractile dysfunction, suggesting hibernation as one of several potential causes. Absence of LGE in dysfunctional segments in ischaemic heart disease may predict functional recovery following revascularization .75 Cardiac magnetic resonance prediction of recovery can be further enhanced by combined use of functional, LGE, and dobutamine stress imaging. Hibernating myocardium has reduced resting function, the absence of LGE and a biphasic response to dobutamine stress.72 Finally, myocardial perfusion can be assessed and quantified by first pass CMR. Resting MBF (mL/min/g) is normal in hibernating myocardium, and hyperaemic blood flow is reduced with subsequent improvement following successful revascularization.76Cardiac magnetic resonance examination allows for accurate assessment of diastolic wall thickness and regional wall motion abnormalities+/K+ ATPase and preserved sarcolemmal membrane function.66 In hibernating myocardium, early acquisition following tracer administration identifies a defect, reflecting impaired blood flow on stress, though delayed early uptake may also be evident on rest in severe LV dysfunction.77 On delayed acquisitions, the isotope has been taken up by metabolically active myocytes in the hibernating region, so the defect is reduced. Stress/redistribution SPECT thus allows quantification of ischaemia and the extent of potential recovery.78 Technetium-based tracers, which bind within myocytes to mitochondria, identify viable myocardium similarly to Thallium SPECT.In SPECT imaging cellular uptake of Thallium is dependent upon a functional NaFigure 10).81 In addition, PET allows the detection and quantification of MPR, which is reduced in hibernation.83Positron emission tomography assessment is most commonly based on the assessment of myocardial glucose uptake with FDG. Tracer signal is proportional to metabolically active myocardium and likelihood of recovery may be predicted by the glucose metabolic rate  recovery rates were similar .86The spatial resolution of CMR LGE enables the detection of small volumes of infarction that may be missed by SPECT or PET. Transmural extent of LGE predicts likelihood of systolic recovery: 60% with 1–25% LGE, 42% with 26–50% LGE, and only 7% of segments with >50% enhancement recovered at 3 months in a cohort with predominantly chronic, mild LVSD (LVEF 43%).Where hibernation co-exists with acute abnormalities a ‘mixed picture’ of imaging findings may result. Definitive classification of abnormalities in this setting is difficult and may require repeated imaging to classify myocardium.Definition: Myocardial infarction follows sustained ischaemia leading to myocyte necrosis and subsequent remodelling and fibrosis.Metabolism: Necrosis occurs when sustained severe ischaemia leads to irreversible structural changes within the myocyte, including mitochondrial swelling and disruption of the sacrolemma.41 In the course of ischaemic injury, necrosis begins in the sub-endocardium where tissue perfusion is lowest and energy consumption is highest, leading to ATP supply exhaustion and accumulation of the by-products of glycolysis. Sub-endocardial infarction commences ∼20 min after ischaemia onset. Prolonged ischaemia leads to increasingly transmural necrosis, which moves as a ‘wave front’ from the endocardium to the epicardium,39 though sometimes with sparing of a thin rim of sub-endocardium.Histology: Characteristic histological changes occur during myocardial infarction, and evolve until the infarcted region undergoes scar replacement. On macroscopic examination there are few detectable changes over the first 4 h. From 4 to 12 h myocardium becomes mottled. Over the next week, the infarct centre becomes pale and yellows while developing red margins, followed by replacement of necrotic infarct by fibrous scar tissue.8889 Between 4 and 12 h, oedema, necrosis, and intra-myocardial haemorrhage are seen. From 12 to 24 h neutrophil infiltration and ongoing necrosis develop. This is followed within 24–48 h by the disappearance of nuclei and striations, and macrophages remove dead cells at the infarct border. Following this granulation tissue and collagen deposition begins, eventually leading to the formation of collagen scar .91Microscopically, myocardium undergoes a series of changes responsible for the macroscopically appreciable abnormalities. During the initial phase, glycogen depletion and oedema, in keeping with severe ischaemia is seen on electron microscopy.Imaging, morphology, and function: Wall motion abnormalities develop before ECG changes or symptoms,92 while TDI systolic velocities decrease rapidly following onset of ischaemia.93 Following transmural infarction, myocardium is akinetic and thins with time. On stress or exercise there is no improvement in wall thickening with the absence of contractile reserve.94 Sub-endocardial infarction results in wall motion abnormalities of varying severities, and may be differentiated from transmural infarction using peak systolic circumferential strain and strain rate on stress echocardiography.9542 In addition, CMR imaging can be used to delineate infarct extent, indicate the area at risk, and detect microvascular and reperfusion injury.97 Late gadolinium enhancement CMR after acute MI displays high signal in the infarcted area due to persistence of gadolinium within areas of increased extracellular volume and abnormal washout kinetics.42 In animal models, infarct enhancement with LGE CMR has been observed within 90 min of the onset of ischaemia.98 In the acute phase, infarct extent may be overestimated due to increased signal and contrast in the oedematous peri-infarct zone.99 In acute myocardial infarction, LGE CMR may show an area of low signal within the otherwise high-signal infarct zone. This reflects microvascular obstruction (MO) leading to an absence of gadolinium delivery to the centre of the infarct. Extensive MO is associated with no-flow on invasive coronary angiography and adverse LV remodelling.100 Within an area of MO, myocardial haemorrhage may occur, causing low signal on T2 and T2* CMR.101 Haemorrhage represents more severe structural change in the setting of acute MI and is also associated with adverse LV remodelling following infarction.102 The combination of the information gained from T2 weighted, early gadolinium, and late gadolinium images allows measurement of the area at risk, infarct size, and myocardial salvage (difference between area at risk and infarct size) .97Cardiac magnetic resonance demonstrates gross anatomical changes associated with infarction including remodelling, wall thinning, and motion abnormalities.103 In chronic infarction, metabolically active myocytes are replaced by scar and the absence of an intact Na+/K+ ATPase leads to lack of uptake of the SPECT tracer within the region of infarction. The limited spatial resolution of SPECT can lead to an under-appreciation of the extent of infarction because small sub-endocardial infarction may not be detected.104At the time of acute infarction SPECT imaging is not usually performed. However in research settings, infarct area as delineated by absent tracer uptake on SPECT correlates well with infarct size on pathological specimens.105 Myocardial perfusion by PET in the acute MI zone is depressed, significantly improves following coronary intervention, and may continue to improve up to 2 weeks later.106In acute myocardial infarction, FDG PET allows detection of infarction and the presence of viable tissue in or adjacent to the infarcted territory. The absence of detectable glucose metabolism is associated with irreversible myocardial injury.107In the setting of chronic myocardial infarction, concordant reduction in signal from both perfusion and metabolism  PET is seen and readily appreciated in trans-mural infarction; however, in sub-endocardial infarction PET may fail to detect small areas of sub-endocardial scar when compared with CMR.Definition: Dysfunctional myocardium of non-ischaemic origin is considered to be myopathic. Myopathy covers a wide range of pathologies. This review will focus on dilated cardiomyopathy, in which pronounced isolated segmental systolic dysfunction is uncommon, with only passing reference to other aetiologies.Metabolism: Normal cardiac function relies upon matching