Cardiac imaging has a pivotal role in the prevention, diagnosis and treatment of ischaemic heart disease. SPECT is most commonly used for clinical myocardial perfusion imaging, whereas PET is the clinical reference standard for the quantification of myocardial perfusion. MRI does not involve exposure to ionizing radiation, similar to echocardiography, which can be performed at the bedside. CT perfusion imaging is not frequently used but CT offers coronary angiography data, and invasive catheter-based methods can measure coronary flow and pressure. Technical improvements to the quantification of pathophysiological parameters of myocardial ischaemia can be achieved. Clinical consensus recommendations on the appropriateness of each technique were derived following a European quantitative cardiac imaging meeting and using a real-time Delphi process. SPECT using new detectors allows the quantification of myocardial blood flow and is now also suited to patients with a high BMI. PET is well suited to patients with multivessel disease to confirm or exclude balanced ischaemia. MRI allows the evaluation of patients with complex disease who would benefit from imaging of function and fibrosis in addition to perfusion. Echocardiography remains the preferred technique for assessing ischaemia in bedside situations, whereas CT has the greatest value for combined quantification of stenosis and characterization of atherosclerosis in relation to myocardial ischaemia. In patients with a high probability of needing invasive treatment, invasive coronary flow and pressure measurement is well suited to guide treatment decisions. In this Consensus Statement, we summarize the strengths and weaknesses as well as the future technological potential of each imaging modality. Cardiac imaging has a pivotal role in the prevention, diagnosis and treatment of ischaemic heart disease. In this Consensus Statement, the authors summarize the use of SPECT, PET, MRI, echocardiography, CT and invasive coronary flow and pressure measurement, and describe the relative strengths and weaknesses of each modality. Noninvasive clinical cardiac imaging continues to undergo rapid evolution, focusing on quantitative perfusion technologies for the assessment of myocardial ischaemia and coronary flow. At present, imaging of myocardial ischaemia stands at a crossroads. During a European meeting on quantitative cardiac imaging, a bench-to-bedside-to-bench perspective was used to summarize the current status and future potential of myocardial ischaemia imaging from the viewpoint of basic scientists and clinical researchers. This approach created discussions, which led to this Consensus Statement on the main advantages and disadvantages of each imaging modality, a clinical consensus on the appropriateness for specific indications and a summary of the latest developments, which together provide a framework for future quantitative imaging of myocardial ischaemia.International guidelines advocate noninvasive testing for patients with suspected ischaemia before proceeding with revascularization decision-making5 has also revealed the existence of abundant small collateral vessels both between (intercoronary) and within (intracoronary) perfusion territories of major coronary arteries7. Importantly, blood supply via well-developed collaterals can reduce the area of myocardium at risk of ischaemia, which can be detected by all myocardial perfusion imaging techniques10. From a physiological perspective, microvascular resistance is closely adjusted at rest via integrated control mechanisms to maintain blood supply commensurate with cardiac workload and to compensate for pressure loss induced by an epicardial stenosis (autoregulation)13  and metabolic (O2 consumption) heterogeneity18. Transmural perfusion gradients and the microcirculation itself are further influenced by cardiac–coronary interaction with or without an epicardial obstruction. Compressive forces exerted by cardiac contraction render the subendocardium particularly vulnerable to ischaemia, especially at elevated heart rate or at low perfusion pressure distal to a stenosis21. The effects of epicardial obstruction, therefore, extend beyond the stenosis into the microcirculation22. The fundamental parameters for the assessment of myocardial ischaemia are regional absolute MBF (in units of millilitres per minute per gram of tissue) and relative perfusion, as well as relative parameters, such as myocardial perfusion reserve (MPR), which is the ratio of MBF under exercise-induced or pharmacologically induced stress to MBF at rest22.The coronary circulation comprises the epicardial conductance vessels (diameter 1–6 mm) feeding an extensive network of small vessels (diameter <300–400 μm) that penetrates the cardiac muscle tissue and is the site of regulation of myocardial blood flow 13 Fig. . When mi)13 Fig.  increaseThe potential of noninvasive assessment of blood flow in the coronary microcirculation as a gatekeeper for invasive coronary angiography is the subject of a growing research effort. Important new insights have emerged regarding the clinical implications of the quantitative and qualitative assessment of myocardial ischaemia using the different myocardial perfusion imaging modalities, such as SPECT, PET, MRI, echocardiography and cardiac CT. In addition to summarizing the current clinical application of qualitative and quantitative ischaemia imaging, we also discuss the emerging possible use of artificial intelligence with deep learning for the detection and characterization of disease.The unifying principle of all noninvasive techniques is that a contrast agent is injected into a peripheral vein. The contrast agent is transported to the heart and acts like a test substance (tracer) for blood and its transport through tissues. If the myocardium is normally perfused, the contrast agent is transported to the myocardium and can be detected with the use of noninvasive imaging modalities. If ischaemia is present, less contrast agent reaches the affected region and/or its wash-in or wash-out is delayed. This process is typically registered by a dynamic series of images that are sensitive to the specific contrast agent used.16 gives quantitative values of MBF and/or MPR. For this type of analysis, we need to know the time course of the contrast agent or tracer in the blood over time, that is, the arterial input function (AIF). The AIF is typically assessed either from the left ventricular cavity or by arterial blood sampling. From these principles, the AIF clearly accounts for variations in left ventricular function. However, collaterals cannot be accounted for and might introduce delayed wash-in23 and, on the basis of the mechanisms shown in Fig. 27. The common goal is to guide patient management and to provide the requisite justification for invasive coronary angiography and intracoronary haemodynamic measurements. Importantly, no single imaging technology can currently provide all measures of coronary circulation, and all imaging techniques have specific advantages and disadvantages while also providing different assessments of the coronary vascular components using anatomical or functional imaging  ; nuclear tracers can also enter the intracellular space or even bind within the myocyte  and basic scientists, were involved in the Quantitative Cardiac Imaging meeting. This Consensus Statement is not, therefore, endorsed by a single specialist society, but is driven by scientists from all disciplines collaborating to provide a multidisciplinary consensus. The content and recommendations in this article emerged from discussions among our diverse team, which aimed to overcome political and professional interests to produce balanced consensus recommendations. In a subsequent real-time us Table .All the authors participated in the Delphi process and judged all imaging modalities, to result in a consensus across modalities. The consensus process was performed after all lectures were given and discussed during the Quantitative Cardiac Imaging meeting and was organized into technical and clinical consensus processes. During the technical consensus process Table , a totalFor the clinical consensus process Fig. , a totalMoreover, in this Consensus Statement, we avoided giving the final verdict on a ‘competition between the methods’, but instead presented the potential relative merits of the methods that are currently available. Differences of opinion will always exist, which cannot entirely be avoided, but our cross-disciplinary Delphi process represents a solid approach to the clinical question. This Delphi process helped to define appropriate clinical indications as well as some of the directions for future technical developments to overcome challenges of SPECT, PET, MRI, echocardiography, CT and invasive coronary flow and pressure measurements. This Consensus Statement also describes major trends and breakthroughs relevant to patients with cardiac disease for all six imaging modalities in the sections below. Although we attempt to give a balanced overview of all the available imaging modalities using the Delphi consensus process, region-specific or institution-specific availability or expertise might increase or