of energy demand and consumption. This requires an appropriate oxygen supply to myocytes, mitochondrial function, ATP transport to the site of energy consumption, and a reliable feedback system to maintain appropriate metabolic rates. Energy depletion, perhaps due to mitochondrial dysfunction, could be a primary reason for impaired myocardial contraction. However, the primary defect may usually be in the contractile apparatus or in calcium handling, which increase metabolic demand. Importantly, myopathy may be an acquired phenomenon in un-infarcted myocardium that has undergone remodelling and may co-exist alongside segments affected by scar, ischaemia, stunning or hibernation. In patients with mild heart failure secondary to idiopathic dilated cardiomyopathy any change myocardial substrate utilization is subtle. In severe heart failure, cellular metabolism changes substantially, with greater glucose and less free fatty acid utilization,109 in most but not all studies.110Histology: Histological abnormalities differ depending on the underlying aetiology including myocyte disarray and interstitial fibrosis111 in hypertrophic cardiomyopathy (HCM) and fibro-fatty replacement in arrhythmogenic right ventricular cardiomyopathy. A reduction of mitochondria in the failing heart is common.28 Differing degrees of myocyte hypertrophy are seen depending upon the aetiology of heart failure. However irrespective of aetiology, a common finding is the expansion of the ECM and fibrosis due to local factors and activation112 of the renin–aldosterone–angiotensin system.113 Collagen types I and III are the major structural components in the cardiac ECM, providing both tensile strength and elasticity.114 In the failing heart, collagen synthesis increases , leading to accumulation of intercellular collagen, limiting ventricular compliance, myocyte function, and contributing to both systolic and diastolic dysfunction .116Imaging, morphology, and function: Functional imaging by echocardiography and CMR supplies important information for prognosis and risk stratification including ejection fraction and left ventricular end diastolic dimensions.118119 In the case of left ventricular hypertrophy, echocardiographic 2D-strain assessment allows differentiation of HCM and hypertensive LV hypertrophy, while TDI enables differentiation of HCM and athlete's heart.121Comprehensive structural assessment by echocardiography and CMR may guide management and allow diagnosis of the underlying cardiomyopathic process. For example, it is possible to differentiate between morphologically similar cardiomyopathies on echocardiography: Improvement in long-axis function on stress TDI allows differentiation between ischaemic and non-ischaemic cardiomyopathy.122 Cardiac magnetic resonance assessment of left atrial transit time also correlates strongly with LV early diastolic pressure.123Tissue Doppler imaging of the mitral annulus and mitral inflow velocity provides a non-invasive estimate of left atrial pressure.124 HCM,125 and ischaemic heart disease.126 Extracellular volume calculation allows measurement of both diffuse fibrotic and infiltrative processes that are unreliably assessed with visual analysis alone.128 T2* mapping allows detection and tracking of iron overload cardiomyopathy.129In many cardiomyopathies, LGE CMR shows characteristics patterns of enhancement. The presence and extent of LGE predicts outcomes in a range of cardiac diseases, including DCM,131 The defects seen have mild stress defect severity ratios (>45%); however, similar abnormalities may be seen in multi-vessel coronary disease precluding the use of SPECT as the sole diagnostic tool in this situation.The ability of SPECT alone to differentiate ischaemic from DCM is uncertain as mild stress perfusion defects are commonly seen with both aetiologies.108 Hyperaemic blood flow by PET is lower in DCM than in healthy controls, 2.23 mL/min/mL vs. 4.33 mL/min/mL in one report132 and perfusion abnormalities in DCM are progressively worse in more severe heart failure133 and carry adverse prognosis.134Decreased free fatty acid metabolism with increased glucose metabolism is found on PET examination in DCM.Different imaging modalities assess different facets of myocardial health and disease and are often complementary. An awareness of the principles underlying acquisition, and the aspect of myocardial health and pathology assessed is crucial.The detection of ‘normal’ myocardium is straightforward, and can be accomplished using any test capable of delivering good quality anatomical images. The most appropriate method will vary depending upon patient and institute: In terms of practicality, availability, and economy this will frequently be echocardiography. Atrial as well as ventricular volumes and function should be carefully assessed to detect more subtle disease. Minor deviations from normal, such as small areas of infarction, may be undetected unless high-resolution imaging methods such as LGE CMR are used.135 Single photon emission computed tomography is the mostly widely used modality worldwide, and PET remains the gold standard. In some patients, it may be desirable to exclude valvular disease or cardiomyopathy making DSE or CMR the most appropriate choice of test.Ischaemia detection or perfusion assessment may be performed using either stress/exercise echo/CMR, CMR first pass perfusion or nuclear imaging, and all are included in current practice guidelines.149 although extended follow of the STICH population recently showed modest 16% reduction in mortality after a median follow-up of 10 years (p = 0.019).150 This may reflect a failure of previous taxonomies rather than a failure of concept; further randomized controlled trials are required.Hibernation may only ever be identified retrospectively. However, in clinical practice the question most often posed relates to the likelihood of contractile recovery in a given coronary territory, or the potential for LV reverse remodelling following revascularization. For this purpose, any of the non-invasive imaging techniques covered may be selected, as long as the limitations of the chosen technique are recognized in decision making. However, randomized controlled trials have generally not shown a greater improvement in either ventricular function or prognosis with coronary revascularization compared to pharmacological treatment in patients with heart failure and a reduced LV ejection fraction who have greater myocardial viability,Partial infarction is best appreciated by CMR examination, with the added benefit that systolic abnormalities not associated with coronary disease may be explained by characteristic abnormalities of cardiomyopathy on LGE CMR.Where infarction and cardiomyopathy co-exist, multi-modality imaging may be necessary, often including coronary imaging to better understand both the dominant aetiology of LVSD and potential for recovery. Tissue Doppler imaging velocities have been shown to differ in DCM and ischaemic heart disease, potentially allowing discrimination of causes of LVSD. Late gadolinium enhancement CMR allows the extent of scarring due to either pathology to be determined, but not the benefit of any specific therapy.Mild perfusion defects, with stress defect severity ratios of >45%, are common in DCM as discussed above. SPECT, PET, or CMR first pass perfusion in combination with coronary angiography may facilitate targeted revascularization, if indicated on conventional grounds, and avoiding unnecessary revascularization.Figure 14 summarizes key imaging findings covered and aims to provide a reference for future studies. A clear taxonomy for myocardial viability and dysfunction provides the basis for randomized controlled trials that will provide the scientific evidence upon which to base clinical decisions.Consistent adoption of standard nomenclature in clinical practice will facilitate thinking and hopefully decision making regardless of local access to different imaging modalities. A.K.M. is funded by a British Heart Foundation (BHF) Project Grant (PG/14/10/30641). S.P. is funded by a BHF Clinical Fellowship (FS/10/62/28409). Funding to pay the Open Access publication charges for this article was provided by The British Heart Foundation (BHF).Conflict of interest: none declared.


The aim of the review was to identify and describe recent advances (over the last 3 years) in cardiac magnetic resonance (CMR) imaging in patients with chronic kidney disease (CKD). We conducted a literature review in line with current guidelines.The authors identified 22 studies. Patients with CKD had left ventricular global and regional dysfunction and adverse remodeling. Stress testing with CMR revealed a reduced stress-response in CKD patients. Native T1 relaxation times (as a surrogate markers of fibrosis) are elevated in CKD patients, proportional to disease duration. Patients with CKD have reduced strain magnitudes and reduced aortic distensibility.CMR has diagnostic utility to identify and characterize cardiac involvement in this patient group. A number of papers have described novel findings over the last 3 years, suggesting that CMR has potential to become more widely used in studies in this patient group. Chronic kidney disease (CKD) covers a wide spectrum of pathology, from early, subclinical changes in renal function in patients with multiple co-morbidities to end-stage renal disease (ESRD) where renal replacement therapy is required to sustain life . In highThis excess of CV disease is intrinsically linked to cardiac structural and functional abnormalities, which start to develop early in CKD. These include left ventricular hypertrophy (LVH), ventricular dilation, cardiac dysfunction, and myocardial fibrosis, which together are sometimes referred to as a “uremic cardiomyopathy” , 7. DeteCMR imaging provides multiparametric information in a single scan, uniquely integrating function with pathology. CMR is the gold standard for quantification of myocardial volumes and function . CMR hasThere are a number of techniques available for characterizing myocardial function , peak systolic strain, strain rate) and pathology  Table .Table 1CCMR has a number of important limitations, including longer examination times than with echocardiography or computed tomography, and lower temporal resolution than echocardiography. CMR is unsuitable for claustrophobic patients, or for patients with hemodynamic instability, as the patient is removed from direct care. Patients with intra-cranial and intra ocular ferromagnetic objects, as well as cochlear implants and certain cardiac pacemakers are contraindicated from undertaking CMR examination . HoweverIn order to provide a focused update on the developments and findings from CMR studies characterizing cardiac involvement in CKD over the last 3 years, a systematic literature review was performed. This was done in accordance with the PRISMA  guidelinOur search was restricted to peer-reviewed journals and human subjects. Editorials, reviews, studies with fewer than 10 patients or those not published in English were excluded.Abstracts of all potential titles were reviewed by KM and KMcD. References of relevant reviews and all full papers were searched to retrieve any additional papers, repeating the process until no new papers were found Table .Table 2RUtilizing CMR, pediatric and adult patients with CKD and incident HD have recently been reported to have LVH, when matched to healthy controls , 20. In Avoidance of fluid overload and targeting blood pressure control in patients on HD may prevent LV dilation and remodeling, and result in LV mass regression—a recent observational study demonstrated that a greater indexed LV mass was independently associated with greater systolic blood pressure and with greater LV indexed end diastolic volume .As an alternative to conventional hemodialysis, nocturnal hemodialysis holds promise. Two recent studies have investigated whether the avoidance of significant fluid shifts by performing dialysis overnight for longer periods of time or more frequently than three times per week might result in myocardial remodeling and regression in LV hypertrophy. Both studies demonstrated LV mass regression , 25, thiFurther insights into the acute effects of HD and hemodiafiltration on myocardial function were recently described in an ambitious study where patients underwent CMR imaging during their dialysis therapy ••. The aHowever, slightly larger studies are possible in the dialysis population by making small changes to in-center dialysis regimens. For example, Odudu has demonstrated in a study of 73 incident HD patients that cooling dialysate fluid could potentially slow cardiac remodeling, with patients randomized to cooled dialysis versus normal HD regimen experiencing a reduction in LV mass and volumes at 1 year . In thisCandidates for renal transplantation could potentially be risk-stratified based on CMR imaging data recently reported , with prOne of the big challenges of imaging the renal population is that it is not possible to use gadolinium-based contrast agents in ESRD patients because of concerns regarding nephrogenic systemic fibrosis . This haCKD is associated with myocardial interstitial fibrosis . Recent A further paper recently published describes native T1 mapping as a robust technique with excellent intra-observer, inter-observer, and inter-study variability assessment . T1 acquT2* mapping has been applied to patients with CKD to investigate for potential iron overload. This is as these patients get erythropoietin and parenteral iron infusions for iron deficiency to due reduced iron absorption and release from tissues . InteresThere are several techniques for assessing myocardial strain with CMR. This is of importance in the renal population, as there is emerging evidence that patients with renal disease have abnormal strain despite normal LV ejection fraction. The bespoke strain methods include phase-contrast , taggingMyocardial tagging derives strain estimation by imaging and tracking tissue markers (“tags”) induced by changes to the tissue magnetization . TaggingPatients with early CKD have been described to have reduced global longitudinal strain and strain rate compared with controls utilizing FT •. This tMyocardial ischemia assessment with CMR can be dichotomized into the assessment of inducible wall-motion abnormalities by infusing dobutamine or by the use of vasodilator-stress perfusion testing to identify an inducible perfusion defect. The use of dobutamine infusion results in a rise in the myocardial metabolic demand, through chronotropic stimulation. Myocardial segments subtended by a stenosed coronary artery are unable to meet the metabolic demands, and appear hypokinetic . DynamicVasodilator-stress testing makes use of vasodilator agents such as adenosine or regadenoson causing a 3-5× fold coronary vasodilatation in normal coronary arteries, while stenosed vessels are unable to vasodilate to the same extent. The infusion of gadolinium contrast at peak stress and at rest enables the clinician to identify regions of inducible ischemia. This is one of the most sensitive non-invasive techniques available for the identification of myocardial ischemia , 60. ThiThe safety and feasibility of dobutamine stress CMR was recently described in patients with ESRD . 93% of Arterial stiffening, through arteriosclerosis, is one of the earliest signs of subclinical cardiac involvement of CKD . CMR enaPatients with a 3 months HD vintage had reduced aortic distensibility and increased aortic pulse wave velocity when compared to healthy controls . Aortic While the main focus of CMR scans is to assess myocardial changes in CKD patients, the initial coronal, longitudinal, and transverse planes of the thoracic cavity and upper abdomen are acquired by radiographers for study planning. This leads to imaging a significant volume of the patients’ bodies beyond the organ of interest, which may reveal important pathology. While this is not directly relevant to characterizing myocardial disease involvement, we felt this is an important point to discuss in view of increased use of CMR in studies in patients with CKD. Recently, a paper reported the incidence of non-cardiac findings in a CKD stage 5 population as being seven times greater than what was previously reported in an all-comers CMR study , 64. Whin < 25). There is a lack of prognostic utility of these novel imaging markers described in the review. There is potential through collaborative work of randomized, multicenter studies assessing the prognostic utility of these markers on composite endpoints.While there has been excellent progress in characterizing cardiac involvement in chronic kidney disease over the last 3 years, there are a number of important limitations, which the authors encountered on reviewing these papers. Most of the studies carried out were observational in nature, not randomized, and investigated small numbers of patients (Another important challenge in this patient group is the relation of timing of imaging to dialysis and the resultant fluctuant fluid changes, which could give differing hemodynamic measurements depending on loading conditions. This is especially important in multicenter studies.Over the last 3 years, there have been a number of studies investigating the CV system in patients with CKD utilizing CMR. This shows that CMR is a multiparametric tool with diagnostic utility in this patient group. While further work needs to be undertaken in these patients, there is potential for CMR-derived endpoints to be utilized in larger studies in this group of patients.