decrease the relative utility of a particular modality.1. SPECT not only has incremental prognostic value over clinical assessment alone but is also important in guiding therapy. The current clinical paradigm that the degree of ischaemia defines the individual risk, which in turn should be used for risk-based decision-making on revascularization or optimized medical therapy, is based on large registries of SPECT perfusion imaging52. Of note, no studies have compared outcomes when therapy is decided on the basis of SPECT versus an alternative test. As SPECT measures any perfusion to the myocyte with a tracer that is bound in the mitochondria, and owing to the temporal resolution, a distinction between primary-vessel and collateral flow cannot be made.SPECT has been the centrepiece of clinical cardiovascular imaging for decades. SPECT-based evaluation of the extent of myocardial ischaemia as a percentage of the left ventricular myocardium, together with concomitantly measured left ventricular function and volumes, is well established for the diagnosis of myocardial ischaemia53 has enabled dynamic imaging to assess the kinetics of perfusion tracers in blood and the myocardium. This information allows compartmental modelling to delineate absolute MBF and coronary flow reserve (CFR) by SPECT. Recent work has shown the feasibility of MBF quantification with CZT SPECT and has provided validation against the microsphere gold standard in an experimental model54 and in humans55 compared with PET. Clinically implementing this approach with SPECT protocols has the potential to provide incremental diagnostic and prognostic value for ischaemia assessment over the previous standard of relative regional perfusion defect measurement57, because it can detect conditions that affect the entire myocardium, such as severe ischaemia in multivessel disease or microvascular dysfunction (mostly in the subendocardium), with the caveat of the limited spatial resolution of SPECT. Therefore, integrating measures of transient post-ischaemic dilatation further improves the diagnostic accuracy and can be calculated in a highly automated fashion58.Detailed technical characteristics of SPECT are listed in Table 60. Compared with regular SPECT, CZT systems increase the effective sensitivity by fourfold to tenfold, and also provide higher spatial and energy resolution60. Accordingly, high-quality images are obtained with shorter acquisition times and/or a smaller injected dose of the radiopharmaceutical, which is beneficial for various groups of patients with complicated disease. Several multicentre studies support the usefulness as well as the diagnostic and prognostic value of CZT-based myocardial perfusion SPECT28. Although early work with these novel systems focused on the reduction in imaging time from 15–30 min with standard SPECT down to 2–3 min with CZT SPECT using a standard amount of injected radioactivity62, the aim of subsequent work was to reduce the amount of injected radioactivity to minimize patient exposure to ionizing radiation. A recent multicentre trial suggests that CZT imaging can be completed with an effective dose of 1 mSv at an image quality that is still superior to that obtained with standard SPECT63.SPECT is most commonly applied for myocardial perfusion imaging. Clinical indications for SPECT are listed in detail in Fig. 64 Quantitative measures of the perfusion defect size have become more widely available as diagnostic and prognostic markers with the introduction of solid-state detector CZT technology.Dynamic imaging enables compartmental modelling and provides absolute measures of myocardial ischaemia, thereby bringing SPECT closer to PET as the reference standard.82Rb, 13N-ammonia, 15O-water and 18F-flurpiridaz66. On the basis of close to 100% extraction, 15O-water PET is considered the clinical gold standard for perfusion quantification given that the image signal is directly proportional to tracer concentration, and tracer kinetic modelling is well established. All other tracers show a varying decrease in extraction with increasing flow, requiring correction to derive MBF  perfusion defects documented with PET hold strong prognostic information beyond that obtained from traditional cardiovascular risk factors22. PET-derived CFR has shown added prognostic value for the identification of at-risk women with more frequent non-obstructive coronary artery disease and potential microvascular dysfunction57. Of particular interest is that apparently normal perfusion images with a homogeneous tracer distribution can be reclassified on the basis of diffusely blunted hyperaemic MBF or CFR; several studies have shown that this subset of patients is at increased risk of future cardiac events82.In a contemporary study, PET had higher accuracy (85%) than coronary CT angiography (74%) or SPECT (77%) for the diagnosis of myocardial ischaemia when taking FFR as a reference standard40 Fig. . The com15O-water and 13N-ammonia require the presence of an on-site cyclotron as a high upfront investment because of the short half-lives of both tracers . By contrast, 82Rb  is produced by a generator that has to be replaced on a monthly basis, which confers a high monthly cost but a low upfront investment. So-called baby cyclotrons have lower cost and are aimed specifically at the production of 13N or 15O and, therefore, also require lower energies and considerably less radiation shielding than common PET cyclotrons. This feature greatly increases the possibility of using 15O-water and 13N-ammonia in hospitals without PET chemistry facilities. 18F-flurpiridaz is a novel tracer that has shown higher accuracy than SPECT83 and also promises quantification using direct parametric reconstruction84. Furthermore, machine learning used for the integration of variables has great potential in clinical practice for identifying patients with myocardial ischaemia and increased risk of events25.Both In summary, cardiac PET is the reference standard for the quantification of perfusion imaging. PET using parametric images showing MBF at the voxel level is now available in routine clinical practice, and PET also allows the derivation of the perfusable tissue index, which is a marker of myocardial viability, thereby expanding the clinical utility of this modality. On the basis of its characteristics, PET is well suited for patients with multivessel disease to confirm or exclude balanced ischaemia, and low-cost baby cyclotrons will improve the cost-effective use of PET.PET is the clinical reference standard for the quantification of myocardial perfusion.15O-water PET and the lower spatial resolution of PET compared with CT or MRI perfusion imaging30.Challenges of PET use include limited visual assessment of quantitative 13N-ammonia cyclotrons, as well as the availability of 18F-labelled tracers, could improve the cost-effectiveness of cardiac PET imaging, as well as logistics and dissemination.Small or Quantitative measures of myocardial ischaemia are provided with the addition of the measurement of viability and functional parameters during a single scan.Hybrid imaging combining PET perfusion imaging with coronary CT angiography data might provide comprehensive assessment, especially in patients with multivessel disease.85, myocardial perfusion MRI has evolved into a clinical modality with excellent sensitivity and specificity for detecting myocardial ischaemia86. Most clinical myocardial perfusion MRI approaches are based on dynamic contrast-enhanced imaging using exogenous gadolinium-based contrast agents. The absence of ionizing radiation and the increasing availability of MRI expertise and equipment promote its routine use to guide clinical interventions. All components of a comprehensive MRI examination  add synergistic information to prognosis88. Long-term follow-up data have demonstrated a strong and independent predictive value of myocardial perfusion MRI for future major adverse cardiac events and death90. The MR INFORM study91 demonstrated that, among patients with stable angina and risk factors for coronary artery disease, the use of myocardial perfusion MRI was associated with a lower incidence of coronary revascularization than the use of FFR and was non-inferior to FFR with respect to major adverse cardiac events.Since its inception92, quantitative approaches93 have gained momentum with technical advances in MRI data acquisition, reconstruction and processing94. Quantitative perfusion analysis provides incremental prognostic value over semiquantitative and qualitative data analysis, with an area under the receiver operating characteristic curve (AUC) of 0.85 versus 0.75 (ref.88). Figure 32. The conversion of signal intensity to contrast concentration is an important step for quantitative assessment  was higher than that for SPECT (0.74) on the basis of visual assessment. This finding is in agreement with the secondary end points of the multicentre MR-IMPACT II study108  or contrast agent injection schemes  are required for quantitative MRI perfusion analysis.Automated voxel-wise quantification and dynamic 3D, whole-heart MRI could improve the detailed and complete assessment of myocardial ischaemia.Evaluation of patients with complex disease is