Remote ischemic preconditioning (RIPC) represents an attractive therapy formyocardial protection, particularly when ischemic events can be anticipated.Although several hypothetic mechanisms have been proposed, no definitemolecular pathways have been elucidated.We evaluated the effect of brachial circulation cuff occlusion on myocardialischemic tolerance, necrosis, and nitric oxide (NO) in patients withischemic heart disease undergoing elective percutaneous coronaryinterventions (PCI).46 patients were randomly allocated into two groups: control and RIPC beforePCI procedures. Electrocardiographic analysis, serum concentrations oftroponin I (cTn-I) were measured at baseline and 24 hours after PCI. A bloodsample from the atherosclerotic plaque was drawn to determine nitrate andnitrites.RIPC increased the availability of NO in the stented coronary artery. Controlpatients presented a small but significant increase in cTn-I, whilst itremained unchanged in preconditioned group. The preconditioning maneuver notonly preserved but also enhanced the sum of R waves.RIPC induced an intracoronary increase of NO levels associated with adecrease in myocardial damage (measured as no increase in cTn-I) withelectrocardiographic increases in the sum of R waves, suggesting an improvedmyocardium after elective PCI. However, to our best knowledge, a directmeasure of NO in the coronary territory, after periphery conditioning and justbefore reperfusion, has not been assessed.The purpose of this study was to evaluate the effect of brachial circulation cuffocclusion on myocardial ischemic tolerance, myocardial necrosis, NO bioavailabilityat the site of angioplasty and renal function in patients with ischemic heartdisease undergoing elective PCI.7 inwhich serum cardiac troponin I (cTn) was increased more than 30% in control patientscompared with those who underwent a RIPC 24 hours after elective PCI, a sample sizeof 14 patients was estimated to provide 80% power and 95% of confidence.Anticipating a 20% of losses, and 15% reduction of elevated cTn-I, a group of 46patients (23 in each of the control and RIPC intervention groups) was assembled.Based on the study by Hoole,9 We included patients of any gender,aged ≥18 years, who signed an informed consent, had documented clinicalevidence of ischemic heart disease, accepted PCI therapeutic procedures and hadconcentrations of serum cTn-I less than three times de 99th percentilevalue. Exclusion criteria include: patients with acute coronary syndromes orhemodynamic instability, those requiring immediate angioplasty and stentingprocedures, pregnant or breastfeeding women, and those patients medicated with drugshaving effects as activators of potassium channels, as glibenclamide ornicorandil.Study protocol was approved by both Ethics and Research Institutional Committees andit was conducted according to the Declaration of Helsinki, Good Clinical Practicesand Mexican Federal Regulations.All patients were medicated with aspirin (300 mg) and clopidogrel (600 mg) the daybefore the PCI. All selected patients concluded the trial.One hour before the PCI procedure, a 12-lead electrocardiogram (ECG) was obtained.Then the ECG was repeated 24 hours after PCI. Electrocardiographic analysiscomprehended the quantitation of the positive or negative ST deviation, new Q waves,and the occurrence of sudden left bundle branch block (LBBB). The summation of Rwaves (ΣR), in mm, was carried out in precordial leads and in all 12leads.th percentile value is 0.04ng/mL. The variation coefficient of the assay is less than 10%10 in our laboratory. Troponin-I wasmeasured at baseline and 24 hours after PCI.Additionally, a peripheral venous blood sample was drawn to measure serumconcentrations of troponin-I by means of monoclonal antibody-immunoassay with aBayer ADVIA 60 hematology analyzer, whose 99After recruitment, patients were randomly allocated in two groups, one serving ascontrols and another in which patients underwent ischemic preconditioning. In theselatter subjects, 1 hour before the PCI procedure a RIPC maneuver was carried outwith patients lying in dorsal decubitus. RIPC was done in the left arm, using threecycles of cuff occlusion, raising the pressure to 200 mm Hg during a period of 5minutes followed by a 5-minute period of cuff deflation. Afterwards, all patientsunderwent a standard PCI procedure, including the stenting of all susceptible andaccessible coronary lesions. The different interventional cardiologists involved inthe study were blinded to the preconditioning maneuver. Before stenting, the tip ofthe catheter was placed just in the site of the atherosclerotic plaque to bestented, and a blood sample was drawn to measure nitrate and nitrites (NOx), thedegradation products of NO, as an indirect measure of disposability of this gas,which in turn is an emblematic marker of endothelial function. NO metabolitesconcentrations were measured using a commercially available colorimetric enzymaticKit , following manufacturer's instructions. Optical density wasdetermined at 540 nm. Since NOx is excreted through the kidney, the ratioNOx/creatinine was estimated in order to rule out the influence of any renalimpairment.11 in grade 0 , grade 1 , grade 2 , grade 3  and grade 4 (most severe pain never experienced).Angina pain experienced during PCI was quantified with a modified scale of theAmerican College of Sports MedicinePeriprocedural myonecrosis/myocardial infarction. Myocardialnecrosis was considered when serum concentration of cTn was above the99th percentile of the reference value.10 Notwithstanding, the diagnosis of myocardialinfarction was based on the updated criteria of the European Society of Cardiology,the American College of Cardiology Foundation, the American Heart Association andthe World Heart Federation (ESC/ACCF/AQHA/WHF) document titled Third UniversalDefinition of Myocardial Infarction.12 This international expert consensus document establishes thatthe preferred biomarker of necrosis is cTn and at least one of the five additionalcriteria: ischemic symptoms; new significant ST/T wave changes or new LBBB; newpathologic Q waves; imaging demonstration of new loss of viable myocardium ; and intracoronary thrombus (identified byangiography or autopsy). Following the same document, a periprocedural myocardialinfarction was considered when cTn elevation exceeded five times the 99thpercentile value of reference in patients with normal basaline values.Patients who experienced some procedural complications, as coronary dissection,longstanding periprocedural arrhythmias or cardiac arrest, were excluded from theanalysis. Thus, only cases with complete successful angioplasty and stenting, suchas cases in which all accessible and relevant lesions were treated, withoutcomplications, with full intraluminal gain, and flow TIMI 3, were considered for theanalysis.13 creatinine clearance equation, before and after the PCIprocedure:Kidney function was estimated measuring serum creatinine and glomerular filtrationrate (GFR) by means of the Cockcroft-GaultGFR= [(140 - age) x weight (kg)/(72 x serum creatinine (mg/dL)] x (0.85 inwomen).Patients were allocated in the five stages of chronic kidney disease (stages I-V),according to their value of GFR . GFRwas estimated before the intervention and 24 hours later.Statistical analysis. All values were expressed as mean± standard deviation. Normal distribution of data was analyzed using theKolmogorov-Smirnov test, differences (before vs. after) in continuous variables wereevaluated using Student's paired t test, whereas unpairedt test was used to evaluate intergroup differences andpercentage of change (deltas). Differences between categorical data, i.e.,frequencies and percentages, were evaluated with z tests. A p value <0.05 wasconsidered as significant. Prism GraphPad(r)  softwarewas used for statistical analysis.ns) in age,gender distribution, occurrence of adiposity, hypertension and diabetes, previousmyocardial infarction and functional renal status. There were more patients in thepreconditioning group medicated with β-blockers (5 subjects) and statins , whereas more control patients were medicatedwith insulin and metformin, in spite of the fact that the proportion of diabetes wassimilar in both groups. Calcium channel blockers and renin-angiotensin axismodulators were prescribed in similar proportion in both groups. Almost undetectablequantities of cTn were found in all patients, and none had, before the intervention,ST abnormalities.All recruited patients completed the study protocol. Angina pain during or after PCI. Only one patient in eachgroup experienced angina pain (grade 4 in both cases) during or immediately afterthe angioplasty procedure.NO bioavailability. Changes in cTn I. ECG changes. Four patients in the control and only one in thepreconditioning groups had ST elevation greater than 1mV 24 hours after PCI . As a whole, it can be seen that PCI procedure had a clear-cut effect on the summationof R waves, in all or only in precordial leads. In comparison, preconditioningmaneuver not only preserved but also enhanced the summation of R waves. All thesechanges in the control and experimental groups reached statistical significance.Renal data. Contrast media injected did not differ betweengroups . 2 (-9.5%) incontrol patients, whilst in preconditioning patients, it fell 6.7 (-10.6%). None ofthose differences were statistically significant.The main findings of this work showed that a RIPC induced an intracoronary increaseof NO levels resulting in a decrease in myocardial damage (measured as no increasein cTn-I) with electrocardiographic increases in the summation of R waves,suggesting an improved myocardium after elective PCI.5 The work ofLoukogeorgais et al.14demonstrated that limb occlusion in one arm diminishes endothelial dysfunction inthe contralateral arm. Several hypothetical mechanisms have been proposed to explainthis phenomenon, mainly the neural and humoral hypothesis. Remote tissue subject toischemia-reperfusion must produce one or several substances  that canstimulate an efferent neural pathway with cardioprotective results or traversing theblood stream can act directly in the endothelium of the coronary vessels, inducing apreservation response .6 Other proposed mechanism is theactivation of the enzymatic system of mitogen-activated protein kinases (MAPKs) p38,Erk1/2 and JNK, in the remote tissue subjected to ischemia-reperfusion that canexert positive modifications yielding to ischemic protection in the distantmyocardium.15 Morerecently, the role of NO has emerged as the pivotal mechanism explaining ischemiaprotection, classical or remote. There is evidence about the induction by RIPC ofincreased activation of endothelial NO synthase (eNOS), rather than increasedexpression,16 as well asan increase of NO production and its oxidation products nitrites/nitrates. Inelegant experiments using the rat cremaster flap in vivo microscopymodel, Küntscher et al. have demonstrated that NO caused higher capillaryflow and faster red blood cell velocity in arterioles and capillaries, whileL-nitroarginine methylesther (L-NAME), a direct inhibitor of NOS, inhibits thepreconditioning effect.17 NO, thesignaling molecule iconic of endothelial function, exerts plentiful biologicalactions that can explain its cardiovascular protection effects: modulation ofexcitability, attenuation of cellular stress response, arteriolar and capillarydilation, antioxidant, antiinflammatory, antifibrotic, antithrombotic andantiapoptotic effects, among others. Besides, NO functions also as an intracellularmessenger, a paracrine molecule, a neurotransmitter, or even as a hormone withdifferent distant effects, generally beneficial.18The mechanisms by which repeated episodes of ischemia-reperfusion in a non-cardiactissue or organ lead to subsequent myocardial protection against ischemia are notcompletely understood. The effect of brief limb ischemia has been studied in bothanimals and humans.2/NO3) levels in the vicinity ofcoronary atherosclerotic plaque after remote preconditioning, just beforeangioplasty intervention, the metabolic changes caused by the preconditioningmaneuver are not at all the only source of NO production. It is now known, forexample, that nitrite can be the source of NO mainly in ischemic or hypoxicconditions, besides the classical NO synthase pathway.19 Even though, the production of NO through thepreconditioning phenomenon is still an explanation of the myocardium salvage shownin our study , as the rescue wasseen in the preconditioned patients and not in the controls.Although our work demonstrated a clear increase in NO , while an increase of atleast five times above the reference value of the 99th percentilesupports the diagnosis of myocardial infarction.20 This graded diagnostic differentiation is based on the factthat a small increase in biomarkers can be seen in multiple conditions, such asheart failure, myocarditis, myocardiopathy, renal insufficiency, pulmonarythromboembolism, fast or slow arrhythmias, ventricular hypertrophy, cardiac toxicity, heart surgery and trauma, anemia, shock and sepsis, amongmany more.On this regard, the sensitivity of current necrosis biomarkers makes it possible todetect minute myocardial necrosis, making apparently easier the diagnosis of thisclinical entity. However, the criteria for the diagnosis of myocardial infarctionand periprocedural myocardial infarction have been modified several times in thelast few years, introducing considerable confusion in the matter.21 in which the former was associated with a mortalityrelative risk of 7.49, whereas, in the latter, mortality did not increase.The importance of periprocedural myocardial infarction or periprocedural myonecrosisresides obviously in the amount of viable myocardial lost during coronarymanipulation, and, for this reason, it seems commonsensical prevent or at leastlimit the occurrence of myocardial injury and its extension. Periproceduralmyocardial infarction is less clinically relevant than spontaneous myocardialinfarction, as it was shown in the ACUITY trial,thpercentile reference value of 0.04 ng/dL. While, at baseline, 11 patients had cTnvalues greater than 0.04, in post-PCI that number increased to 19. In comparison, inthe experimental group, mean cTn values did not exceed the 99thpercentile reference value both at baseline and post-PCI (0.02 to 0.04 ng/dL). Atbaseline, 8 patients had cTn values greater than 0.04, and after PCI only 9 showed ahigh value. These results call attention to the salvage of myocardium during PCIwith the use of an easy to do, cheap and almost harmless preconditioningmaneuver.Our study showed that in the control group a definite periprocedural myocardial lossoccurred. In those patients, mean cTn value increased seven times (0.1 to 0.7 ng/dL)from baseline to post-intervention, meaning 17.5 times the 9922 More recently, in the era of coronaryintervention, the meaning of the evolution of R wave's voltages in different phasesof myocardial ischemia and reperfusion has attracted again more attention.23 In the classicalelectrophysiological explanation, electric activated myocardial cells generateaction potentials represented by vectors, whose frontal heads are positivelycharged. Necrotic or extremely ischemic myocardial cells cannot generate theseelectrical forces. Diverse clinical and experimental studies have shown that R waveamplitude decreases notoriously during acute ischemia, but increases its voltageduring reperfusion.24 This phenomenon probably indicatesthat during an undetermined period of time myocardial cells attacked by ischemia arenot dead, but just in a critical pre-mortem state of extremeinjury, keeping only the basic supporting life systems. But if flow isreestablished, these myocardial ischemic cells can restore fully its vitality andfunctionality. It has been described that, in humans, undergoing coronaryangioplasty, during the brief episodes of ischemia caused by balloon inflation, Rwave amplitude increases significantly in almost all ECG leads. Although the realcause of this voltage gain in the summation of R wave has not been convincinglydisclosed , anyhow this phenomenon is associated with acute ischemia, differentfrom the phenomenon observed in this work.25 So, the amplitude variation of R waves represents this"entrance and exit" of the cells in the ischemic dimly zone. Our data show that,while in control patients myocardial loss occurred, in patients who underwent apreconditioning maneuver, myocardium was