improved by the quantification of function, fibrosis and perfusion, and fractal analysis might allow obstructive and microvascular disease to be differentiated.119. The microbubbles consist of a gas core and typically a lipid or albumin shell. Ultrasound microbubbles remain entirely intravascular and can oscillate in resonance, producing the signals from individual microbubbles120. During infusion and steady state, signals emanating from microbubbles reflect the relative microvascular blood volume121. Microbubbles can be cleared from the myocardium by applying a series of high-power ultrasound pulses, and the myocardial replenishment is assessed by reverting to low-power imaging  is used, whereas dynamic (4D) imaging allows the quantification of MBF but requires multiple scans over time. Dynamic CT perfusion imaging might provide the greatest clinical value but challenges with this modality include increased radiation dose, motion artefacts and image quality limitations140. A meta-analysis showed higher sensitivity (0.85 versus 0.72) but lower specificity (0.81 versus 0.90) for dynamic compared with static CT perfusion imaging141. The greatest role of CT in relation to myocardial ischaemia might be in stenosis and plaque quantification.Cardiac CT is widely available with widespread clinical application for noninvasive coronary angiography and has a class I (level of evidence B) recommendation in the 2019 European guidelines, together with functional imaging, for use in individuals with a low-to-intermediate clinical likelihood of coronary artery disease142 . Importantly, computational fluid dynamics modelling to estimate FFR relies on mathematical assumptions and equal responses by the microcirculation to vasodilators. Moreover, and in contrast to invasive FFR, noninvasively estimated FFR does not account for collateral flow in the same manner157. To what extent the implementation of CT–FFR will translate into improved patient outcomes still needs to be elucidated. Of note, a meta-analysis showed that CT perfusion has a higher specificity than CT–FFR (86% versus 78%)141. The randomized CATCH-2 trial158 demonstrated that the addition of CT myocardial perfusion imaging to coronary CT angiography alone safely reduces the need for invasive examination and treatment . In a two-centre study, semiquantitative static CT myocardial perfusion imaging achieved a similar performance to perfusion MRI compared with the reference standard of invasive angiography and SPECT160. This finding was supported in a meta-analysis, which showed similar negative likelihood ratios for perfusion imaging using PET, MRI or CT of 0.14, 0.14 and 0.12, respectively73. Importantly, in the 2-year follow-up of the CORE320 study161, the combination of CT angiography and semiquantitative CT perfusion showed similar accuracy in predicting cardiovascular events to invasive coronary angiography and SPECT combined. In another single-centre study, MBF derived from dynamic CT perfusion had independent predictive value, with a hazard ratio of 5.7 when adjusted for obstructive coronary artery disease on CT angiography162.Cardiac CT has undergone exponential growth in the past decade, and clinical indications are listed in detail in Fig. ent Fig. . The CRE164, and the semiquantitative transmural perfusion ratio might improve diagnosis of myocardial ischaemia compared with using the MBF165. Low kilovolt scanning (70–80 kV) enables a substantial reduction in radiation dose, while increasing contrast-to-noise ratio166. New photon-counting energy-selective X-ray detectors are being developed for improved contrast and reduced radiation dose167  or resting distal coronary-to-aortic pressure ratio (Pd/Pa). iFR is defined as the ratio of distal coronary pressure to aortic pressure at a distinct time in cardiac diastole, termed the wave-free period  is calculated as the intracoronary flow velocity integral (CFVI) during balloon occlusion as a fraction of CFVI during coronary patency. The coronary pressure-derived CFI  is calculated as the coronary wedge pressure minus venous back pressure as a fraction of the aortic pressure minus venous back pressure. When both Doppler velocity and coronary pressure measurements are performed, the total collateral resistance can also be calculated, as well as the individual resistances in the components of the collateral pathway. CFI and CFIp are the most applicable techniques, and values of >0.30 are generally considered to indicate adequate collateral artery function, substantiated by the absence of angina or electrocardiogram changes during balloon occlusion38. This situation might be improved using less complex invasive measurements, such as iFR, which compared with an FFR-guided strategy leads to fewer revascularizations while providing equivalent 1-year clinical outcomes179. Resting Pd/Pa has so far been investigated only in diagnostic studies and has shown similar accuracy to iFR182. Considering the limitations of coronary pressure-based techniques, the decision to revascularize should optimally be on the basis of the combination of imaging ischaemia tests and coronary pressure measurement, the results of which should be interpreted in relation to the symptoms of the individual patient to determine the risk–benefit ratio of a coronary intervention.Clinical indications for invasive approaches are listed in detail in Fig. 180. This approach is currently being evaluated in a multicentre setting in the DEFINE-FLOW study183. Meanwhile, it is important to realize that the current technology for direct flow measurement is fairly outdated and technically demanding, and substantial technical revisions are expected shortly. However, current ischaemia-guided or coronary pressure-guided coronary interventions are already superior to angiography-based decision-making alone179. Artificial intelligence, mainly in the form of machine learning and intelligent algorithms, is increasingly being recognized as a tool to aid invasive diagnostics184 and to improve the safety and accuracy of invasive physiology techniques. Examples are the automated interpretation of aortic pressure traces and iFR pullback traces to identify inaccurate pressure readings that might influence FFR and/or iFR values or their interpretation and affect decision-making.The suboptimal discriminative value of FFR can be addressed by the  direct measurement of coronary flow, instead of its estimation from coronary pressure measurementPd/Pa. The combined measurement of pressure and flow should have the highest discriminative capacity and prognostic value but requires further testing. On the basis of their characteristics, invasive measurements have the greatest value in patients with a high likelihood of requiring invasive treatment.In summary, FFR measurements can substantially reduce the need for revascularization compared with visual assessment alone, without impairing long-term clinical outcomes. However, the limited uptake of invasive measurement of FFR in clinical practice is related to the complexity of the procedure, which can be overcome using measurement of iFR and Invasive catheter-based methods can be used to measure coronary flow and pressure.39).Challenges of invasive coronary flow and pressure measurements include the diagnostic and prognostic characteristics of FFR, the complexity of the procedure and its limited uptake in clinical practice (used in <6% of patientsPd/Pa are simpler than FFR but have similar prognostic and diagnostic value and might improve the clinical uptake of coronary pressure measurements.iFR and resting The combined assessment of CFR and FFR promises the greatest discriminative value for individual pathophysiology but requires testing in trials.In patients with a high likelihood of requiring invasive treatment, invasive coronary flow and pressure measurement is well suited to guide treatment decision-making.Invasive coronary pressure and flow measurements allow coronary collateral function to be quantified.Artificial intelligence might further improve the accuracy and interpretation of coronary pressure readings and could improve coronary flow assessment.Current cardiac imaging modalities offer widespread utility to assess myocardial ischaemia quantitatively, without the risks of invasive investigation. Among the myocardial perfusion imaging tests, PET is the reference standard for quantification, and SPECT is most commonly used. Although MRI is less commonly used than SPECT, MRI avoids ionizing radiation, as does echocardiography. Echocardiography has similar advantages to those of MRI and can be performed at the bedside. CT is not frequently used for perfusion imaging but offers coronary angiography including assessment of plaque burden and can provide a geometric framework for model-based estimation of CT–FFR. Intracoronary measurements of pressure and flow velocity provide comprehensive haemodynamic information to guide invasive treatment. All six ischaemia imaging techniques have distinct advantages and disadvantages Table .18F-labelled PET tracers could improve logistics, and hybrid PET–CT might provide comprehensive assessment, especially in patients with multivessel disease. Automated voxel-wise perfusion quantification of