better preserved.Furthermore, the myocardial preservation effect of preconditioning was confirmed inour study with ECG data. ECG is a time-honored diagnostic tool in the clinicalrecognition of myocardial infarction, its topographic localization, estimation ofinfarction size and prognosis. Several indexes and scoring electrocardiographicsystems were developed to reflect the functional state of the left ventricle intimes previous to image technologies apt to estimate very accurately systolic anddiastolic properties of the left ventricle. Unfortunately, the correlation amongseveral ECG scores and ejection fraction was rather poor.26 In our patients, the preconditioning maneuver had nopositive change in renal functionality.On the other hand, our results showed that renal function was impaired in bothgroups. The magnitude of the renal derangement was noticeable, but not prominent,far away from the boundaries of the contrast-induced nephropathy (a 25% increase ofserum creatinine or 0.5 mg/dL absolute augment).The easy to do, inexpensive and harmless arm cuff occlusion maneuver carried outbefore PCI can protect from myocardial damage caused by coronary intervention itselfand post-angioplasty reperfusion lesion, due to greater NO bioavailability in theatherosclerotic lesion.6 Whilein the first "window" myocardial preconditioning provokes vasodilation, in thesecond "window", various downregulation changes occurred in proteins and theexpression genes encoding several proteins related to oxidation, heat shockprotective response, and activation of NF-κB, among others. Several otherinvestigations point out that NO can act as a mediator of "second-window"ischemic preconditioning27over the opening of the end effector of late preconditioning, the mitochondrialATP-sensitive potassium (mitoK-ATP)28 channel. In addition, it has to be proven that NO actsin both windows of the preconditioning phenomenon, as well as which is theisoenzyme responsible for its increase production (eNOS or iNOS).Even with a clear participation of NO in decreasing myocardial damage, thecomplexity of preconditioning phenomena still needs more profound studies. Forexample, that phenomenon is known to have two phases, an early one ("firstwindow"), beginning almost immediately and lasting several hours, and a delayedone ("second window"), starting 12 to 24 hours later and with a longer durationof 48-72 hours, termed the "Second Window of Protection" (SWOP) or late ischemicpreconditioning.Finally, the clinical and prognostic consequences of the myocardium salvageresulting from the preconditioning maneuver have yet to be tested in the longrange.


Myocardial tissue differentiation applying Cardiovascular magnetic resonance (CMR) offers the capability to detect myocardial injury already in preserved ejection fraction. Detection of edema is a unique capability of CMR. Conventional T2 imaging suffers from technical challenges related to diseases specific issues like tachycardia, atrial fibrillation and pericardial effusion. T2-mapping seems to be more stable based on visual assessment. Little is known about its dependency of disease relate abnormalities. We aimed to investigate on the influence of heart rhythm abnormalities on T2 mapping.4 + NaCL doped water bottles to achieve enough load for MRI. We applied a T2 prepared SSFP- based T2 mapping technique with the following parameters: voxel size: 1.6 × 1.6 × 6 mm³, TR 2.7 ms, flip angle 70°, TE 1,15 ms; GRAPPA reduction factor 2. Sinus rhythm heart rates of 60, 80,100 and 120 bpm were simulated using an ECG simulator . Arrhythmia was simulated using a commercial ECG simulation device . To assess repeatability of the T2 times, the T2 maps were acquired 6 times for each heart rate and rhythm. T2 times were quantified based on the inline T2 maps by drawing a ROI covering the entire phantom intersection using cvi42 5.0 .We performed phantom experiments using a 1.5 Tesla Siemen Avanto Fit  equipped with a 32-channel cardiac coil. The T2 phantom consisted of five tubes figure . They weT2 times were evaluable in all settings. T2 times did not show significant differences depending on heart rate variability within each tube . Details are given in table The influence of heart rhythm abnormalities and heart rate on T2-times seems to be not relevant. That gives the possibility to identify myocardial edema also in patients with arrhythmia. Further patient studies are needed.


Sacubitril/valsartan is a combination drug described as a new class of dual-acting angiotensin receptor-neprilysin inhibitor (ARNi) for heart failure. We present a case of a patient with NYHA class IV systolic heart failure who was refractory to all other classes of heart failure medications and was started on this new medication. On sacubitril/valsartan, he developed cardiogenic shock. This led us to reevaluate the use and risks of this medication in the class IV heart failure population. In the American Heart Association (AHA)/American College of Cardiology (ACC) guidelines , congestSacubitril/valsartan  is an orally acting supramolecular sodium salt complex of the neprilysin inhibitor prodrug sacubitril and the angiotensin receptor blocker (ARB) valsartan, which was recently approved for the treatment of chronic heart failure (NYHA classes II–IV) with reduced ejection fraction (HFrEF) . This drA 76-year-old male with a history of systolic CHF, NYHA class IV, presented with worsening shortness of breath over 4 weeks and fleeting chest pains. He mentioned having orthopnea and cough with blood-tinged sputum. On examination, he was tachycardiac, and heart rate was irregular, but other vitals were stable; he did not have jugular venous distention but had basilar crackles. He also had a history of coronary artery disease and an implantable cardioverter-defibrillator (ICD) for secondary prevention. EKG showed atrial fibrillation (AF) with a rapid ventricular rate and a right bundle branch block. Labs were unremarkable except an elevated B-type natriuretic peptide (BNP). A recent echocardiogram demonstrated an ejection fraction of 22% with global left ventricular hypokinesis. His St. Jude Medical Fortify Assura VR single-lead ICD was interrogated and was functioning normally. Along with diuresis, he was started on IV diltiazem drip for his uncontrolled AF. He had been intolerant to guideline-directed heart failure therapy in the past. Prior to his admission, treatment with lisinopril resulted in severe cough, losartan caused symptomatic hypotension, and carvedilol caused shortness of breath. Since his BP was 137/85, a decision was made to start the patient on low-dose sacubitril/valsartan without any other medications given the intolerance to routine HF medications. Within 2 doses and 24 hours of starting the medication, he had an episode of severe hypotension requiring pressor support for cardiogenic shock . SacubitIn the large, randomized, double-blind PARADIGM-HF trial, sacubitril/valsartan has demonstrated substantial reductions in all-cause mortality due to heart failure without altering its safety profile when compared to the standard treatment for heart failure . On compBesides the cardiac side effect profile, recently some light has been shed on the noncardiac side effects of this medication with long-term use. These include amyloid deposition in the eye and the brain, which theoretically can lead to visual and cognitive impairment , 6. FromWe present a case of severe hypotension/cardiogenic shock that occurred after starting sacubitril/valsartan in a patient with NYHA grade IV heart failure. We feel the use of this medication should be limited to patients with NYHA class II and III systolic HF, which was most of the enrolled population in PARADIGM-HF. If any class IV patients were included, few patients who were hypotensive in the run-in period were not enrolled. As stated in the ACC/AHA guidelines, the incidence of severe hypotension and cardiogenic shock is likely to be higher in patients with NYHA class IV systolic heart failure, warranting at least added caution when using it in these patients. It is possible that visual and cognitive side effects will play an important role in patients who are on long-term use of this medication, thus likely necessitating regular testing.


DW) from 3D CT images for estimating the size‐specific dose. DW is the metric that characterizes the patient size and attenuation. In this study, DW was calculated for standard CTDI phantoms and patient images. Two types of phantom were used, one representing the head with a diameter of 16 cm and the other representing the body with a diameter of 32 cm. Images of 63 patients were also taken, 32 who had undergone a CT head examination and 31 who had undergone a CT thorax examination. There are three main parts to our algorithm for automated DW calculation. The first part is to read 3D images and convert the CT data into Hounsfield units (HU). The second part is to find the contour of the phantoms or patients automatically. And the third part is to automate the calculation of DW based on the automated contouring for every slice . The results of this study show that the automated calculation of DW and the manual calculation are in good agreement for phantoms and patients. The differences between the automated calculation of DW and the manual calculation are less than 0.5%. The results of this study also show that the estimating of DW,all using DW,n=1  produces percentage differences of −0.92%±3.37% and 6.75%±1.92%, and estimating DW,all using DW,n=9 produces percentage differences of 0.23%±0.16% and 0.87%±0.36%, for thorax and head examinations, respectively. From this study, the percentage differences between normalized size‐specific dose estimate for every slice  and nSSDEn=1 are 0.74%±2.82% and −4.35%±1.18% for thorax and head examinations, respectively; between nSSDEall and nSSDEn=9 are 0.00%±0.46% and −0.60%±0.24% for thorax and head examinations, respectively.The purpose of this study is to accurately and effectively automate the calculation of the water‐equivalent diameter (PACS number(s): 87.57.Q‐, 87.57.uq‐ CT dose is an important concept in the medical community,There are limitations to the CTDI values that are calculated using standard PMMA phantoms, which are typically 14 to 15 cm long and 16 cm in diameter to represent a patient's head or 32 cm in diameter to represent a patient's body. The first limitation is that the length of phantom is too short for measuring scattered radiation.Regarding the first limitation, CTDI is often measured using a 10 cm ionization chamber, which is considered too short because it excludes any contribution from radiation scattered beyond the relatively short range of integration along the Z‐direction, and it tends to undervalue the cumulative dose at the center position, as reported by many investigators.(29)In this report, patient size is estimated based on a geometrical parameter of the patient called the effective diameter (ED). Look‐up tables in the report provide conversion factors that can be applied to CTDIVOL to calculate SSDE. Conversion factors are based on four different measurements: anterior‐posterior (AP), lateral (LAT), AP+LAT, and effective diameter.The second limitation has been evaluated by many authors who have reported that the dose to the patient depends on the size of patients.DW). It had previously been proposed by Huda et al.,The effective diameter is a simple physical measure of patient size, and does not account for patient composition and attenuation properties.DW can be calculated either by a semiautomated  or by a fully automated method. The purpose of this study was to calculate the water‐equivalent diameter (DW) from CT images using a fully automated method. The resulting estimate should be sufficiently accurate for computing the size‐specific dose estimate (SSDE). The study also investigated the difference between the water‐equivalent diameter using different numbers of slices, n , and the water‐equivalent diameter using all slices .The value of DW calculations were standard CTDI phantoms (Leeds Test Objects (LTO) Medical Imaging Phantoms, Boroughbridge, UK) and patients. The phantoms consisted of two PMMA cylinders, one cylinder representing the head (16 cm diameter), and when nested inside the other representing the body (32 cm). The length of each cylinder was 14 cm. The head phantom was scanned by a CT scan Siemens SOMATOM Sensation 64 , installed at Dr. Karyadi Hospital, Semarang, Indonesia. The scanning parameters were: head spiral for adult study, slice thickness 0.3 cm, voltage 120 kVp, exposure 370 mAs, reconstruction diameter 18.7 cm, convolution kernel H20s. The body phantom was scanned by the same scanner with: abdomen routine for adult study, slice thickness 0.3 cm, voltage 120 kVp, exposure 200 mAs, reconstruction diameter 35.0 cm, and convolution kernel B30f.The objects for the There were 63 patients, 32 who underwent a CT head examination and 31 who underwent a CT thorax examination. The patients who underwent CT head examinations comprised 20 females and 12 males, with ages between 16 and 77 years. Those who underwent CT thorax examinations comprised 13 females and 18 males aged between 13 and 85 years.The patients were scanned by a CT scan Siemens SOMATOM Emotion 6 at the Prof. Dr. Margono Hospital, Purwokerto, Indonesia. The scanning parameters for the head were: slice thickness 0.4 cm, voltage 130 kVp, tube current 167 mA, rotation time 1500 ms, reconstruction diameter 20.0 cm, number of slices 24, and convolution kernel H31s. The scanning parameters for the thorax were: slice thickness 1.0 cm, voltage 130 kVp, tube current 35–133 mA, rotation time 600 ms, reconstruction diameter 28.1 cm, number of slices 29–37, and convolution kernel B20s.DW, AAPM suggested that the ROI be defined to include all of the patient, but no peripheral objects.In order to estimate DW calculation. There were three main parts to the algorithm. The first part is to read the 3D images and convert the CT data into Hounsfield units (HU). The second part is to contour the patients or phantoms automatically. And the third part is to automate the calculation of DW based on the automated contouring for every slice.−1024 to +3071. The pixel value was displayed in the clinical application according to the average attenuation of the tissue on the Hounsfield scale. Water has an attenuation of 0 Hounsfield units (HU), air is −1000 HU, bone is typically +400 HU or greater, and metallic implants are usually 1000+ HU.Some of the CT images were stored as CT data and some were stored in Hounsfield units (HU). A typical CT dataset ranges from 0 to 4095, although the real pixel values used only part of this range. Hounsfield units correspond to a scale from S is the slope and I is the intercept. Normally, the value of slope and intercept are stored in the DICOM file itself. The tags are generally called the rescale slope and the rescale intercept, and typically have values of 1 and −1024, respectively. Tag  is for the rescale intercept and tag  is for the rescale slope.We applied a linear transformation to convert the CT data to Hounsfield units using −200. This value was selected because the border between the patient and its surroundings is skin with HU values of approximately zero, while the surroundings outside the patient are air or other materials with HU values lower than −200. The thresholding produces binary images. However, thresholding alone was not be able to contour the patient completely because of the presence of other objects inside the patient with HU values lower than −200. To overcome this problem, we used edge detection to identify these objects and labeled them using their areas. The largest area identified was considered to be the border of the patient or phantom.After converting the CT data to Hounsfield units, automated patient or phantom contouring was performed using an algorithm designed to produce accurate results with a relatively fast computation time. The algorithm uses a combination of basic segmentation techniques and specific information about the border of the patient body. The first step was thresholding, using a HU value of DW is calculated. The results of the automated contouring are used to crop the original images, and the area of the cropped image and the average HU value are calculated. DW is then calculated using After automated contouring, AROI is the area of the patient after cropping and HUROI¯ is the average HU value of the patient or phantom. After the automated DW calculation is completed for one