whole-heart MRI could improve the assessment of myocardial ischaemia to facilitate the evaluation of patients with complex disease and the differentiation between obstructive and microvascular disease. High frame rate echocardiography allows the estimation of myocardial blood velocity with improved image quality, and machine learning can be used for automated and fast myocardial segmentation. CT with increased rotation speed, photon-counting detectors and machine learning could overcome temporal resolution challenges, beam and scatter artefacts, and low contrast-to-noise ratios of CT perfusion imaging for use in patients with borderline coronary stenosis on CT angiography. Invasive coronary measurements of iFR and resting Pd/Pa is simpler than measurement of FFR but have similar prognostic and diagnostic value and might improve the so-far limited uptake of coronary pressure measurements. The combined assessment of CFR and FFR provides the greatest promise in discriminating individual pathophysiologies.The diagnostic potential of these imaging techniques is substantially improved by technical advances that can yield quantitative measures of myocardial perfusion. Dedicated cardiac SPECT cameras have emerged for improved sensitivity and resolution at lower doses of radiation, and dynamic imaging enables compartmental modelling and thereby provides absolute measures of myocardial ischaemia. Small cyclotrons and the availability of No single quantitative perfusion imaging technique is best for all types of patient, for all disease stages or at all clinical centres, as usage also depends on the availability of local expertise. Using a Delphi consensus process, we have identified the most appropriate clinical scenario for each diagnostic test for myocardial ischaemia Fig. . SPECT w134 showed that a much more comprehensive, pre-catheterization, quantitative, multimodality imaging strategy is required in patients with suspected ischaemia. This approach helps to identify the most appropriate treatment strategy with or without coronary revascularization and might translate into lower morbidity and mortality. Therefore, in the time of personalized medicine, perfusion imaging provides robust, quantitative assessment of myocardial ischaemia that can be used to guide individual risk stratification and direct treatment decision-making. Future studies will incorporate the emerging computational support of machine learning to benefit complex decision-making about the need for coronary revascularization.All imaging modalities share the requirement to take coronary pathophysiology into account in the interpretation of noninvasive perfusion imaging and invasive coronary pressure and flow data. Quantification of myocardial perfusion by imaging can provide accurate measures of the burden of ischaemia to determine individualized treatment strategies. This assessment is very important because the ORBITA studyComputational fluid dynamics simulation of coronary blood flow. The video shows a Gd-DOTA bolus as it is transported by pulsatile blood flow along the epicardial arteriesSupplementary Video 1 | Magnified view of a portion of Supplementary Video 1. The video shows the complex dynamics of a Gd-DOTA bolus as it is transported through the epicardial vesselsSupplementary Video 2 |


Background: Pregnancy causes multiple hemodynamic changes that place significant stress on the cardiovascular system. With advancements in medical care, individuals with complex congenital heart disease are living into their childbearing years. Much remains to be understood about the effects and management of pregnancy in individuals with complex congenital heart disease.Case Report: We describe the management and delivery of a 29-year-old pregnant female with repaired tetralogy of Fallot or ventricular septal defect with pulmonary atresia. The patient presented at 21 weeks’ gestation with New York Heart Association class II symptoms and pulmonary conduit stenosis, with a mean gradient of 52 mmHg. At 36.5 weeks’ gestation, she developed severe pulmonary conduit stenosis with a mean gradient of >75 mmHg. The patient was admitted at 37 weeks’ gestation for planned delivery. After a successful cesarean section and bilateral tubal ligation, the patient had an uncomplicated postoperative course. She was scheduled for follow-up for severe conduit stenosis at 6 weeks postpartum to discuss management options.Conclusion: Management of a pregnant patient with adult congenital heart disease should involve risk stratification for complications (commonly congestive heart failure exacerbation and arrhythmias) using tools such as the modified World Health Organization pregnancy risk classification. Based on the risk category, decisions must be made about frequency of follow-up, anesthesia, and mode of delivery. Patients in moderate to high-risk stratification should be managed by a multidisciplinary team at a specialty center, and all patients should undergo an anesthesia consultation prior to delivery. The decision for vaginal or cesarean delivery should be made on a case-by-case basis with consideration given to patient preference. Patients with asymptomatic moderate to severe pulmonic stenosis can be managed conservatively with appropriate follow-up and cardiac imaging, allowing intervention to be completed after delivery. Pregnancy results in many hemodynamic changes that may be deleterious to patients with certain congenital abnormalities. Plasma volume increases 40% in the first trimester, coupled with an increase in stroke volume and heart rate, which culminates in a 20% to 50% increase in cardiac output by 24 weeks of gestation3 and up to 1 mm of aortic dilation.4 The placenta, through nitric oxide/prostaglandin production, creates an approximate 35% decrease in systemic vascular resistance and an approximate 10 mmHg decrease in systolic and diastolic pressure.3Approximately 500,000 women with adult congenital heart disease (ACHD) are estimated to have reached reproductive age in the United States.5 Immediately following delivery, regardless of the amount of blood loss , cardiac output transiently increases 60% to 80% during the first hour.7In addition to the physiologic stress on the cardiovascular system throughout pregnancy, delivery of the fetus can be even more challenging for a patient with a tenuous hemodynamic state. With each uterine contraction during vaginal delivery, 300 to 500 cc of blood from the uteroplacental circulation is sent to the systemic circulation.When patients with ACHD become pregnant, the physiologic stress of pregnancy on a heart with congenital abnormalities may potentially pose a threat to both the mother and thus secondarily to the unborn child. In this case, we report the successful management of a patient with repaired tetralogy of Fallot and subsequent severe pulmonary conduit stenosis during pregnancy and delivery.A 29-year-old female in her second pregnancy, with a history of tetralogy of Fallot or ventricular septal defect with pulmonary atresia, had undergone 4 surgeries during her childhood, including a modified Blalock-Taussig shunt, patch repair of ventricular septal defect, and a right ventricle (RV) to pulmonary artery (PA) conduit. At 20 weeks’ gestation during her first pregnancy, she developed severe symptomatic stenosis of the RV to PA conduit with a Doppler gradient of 98 mmHg, thus requiring a 22-mm balloon dilatation and Genesis XD stent as a temporizing measure until definitive repair could be undertaken postpartum. However, she was lost to follow-up after delivery of her first child and did not undergo postpartum repair of her RV to PA conduit stenosis.The patient presented to our clinic during her second pregnancy at 21 weeks of gestation. Thus far, her pregnancy had been uncomplicated and prenatal testing to date had found no abnormalities in fetal development. On presentation, she admitted to mild dyspnea on exertion at a distance of 20 yards. On examination, the patient was tachycardic and normotensive with normal oxygenation. She was euvolemic with hemoglobin of 13.5 g/dL and creatinine of 0.7 mg/dL. Echocardiogram showed normal left ventricular ejection fraction (LVEF) of 60% to 65%, with mild right atrial (RA) dilatation, evidence of RV hypertrophy, and an estimated RV pressure of 82 mmHg. The PA conduit was severely stenosed, with a mean gradient of 52 mmHg and unrestricted pulmonic valve insufficiency. Our assessment determined her modified World Health Organization (WHO) pregnancy risk classification to be II-III .She was seen again in clinic at 34 weeks’ gestation. Her symptoms and repeat echocardiogram were unchanged from the previous visit. However, at 36.5 weeks’ gestation, 2-dimensional echocardiogram done in preparation for delivery identified severe conduit stenosis with a mean gradient of >75 mmHg, peak gradient of 98 mmHg with a peak velocity of 5 m/s, and unrestricted pulmonic valve insufficiency. The patient's RV pressures at the time also exceeded 71 mmHg. Despite the severe restenosis and unrestricted insufficiency of her PA conduit, her symptoms remained New York Heart Association (NYHA) class II. The plan was to admit the patient prior to cesarean section for assessment of heart failure