slice, it is continued for all the slices in the scan range. This gives the DW values for all slices, and the average DW,all.where DW calculation were compared to those calculated manually where the contouring was done freehand. Comparisons were made for both head and body phantoms, and for patient thorax and head. The automated and manual DW calculations for the patients were then correlated by regression.The results of the automated DW were also calculated theoretically for the phantoms. The phantoms were made from PMMA material with ρ=1.19 g/cm3, approximately 120 HU, 16 cm in diameter for head phantom and 32 cm in diameter for body phantom.In addition to the automated and manual calculations, the values of DW,all) gives an accurate result. However, it is not practical clinically because it requires a long time for calculation, especially in the case of modern CT scanners that produce more than 500 images  for every examination. We postulated that the value of DW,all could be estimated to an acceptable accuracy by using just a few (n) slices . In this study, we investigated the effect of using just n slices  to produce an estimate DW,all. The position of every slice used for calculating DW,n and DW,all is indicated in The calculation of water‐equivalent diameter using all slices  between DW calculation is to estimate the size‐specific dose (SSDE). The SSDE value is determined by two main factors, namely the characteristic of the patient in terms of DW and the output dose of CT scanner in terms of the volume CT dose index (CTDIVOL).The goal of the CTDIVOL values were calculated using ImPACT CT Patient Dosimetry Calculator version 1.0.1a. The exposure parameters , manufacturer name and the type of scanner in each patient were put into the ImPACT CT in order to calculate the CTDIVOL. Because the tube current for thorax examination spanned a wide range (35 mA to 133 mA), we calculated the normalized CTDIVOL (nCTDIVOL) instead of CTDIVOL for both thorax and head examinations. The unit of nCTDIVOL is mGy/100 mAs.The nCTDIVOL and DW, we calculated the value of normalized SSDE (nSSDE) using (k(DW)) from nCTDIVOL to nSSDE is adapted from AAPM Task Group 220:After determining the values of k(DW) depends on the type of phantom. For this study, there were two phantoms, namely the head CTDI phantom (16 cm in diameter) and the body CTDI phantom (32 cm in diameter).The value of DW for the body and head phantoms using automated and manual calculations from the images and using theoretical calculations are shown in DW values for the body and head phantoms based on automated and manual calculations along the longitudinal axis are shown in The results of contouring both automatically and manually are shown in DW is very good.The standard errors in the automated and manual methods are very small, indicating that the methods are precise. The theoretical result falls within the estimated errors , indicating that the methods are accurate. The percentage differences the automated calculations to the manual calculations are less than 0.4%. The results indicate that the accuracy of automated calculation of DW for the patient thorax and head are shown in R2=0.999 for both the thorax and the head, and a slope of 1.008 for thorax and 1.003 for head. The manual values for DW are 22.48±2.88 cm and 18.29±0.79 cm for the thorax and the head, respectively. The automated values for DW are 22.54±2.90 cm and 18.28±0.79 cm for the thorax and the head, respectively. The percentage differences between the automated and manual calculations of DW are less than 0.5%, which is very small compared to the permitted tolerance, which is 10%.DW from patient images are very close to the manual calculations.The automated and manual DW values along the longitudinal axis for the thorax and head for one of the patients are shown in DW values are lower than the surroundings, because the main composition of the lung is air with HU value around −1000. DW values in the head region are relatively flat, except in the area close to the apex of head.DW,all). The average of DW,all for thorax and head examinations are listed in DW,all for head examinations is relatively small (±0.9 cm). On the other hand, the standard deviation of DW,all for thorax examination is relatively high (±2.6 cm). DW,all based on the gender. It can be seen that there is no significant difference of DW,all between male and female patients in the thorax region, but in the head region the DW,all value for female patients is slightly higher (about 1 cm) than for male patients.AAPM TG‐220 recommended that water‐equivalent diameter be calculated as the average for every slice along the longitudinal axis  increases. The percentage difference for n=9 slices is 0.87%±0.36% or about 1%. On the other hand, in the thorax region, the average percentage difference between DW,n=1 using the central slice and DW,all is relatively small (−0.92%), but there is a high standard deviation (±3.37%). The standard deviation decreases with increasing of number of slices used (n). At n=9, the standard deviation of percentage difference is very small (±0.16%).Percentage differences between the average CTDIVOL (nCTDIVOL) values were 9.30 mGy/100 mAs and 25.10 mGy/100 mAs for thorax and head examination, respectively. The normalized SSDE (nSSDE) values based on a manual calculation of DW are 15.15±1.58 mGy/100 mAs and 23.15±0.70 mGy/100 mAs for thorax and head, respectively. The nSSDE values based on an automated calculation of DW are 15.12±1.59 mGy/100 mAs and 23.16±0.71 mGy/100 mAs for thorax and head, respectively. The percentage differences of nSSDE between the automated and manual calculations are less than 0.5%. As indicated in nSSDE values depend on DW. It can be seen that the nSSDE decreases exponentially with increasing DW.The normalized nSSDE for thorax and head examinations is listed in nSSDE for head examination is smaller (±0.88 mGy/100 mAs) than for thorax examination (±1.44 mGy/100 mAs).The average nSSDEn with n=1,3,5,7 and 9 slices to the nSSDEall are shown in nSSDEn with n=9 slices and the average nSSDEall are very small .The percentage differences between DW) automatically from axial CT images. A number of authors have reported the calculation of the patient diameter. Cristianson et al.DW by 4.5% and 9.9%, respectively. In contrast, the calculation of the diameter for axial images requires no patient centering to attain high accuracy.The aim of this study was to calculate the water‐equivalent diameter  Celeron CPU 1005M, 1.90 GHz, installed memory RAM 2.0 GB, and 32‐bit operating system), the automated calculation for each slice took less than 1 s.Our method allows DW,all). However, a previous study suggested that DW could be estimated from the central image in the scan range. Leng et al.DW,all correlated extremely well with a DW,n=1 from a central image in the scan range. The important finding from this study is that the DW,n=1 value of the central image approaches the value of average of DW,all only for thorax examinations. In the case of head examinations, however, the DW,n=1 value of the central image is always greater than the average of DW,all, with a percentage difference of 6.75%±1.92%. The DW,n values using n=9 slices produce a relatively small percentage difference , compared to DW,all for both thorax and head examinations.Because patient dimension and attenuation can vary considerably along the longitudinal axis, the water‐equivalent diameter be calculated for every slice or for all positions along that axis . The percentage differences of the automated results from the manual DW calculations were less than 0.5%, which is promising for the implementation of this method in the clinical environment. We found that the average value of water‐equivalent diameter from all slices  could be estimated accurately using slices only, distributed along the longitudinal axis . Using nine slices, the percentage difference between DW,n=9 and DW,all was about 1%.We have proposed and tested a new algorithm for the automated calculation of water‐equivalent diameter , No. 237h/I1.C01/PL/2015 and No. 006n/I1.C01/ PL/2016. The authors would like to thank Mr. Masdi from Prof. Dr. Margono Hospital, Purwokerto, Indonesia.This work is licensed under a Creative Commons Attribution 3.0 Unported License.