and bilateral tubal ligation at 37 weeks’ gestation.As planned, she was admitted at 37 weeks for delivery and was cared for by a multidisciplinary team involving obstetrics, ACHD specialists, heart failure specialists, obstetric anesthesia, maternal fetal medicine, and the neonatal intensive care unit.The patient underwent a successful low transverse cesarean section and bilateral tubal ligation under epidural block with an estimated blood loss of 1,100 mL. Postdelivery echocardiogram showed normal LVEF of 55% to 60%, RA and RV dilatation with RV hypertrophy, and no change in RV pressure or valve gradient. The RV to PA conduit stenosis had decreased to a peak velocity of <4.8 m/s and a mean gradient of <56 mmHg with unrestricted insufficiency.The patient had an uncomplicated postoperative course, only requiring some gentle hydration, and was discharged 3 days postpartum. She was scheduled for follow-up for severe conduit stenosis at 6 weeks postpartum to discuss management options.8 the CARPREG II,9 the ZAHARA (Zwangerschap bij Aangeboren Hartaf-wijkingen) score,10 and the modified WHO pregnancy risk classification.11 These scores take into account a patient's cardiac history , NYHA heart failure classification, and current cardiac state  to provide a cardiac event risk assessment for the pregnancy.13 The 2017 American Heart Association guidelines recommend the use of the modified WHO pregnancy risk classification.3 High-risk groups—patients with Marfan syndrome with aortic root dilation >45 mm, bicuspid aortic valve with aortic dilatation >50 mm, pulmonary hypertension, severe coarctation, severe mitral stenosis or aortic stenosis, and LVEF <30%—are designated as WHO pregnancy risk classification IV and have an extremely high risk of mortality or severe morbidity; as a result, pregnancy is not recommended for these patients.3The initial assessment of a patient with ACHD should occur prior to pregnancy, and the physician should determine the risk of proceeding. Multiple models have been developed for this purpose, including the CARPREG (Cardiac Disease in Pregnancy) risk index,11 The European Society of Cardiology 2018 recommendations for this classification are cardiac and obstetric specialist monitoring through pregnancy, delivery, and puerperium.11We determined that our patient was WHO pregnancy risk classification II-III—moderately increased risk of maternal mortality and moderate morbidity—because she had a repaired tetralogy of Fallot with severe pulmonary conduit stenosis.14 Arrhythmias tend to be the second most common cardiac complication in these patients, with an overall incidence of 4.5%; supraventricular tachycardia was the most common arrhythmia observed, followed by ventricular tachyarrhythmia.15 Cardiac death is much rarer, only having been observed as a complication in 1% of pregnancies of mothers with heart disease, congenital and acquired.8 The pregnancies of patients with repaired pulmonary atresia and ventricular septal defect resulted in a miscarriage 35% of the time, and 20% of patients developed heart failure.15 Additionally, patients with repaired tetralogy of Fallot had an increased rate of cardiac arrhythmia (6.4%) and heart failure (2.4%).15Many risks are involved as a patient with ACHD progresses through pregnancy. These risks vary by the congenital anomaly, but in general, include congestive heart failure exacerbation, arrhythmias, aortic root dilation leading to rupture, and cardiac death. A 2017 retrospective study of patients with ACHD found that all patients, regardless of ACHD complexity, had higher odds ratios for congestive heart failure development compared to controls: 9.7 and 56.6 for patients with noncomplex and complex congenital heart disease, respectively.16As a part of the initial pregnancy evaluation, a delivery plan should be developed that involves discussions about the necessity for transfer to a specialty center, mode of delivery, and intrapartum anesthesia. Patients with ACHD who are categorized with moderate to high maternal/fetal risk based on the modified WHO pregnancy risk classification should have an anesthesia consultation. Certain indications require a cesarean delivery; in these cases, understanding the effects of epidural anesthesia on patients with ACHD is important. Care must be taken with the use of epidural anesthesia, as it has been found to cause hypotension in >30% of cases secondary to decreases in sympathetic tone.11 Our patient requested tubal ligation at delivery, and thus cesarean section was chosen as the best option for performing both delivery of the fetus and sterilization. The cesarean section also allowed for a controlled delivery setting, as excessive blood loss would lead to reduction in RV preload, which would be detrimental to our patient with RV to PA conduit stenosis. To minimize the risk of deterioration as gestation progressed and ensure availability of the specialist team, delivery was planned at 37 weeks.The mode of delivery also needs to be considered. The European Society of Cardiology 2018 guidelines recommend that patients with pulmonic stenosis undergo vaginal delivery.17 When severe pulmonic stenosis becomes symptomatic, similar to when our patient was 20 years old with her first pregnancy, percutaneous pulmonic valve valvuloplasty is recommended.11The challenge of this specific case was the presence of severe pulmonary conduit stenosis with a mean gradient >75 mmHg in addition to RV hypertrophy and elevated RV pressures. Research on RV to PA conduit stenosis and/or insufficiency during pregnancy is limited; however, some prognostic and management information can be inferred from patients with pulmonic valve disease. Mild and moderate pulmonic stenosis tend to be well tolerated, but if severe pulmonic stenosis is present, follow-up appointments with echocardiography are recommended every 2 months to follow RV function.18 Benefits of general anesthesia include the avoidance of profound sympathetic block, commonly seen in spinal and epidural techniques, and the ability to concomitantly use transesophageal echocardiography.19 Regional  anesthesia preserves the mother's baseline ventilation and perfusion state. Epidural anesthesia also allows for continuous anesthetic and analgesic infusion, allowing for adjustment during delivery to minimize pain. Additionally, regional anesthesia can be reversed more expediently, while general anesthesia can take longer for recovery.Once the decision to perform a cesarean section was made, our multidisciplinary team needed to decide on the optimal form of anesthesia: general or regional. Overall anesthetic considerations include control of hypervolemia, acidosis, and minimal pulmonary vascular resistance/systemic vascular resistance alterations.20 Also, for patients undergoing a planned cesarean section, regional anesthesia is preferred to general anesthesia. For patients with ACHD, the regional block can be started initially with a spinal approach and gentle titration of epidural block to minimize hemodynamic instability.20 With obstruction of the RV outflow, reducing catecholamine release and subsequent stress on the RV is imperative.Because of the patient's RV dysfunction, the team decided to use epidural anesthesia. General anesthesia is often avoided in patients with RV dysfunction because all induction and inhalational agents, apart from etomidate, tend to reduce RV contractility, and mechanical ventilation increases pulmonary vascular resistance.All pregnant patients with complex ACHD and a WHO pregnancy risk classification of II-III or higher should be closely managed by a multidisciplinary team at a single tertiary center to ensure the safest outcome for mother and child. Predelivery consultations should be arranged with cardiology, obstetrics, and anesthesia. A primary and contingency plan, in case of maternal or fetal deterioration, should be made far in advance of delivery. Mode of delivery and anesthesia decisions should be made on a case-by-case basis, taking into account specialist opinions, patient wishes, and the nature of the ACHD. Patients with severe pulmonic stenosis can be managed conservatively through pregnancy with strict follow-up and specialty care. Our patient had severe pulmonic stenosis with a mean gradient >75 mmHg but did not require intervention during pregnancy. Appropriate medical management can result in a successful delivery, allowing intervention for pulmonic stenosis to be completed at a later date without the complicating factors of pregnancy.


In patients with heart failure (HF), the exhaled concentrations of hydrogen after a breath test—a non-invasive assessment of small intestinal overgrowth- has been related to HF severity and higher risk of adverse outcomes. Indeed, two intestinal bacterial metabolites—blood Trimethylamine N-Oxide (TMAO) and butyrate—have been related to a worse prognosis in HF. However, the relationship between the exhaled concentrations of hydrogen after a breath test and these two metabolites remains unknown. Thus, in this post-hoc analysis, we sought to evaluate whether these two metabolites are associated with the exhaled concentrations of hydrogen after a breath test in patients with a recent admission for HF. We included 60 patients with a recent hospitalization for HF. Cumulative hydrogen over time was integrated into a single measurement by the area under the concentration curve (AUC-H2). A linear regression multivariable analysis was used to evaluate the associations. A 2-sided p-value < 0.05 was considered to be statistically significant. The median (p25–p75) amino-terminal pro-brain natriuretic peptide, AUC-H2, TMAO, and Butyrate were 4789 pg/ml (1956–11149), 1615 (700–2585), 0.68 (0.42–1.12), and 0.22 ± 13, respectively. After multivariate adjustment, TMAO and butyrate were significantly associated with AUC-H2 . For TMAO, this association was positive and for butyrate, negative. Bacterial-origin metabolites TMAO and Butyrate were independently related to AUC-H2 in patients with a recent hospitalization for acute HF. HF has been linked to intestinal bacterial overgrowth, low bacterial richness, increased intestinal permeability, dysbiosis, and the presence of bacterial metabolites in the bloodstream3. Additionally, an altered intestinal microbiome has been pointed out as a potential player in HF progression4. In recent work, we found that the exhaled concentration of hydrogen after a lactulose breath test—a surrogate of small intestinal overgrowth (SIBO)—was associated with greater inflammatory activity, HF severity, and a higher risk of adverse outcomes in 102 patients with HF5. Recent evidence also supports a crucial role in cardiovascular diseases for some gut bacterial metabolites6. For instance, trimethylamine N-Oxide (TMAO) was associated with a strong pro-atherosclerotic activity7 and with a higher risk of adverse cardiovascular events in different CV-scenarios, including HF8. In contrast, butyrate, a short-chain fatty acid, shows anti-inflammatory properties in the intestinal mucosa by inducing colonic regulatory T cells and may control local dysbiosis, inflammation, and permeability3. In the HF setting, some studies have reported a reduction of butyrate-producing bacteria in some patients, together with the activation of the immune system2.There is increasing evidence about the role of gut disturbances in heart failure (HF)Aiming to evaluate whether TMAO and butyrate share a common pathophysiological link with SIBO, in this post-hoc analysis, we sought to evaluate whether serum samples of TMAO and butyrate are associated with the exhaled concentration of hydrogen after a lactulose test in a cohort of patients with a recent HF decompensation.5. In this sub-analysis, we only included patients with a recent hospitalization for acute HF (within the previous 30 days) in which metabolite samples were available . Serum samples and lactulose breath tests were performed the same day in an outpatient visit. Lactulose breath test consisted of measuring the amount of hydrogen principally produced by intestinal bacteria after ingestion of a glucose-substrate (lactulose) in one breath over repeated times . The highest concentrations of hydrogen are presumed to be associated with bacterial overgrowth in the small intestine, which presents a low number of bacteria in physiological conditions9. Over time, these cumulative hydrogen measurements were integrated into a single measure by the area under the concentration curve (AUC-H2) using the trapezoid method11. A positive result of SIBO was defined by a rise of ≥ 20 ppm in 90 min (after baseline) or by baseline levels of hydrogen > 20 ppm. Serum TMAO and butyrate were measured using a 600 MHz NMR Bruker spectrometer. Interleukin-1β, interleukin-6, interleukin-10, and tumor necrosis factor-α (TNF-α) were measured from frozen samples using a commercial assay [HSCYTMAG-60SK (Milliplex High Sensitivity Human Cytokine Magnetic Panel)]. A comprehensive transthoracic echocardiographic examination was performed using commercially available systems . All methods were carried out according to relevant guidelines and regulations. All experimental protocols were approved by the ethics and research committee of the Hospital Clínico Universitario of Valencia. Informed consent was obtained from all subjects.Study population and study protocol were previously described elsewhere2). Thus, the criteria for variables selection for both models were mostly based on prior knowledge/biological plausibility, independent of the p-value. All variables included in Table Continuous variables are expressed as mean ± standard deviation (SD) or median (p25–p75) when appropriate. Discrete variables are summarized as percentages. Linear regression multivariable analyses were used to evaluate the association among TMAO and butyrate with AUC-H2. A first multivariate model was performed, adjusting for age and sex Model 1). A second final multivariate analysis was performed, adjusting for well-recognized variables associated with HF-severity and those previously related to both metabolite disturbances in HF (Model 2). The model's predictive ability of this second model was assessed by the coefficient of determination (R. A seconThe median (p25–p75) age of the study population was 74 (70–78) years, and 75% were males. The proportion of patients with reduced (< 40%), preserved (≥ 50%), and midrange 41–49%) LVEF were 45%, 42%, and 13%, respectively. Ischemic was the most frequent etiology (42%). NYHA III–IV and peripheral edemas rates were 47% and 65%, respectively. Median (p25-p75) GFR and amino-terminal pro-brain natriuretic peptide (NT-proBNP), were 46.3 (31.6–69.3) and 4789 pg/ml (1956–11149), respectively. SIBO was positive in 27 patients (45%), and the median (percentile 25%-percentile 75%) value of AUC-H2 was 1615 (700–2585). The median of TMAO and the mean of butyrate results were 0.68 (0.42–1.12) and 0.22 ± 13. All the characteristics of the study population are summarized in Table –49% LVEFIn univariate analysis, TMAO and butyrate were significantly associated with AUC-H2 . For TMAO, this association was positive and negative for butyrate , interleukin-1β (12%), interleukin-6 (11.5%), butyrate (11.1%), TMAO (9.7%), hemoglobin (8.3%), SBP (5.1%), LVEF (4%), age (3.3%), and sex (< 0.01%) (Drop-in R2). The TMAO and butyrate models accounted for 60.5% and 45.7% of the variability in AUC-H2.Using RThe potential role of the gut microbiota in the pathogenesis of metabolic and inflammatory disturbances in HF has been partially unveiled. In the current work, higher TMAO and lower butyrate identified a subset of patients with higher exhaled hydrogen after a lactulose breath test. Current findings suggest both metabolites disturbances share a common pathophysiological pathway with SIBO in patients with a recent episode of acute HF.2. In HF, TMAO is associated with greater HF-severity and worse prognosis8. On the other side, butyrate belongs to the short-chain fatty acids (SCFAs) family. They are mainly produced in the colon by bacterial fermentation of dietary fiber12. Loss of butyrate-producing bacteria may result in a dysfunctional intestinal mucosal barrier and leakage of microbial products such as lipopolysaccharide (LPS) that activate the innate immune system triggering inflammation3. Recent sequencing-based studies in HF patients have reported a relative reduction in taxa from the Lachnospiracea or Ruminococcacea families, species known for their capacity for butyrate production13. Interestingly, depletion of the known butyrate producer Eubacterium Halli and Lachnospiracea are associated with increased plasma levels of soluble CD25, more severe disease, and a higher risk of death or heart transplantation13.TMAO is generated from dietary nutrients such as phosphatidylcholine, choline, and L-carnitine . Once ingested, multiple gut microbial enzyme complexes transform these molecules and their products circulate by the portal vein to the liver, where the flavin-containing monooxygenases produce TMAOIn summary, our study shows that TMAO and butyrate levels in patients with HF may have a role in identifying those patients with a higher risk of gut microbiota derangements linked to the activation of deleterious metabolic and inflammation pathways. These findings endorse the abdominal and dysbiosis contribution in the pathophysiology of HF.14. Third, we did not register the type of dietary regimen, or the drugs consumed that may largely influence both metabolites' values. Finally, the clinical implications of these findings need to be settled with bigger studies. For instance, further studies should: (a) explore the potential utility of higher TMAO and lower butyrate for identifying an underlying SIBO in patients with a recent episode of acute HF and other pathologies, (b) confirm the causal contribution of SIBO for explaining metabolites disturbances in the clinical setting.Important limitations deserved to be acknowledged. First, this is an observational, small, and single-center study. Second, the exhaled breath-tests are not considered the gold-standard for SIBO diagnosis; however, there is evidence showing an acceptable accuracy levelBacterial-origin metabolites TMAO and butyrate were independently related to AUC-H2 in patients with a recent hospitalization for acute HF. Further studies are needed to confirm the current findings and explore the clinical implication of them.Supplementary information.


A comprehensive list of porcine, ovine, and canine models of disease are presented, and the translational importance of these studies to clinical success is highlighted through a brief overview of recent devices approved by the FDA alongside associated clinical trials and preclinical animal reports.•Increasing the use of large animal models of HF holds significant potential for identifying new mechanisms underlying this disease and providing valuable information regarding the safety and efficacy of new therapies, thus, improving physiological and economical translation of animal research to the successful treatment of human HF. Preclinical large animal models of heart failure (HF) play a critical and expanding role in translating basic science findings to the development and clinical approval of novel therapeutics and devices. The complex combination of cardiovascular events and risk factors leading to HF has proved challenging for the development of new treatments for these patients. This state-of-the-art review presents historical and recent studies in porcine, ovine, and canine models of HF and outlines existing methodologies and physiological phenotypes. The translational importance of large animal studies to clinical success is also highlighted with an overview of recent devices approved by the Food and Drug Administration, together with preclinical HF animal studies used to aid both development and safety and/or efficacy testing. Increasing the use of large animal models of HF holds significant potential for identifying the novel mechanisms underlying the clinical condition and to improving physiological and economical translation of animal research to successfully treat human HF.  The complexity of heart failure (HF) has challenged the scientific community for decades. Multifaceted signatures of pathophysiological mechanisms driving HF are under intense investigation. However, the heterogeneous nature of the disease has limited therapeutic advances in the field. Not surprisingly, the prevalence of HF continues to increase at an alarming rate. Currently, it is estimated that 6.5 million people in United States have HF; by 2030, HF will affect >8 million people . In addiA defining characteristic of HF is the inability of the heart to pump enough blood to the body, which leads to poor quality of life for patients with this condition. In the past 30 years, the diagnosis of HF has evolved 2 primary categories: 1) HF with reduced ejection fraction (HFrEF), characterized by a resting ejection fraction (EF) of ≤40% and traditionally referred to as systolic HF; and 2) HF with preserved ejection fraction (HFpEF), characterized by a resting EF of ≥50% and traditionally referred to as diastolic HF , comorbidities , and disease modifiers  associated with HF has made improving therapeutic options for treating the overall syndrome difficult. Contributing to these difficulties is the lack of ideal animal models that reliably replicate most of the pathophysiological features often found in human HF. Large animal models of HF  have some advantages in terms of clinical translation given key determinants of myocardial work and energy consumption, such as left ventricular (LV) wall tension, heart rate, and vascular wall-to-lumen ratios are more similar to humans , 12, 13.This state-of-the-art review outlines existing methodologies and physiological phenotypes of several HF models developed in large animals . HistoriChronic pressure overload resulting from aortic valve stenosis or systemic hypertension may ultimately lead to HF ,15. OverGiven the significant number of HF patients with antecedent hypertension and/or aortic stenosis, numerous large animal models of pressure overload−induced HF have been developed to enhance our understanding of how these pathological mechanisms contribute to disease development. Many of these models have incorporated parallel comorbidities, such as obesity, type 2 diabetes, and chronic kidney disease, into the overall design in an effort to more comprehensively imitate the clinical syndrome, alongside traditional physiological features of HF . As a result, animal models of experimental pressure overload−induced HF have been developed using surgical techniques such as transthoracic aortic constriction , renal wrapping, and renal microembolization in pigs, sheep, and dogs. Endocrine-mediated methods based on high-salt diets like deoxycorticosterone acetate have also been used. Transthoracic aortic constriction methods attempt to recreate aortic stenosis by narrowing the aorta, which results in both local increases in myocardial afterload and neurohumoral involvement; the severity of each depends on the location of the aortic constriction . Aortic banding increases the LV aortic pressure gradient, induces concentric LV hypertrophy, increases myocardial stiffness, and impairs myocardial relaxation similar to that observed in aortic stenosis. However, aortic banding fails to recapitulate calcification and fibrotic lesions in the aortic valve or significant increases in vascular stiffness occurring along the length of the aorta as often seen in human aortic stenosis. Renal wrapping, renal microembolization, and implantation of deoxycorticosterone acetate pellets induce systemic hypertension via neurohumoral activation. Although effective, these methods are limited by their inability to incorporate genetic factors that often contribute to developing hypertension and use supra-physiological doses of salt that may also have disproportionate impacts on neurogenic and neurohormonal activation. With these general strengths and weakness in mind, the following sections discuss existing large animal models of pressure overload−induced HF and highlight the physiological and molecular phenotypes associated with each.Several different studies have examined aortic banding in swine in the absence of comorbidities. Cardiac pressure overload was induced by constricting the ascending aorta in 45-day-old Yorkshire pigs using a 60- to 70-mm Hg systolic pressure gradient over 2 months , 22, 23.Aortic banding was also used to induce chronic pressure overload−induced HF in both 3- and 8-month-old Yucatan miniature swine using a 50- or 70-mm Hg systolic pressure gradient, respectively, placed on the ascending aorta over 6 months see , 31, 32.Other models of HF developed by using aortic banding in pigs included studies by Ishikawa et al.  and YarbA more recent attempt investigated the heterogeneous aspects of HF by including comorbidities via a combination of Western diet (10 months) and chronic pressure overload using aortic banding  in female Ossabaw swine , a uniquIn contrast to swine models, the development of systolic dysfunction tends to precede diastolic dysfunction in ovine models of pressure overload−induced HF. Aortic banding of the ascending aorta in sheep was accomplished using a number of different methods, varying from static banding in young animals  to adjusAcute and chronic models of canine pressure overload-induced HF have been heavily used for >40 years. The use of dog models has diminished over time in part due to its extensive collateral circulation in dogs, which differs dramatically from that of humans and other large animals  . We refeHistorical studies led to the development of canine models of systemic hypertension by clamping of a renal artery  and wrapTwo more recent swine models induced systemic pressure overload via hypertension using a combination of factors layered with comorbidities relevant to HFpEF. Sorop et al.  combinedThe second of these studies included the combination of deoxycorticosterone acetate with Western diet for 12 weeks in Landrace swine . HemodynCardiac cell death associated with aberrant heart dysfunction is the main characteristic of a myocardial infarction (MI), which can ultimately lead to HF ,69. ThisCardiac structural, functional, and metabolic characterization after MI reveal disruption of the contractile apparatus, mitochondrial impairment, endothelial dysfunction, and increased cell death ,72. CoroExperimental models of MI-induced HF include ischemia/reperfusion (I/R), non-reversible coronary occlusion induced by coronary ligation or ameroid constrictors, and coronary microembolization. Each technique incorporates clinical features that encompass central and peripheral modifications observed in patients with HFrEF caused by MI. An I/R approach acutely occludes coronary blood flow to the myocardium followed by reintroduction of blood flow to the ischemic area ,76. MoleNon-reversible coronary occlusion is performed by suture ligation or ameroid constrictor placement without reperfusion. The coronary ligation by suture is an immediate approach to develop acute MI, whereas ameroid constrictors can mimic MI resulting from coronary stenosis due to progressive atherosclerotic plaque formation. Limitations to this technique include permanent occlusion of vascular flow to the myocardium, which is rarely seen clinically because routine treatment includes reperfusion of the ischemic myocardium via PCI or coronary artery bypass grafting.Finally, coronary microembolizations are sequential injections of microspheres that can be performed acutely and/or over time ,79. AccuOcclusion times of coronary arteries from 30 to 180 min in duration have been shown to cause an ischemic insult significant enough to induce myocardium cell death ,71,75. GIn Yorkshire swine, differences in MI-induced HF following occlusion of the proximal LAD or LCx was examined using an I/R protocol produced by inflation of an intracoronary angioplasty balloon for 120 min . After 3Ovine models of I/R were also used to examine MI-induced HF. Charles et al.  examinedvan der Velden et al.  studied Ameroid constrictors were also used with and without comorbidities such as obesity and type 2 diabetes in swine to induce MI and HF. Early studies placed 2.0- to 2.5-mm ameroid constrictors around the LCx coronary artery, with gradual occlusion of blood flow resulting in a highly variable infarct size (5% to 37% of the LV) ,97. ReceOvine models of ischemic heart disease induced by ameroid constrictor were also used. Chekanov et al.  analyzedAttempting to replicate acute MI and subsequent HF in a dog model of coronary microembolization, Franciosa et al.  acutely A cardiac magnetic resonance study infused microbeads 100 to 300 μm in diameter into the LAD coronary artery of farm pigs (34 kg), which resulted in decreased EF (36%) 1 week after microembolization . In 4- tIn adult Merino Wether sheep (51 kg), an average of 5 embolization procedures was administered every 2 weeks using 90-μm polystyrene microspheres in both the LAD and LCx coronary arteries ,109. SevRecent work combined I/R and coronary microembolization protocols in Yorkshire swine (38 to 43 kg) . In thisThe pathological interaction between arrhythmia and HF is well established, increasing both the risk of developing HF and morbidity and/or mortality in established HF cases . RecentlOriginally reported in 1962 , a signimax) and increased biomarkers of HF  21 days after introduction of the arrhythmic stimulus , axial flow pumps, and left atrial-to-femoral arterial ventricular assist devices. These devices mechanically assist the myocardium, providing short-term systemic hemodynamic support and minimizing myocardial workload during ischemic events complicated by cardiogenic shock or during high-risk PCI procedures , 137. IAmax, stroke work, pre-load recruitable stroke work) to a greater extent than the Impella.The impact of TandemHeart on hemodynamics and cardiac morphology has been investigated in porcine models of acute MI or ventricular arrhythmia , 155. Fohttps://www.fda.gov/medical-devices/medical-device-recalls/abbott-recalls-centrimag-circulatory-support-system-motor-due-pump-and-motor-issues). Difficulties with the device occurred after FDA approval, despite several preclinical studies in both sheep , and a multicenter study that showed short-term support with low incidence of device-related complications and no device failure in cardiogenic shock patients 30 days after CentriMag implantation , which was recalled due to a calibrating system error linked to electromagnetic interference, which caused the device to stop (th sheep , 166 andth sheep , 3 registh sheep  (CentriMantation . These fPreclinical large animal models play a critical and expanding role in translating basic science findings to the development and clinical approval of novel cardiovascular therapeutics. As recently examined in mice , researc


Mitral valve prolapse is the most frequent valvular defect associated with a wide range of electro-hemodynamic abnormalities, leading to heart failure, arrhythmias and sudden cardiac death. Mitral valve prolapse, first described from Barlow in the 1960s, is defined as displacement of mitral leaflet tissue into the left atrium past the mitral annular plane during systole. The correlation between mitral valve prolapse and sudden cardiac death has been investigated and clarified by various studies in recent years. However, identifying patients at risk and applying measures to prevent those from sudden cardiac death is challenging.We report on a 61-year-old female patient who had undergone an aborted sudden cardiac death. An arrythmogenic mitral valve prolapse was diagnosed. In addition, electrocardiographically and morphologically risk markers for sudden cardiac death were found in this case. We performed an ICD implantation as secondary prophylaxis and intended to reconstruct the mitral valve.This article examines the association of mitral valve prolapse with sudden cardiac death, the underlying pathophysiological mechanisms and the strategies leading to identify the risk group. We report on a patient who had undergone out-of-hospital cardiopulmonary resuscitation. The 61 years old female patient was without any significant previous illness and did not take any medication regularly. The collapse was preceded by malaise and nausea for 10 min. The patient’s partner started cardiopulmonary resuscitation after calling the rescue service. The emergency physician diagnosed ventricular fibrillation Fig. . High-sePhysical examination on admission: Obese 61-year-old woman (BMI 30.1 kg/m2), pulse 60/min, blood pressure 120/80 mmHg, temperature 36 °C, O2 saturation 94% under mechanical ventilation. Heart, lungs, and abdomen unremarkable.Laboratory studies: Complete blood count: unremarkable. Plasma coagulation study: normal, D-dimers within normal limits, Clinical chemistry: C-reactive protein 6 mg/L , all other values within normal limits.ECG: Sinus rhythm, HF 60, no AV-Block, no QT time prolongation, inverted T-waves in the inferior leads  Fig. b.Fast echocardiography: Normal systolic right and left ventricular systolic function, severe mitral regurgitation, no pericardial effusion.Chest x-ray: Normal cardiac size with evidence of pulmonary venous congestion.Intensive care therapy achieved stabilization of the patient’s general condition. Controlled ventilation was stopped on the fourth day. Except for a hypoactive delirium, which was adequately controlled by administration of a neuroleptikum, no neurological deficits were manifested.Evaluation of the 12-lead ECG did not reveal any evidence of ECG changes, which are normally associated with canalopathies .However, we have registered recurrent ventricular salves during monitoring Fig. c. In addFollow-up echocardiography showed a significant mitral valve insufficiency with preserved left ventricular pump function. The left ventricle demonstrated mild endsystolic and enddiastolic dilatation. A severe dilatation of the left atrium (LA area 45 cm2) was noticed Fig. a. The laTransesophageal echocardiography was performed to evaluate the mitral valve more precisely. A high-grade eccentric mitral valve insufficiency due to a pronounced PML and a mild AML prolapse could be demonstrated Fig. c. EspeciFor further clarification of the arrhythmogenic event, we ordered a CMR. This exploration has shown a discreet mid-wall LGE in the LV inferobasal region Fig. a. AdditiRegarding the severe mitral valvular insufficiency due to the MVP, the case was discussed in the heart team. It was decided to provide the patient with an internal automatic cardioverter defibrillator (ICD) first and to repair the mitral valve by mini invasive surgery in 3 months.The patient showed regression of the delirium and an increasing mobility. After implantation of an ICD device Fig. a, the paMVP is a relatively common cardiac valvular disorder, affecting about 1–3% of the population. Characteristics include superior displacement of mitral valve leaflet(s) during systole by at least 2 mm, myxomatous degeneration, and thickening of the leaflets [A clinical-pathological investigation performed in Italy, which lasted 21 years and included young persons (< 35 years of age) MVP dying suddenly, has found that the third most common cardiac condition associated with SCD with an incidence of 12% is due to an “arrhythmogenic MVP”, succeeding arrhythmogenic right ventricular dysplasia (24%) and atherosclerotic coronary artery disease (20%) [Two factors are considered fundamental for the occurrence of SCD in patients with MVP: LV myocardial fibrosis (substrate) and complex ventricular ectopy (trigger). Perhaps a consequence of mechanical traction exerted by the prolapsing leaflet, the fibrosis is most often localized to the posterior base of the left ventricle or the papillary muscles, which are most susceptible to the mechanical stretch forces exerted by the billowing leaflets .The prolapsing mitral valve exercises traction on the papillary muscles, activating the local stretch receptors and causing membrane depolarization of the nerve endings with abnormal mechanoelectrical feedback to the central nervous system causing VT or VF .A genetic background has been associated with MVP and SCD. MVP can be familial in 35–50% of cases . A typicThe association between presence of MVP and occurrence of SCD has been estimated to be low. Meanwhile some studies and case reports have indicated that mitral valve prolapse may be a trigger for ventricular fibrillation. Thus, there is evidence for a significantly increased risk of SCD as well as risk for ventricular tachycardia in patients with MVP . The preVentricular tachycardia seems to be more common in female MVP patients, with some studies demonstrating that 70 to 90% of affected individuals are women . The reaPremature ventricular contractions (PVC) are observed in the general population of MVP patients, with insignificantly difference between patients with and without SCD .It had observed that the origin of PVC was majoretly the posterobasal segment of the LV. This constellation could be explained by a mechanical overload of the left ventricle in this area due to the defective functioning mitral valve . This obThe echocardiography allows a precise evaluation of the mitral valve. In addition to estimating the severity of mitral regurgitation and its mechanism, the echocardiography permits screening of risk parameters for sudden cardiac death due to MVP.A possible signal of a high SCD-risk is a spiked high velocity signal across the lateral mitral annulus on echocardiography (“Pickelhaube sign”). This echocardiographic sign is more likely to be present in patients with (67%) than without (22%) ventricular arrhythmias.A distinctive spiked signal (≥16 cm/s) appears to be a signal of a significant elevated SCD Risk .A possible physiopathological explanation of this phenomenon is that the prolapsing leaflet tugs the posteromedial papillary muscle; consequently, the adjacent posterobasal area will be pressed toward the apex. Several studies have looked into the significance of this sign and its ability to detect patients with MVP and SCD risk. A study examined MVP patients simultaneously with CMR and echocardiography and has observed that only patients with Pickelhaube sign present LGE in the CMR. Therefore it was concluded that this sign an indicator of a malignant phenotype bileaflet mitral valve prolapse . HoweverFocal or diffuse myocardial fibrosis has been linked to ventricular arrhythmia and/or sudden cardiac arrest. Speckle-tracking echocardiography allows an assessment of left ventricular mechanical dispersion, which is an indicator of heterogeneity of ventricular contraction. MVP patients had significantly higher mechanical dispersion compared with controls despite similar LV ejection fraction, according to a study exploring MVP-patients with documented ventricular arrhythmia and MVP-patients without significant arrhythmia .Furthermore, mitral annular disjunction (MAD), recently described entity, is characterized by detachment of the roots of the annulus from the ventricular myocardium to which it would normally be attached . SeveralAn interesting finding has been examined by a study; MAD might be considered as an independent risk factor for SCD, apart from the presence of a MVP. 22% of patients who suffered VT do not express any mitral valve anomaly .Cardiac magnetic resonance (CMR) imaging is a noninvasive and powerful technique, with the ability to characterize myocardial tissue architecture and asses myocardial abnormalities. In addition, the CMR provides in a case of MVP and aborted SCD or VT important information.CMR imaging with particular focus on delayed gadolinium enhancement of posterobasal myocardium and of the papillary muscles not only helps establish the diagnosis of MVP, it may leads to a risk stratification . DelayedDue to the lack of uniform recommendations, an individualized therapy from patient with MVP and symptomatic ventricular arrhythmias should be considered, relying on the expertise of the medical team in each center.A study demonstrated that ablation is feasible in MVP patients with symptomatic, drug-refractory ventricular arrhythmias. Moreover. Ablation can reduce symptomatic PVBs and appropriate ICD shocks during follow-up .Mitral valve reconstruction results in a reduction of the ventricular volume load. It relieves stretch on the papillary muscles und facilitates ventricular reverse remodeling. Mitral valve surgery was found to be beneficial in reducing ventricular arrhythmias in a few studies . InteresFurthermore, a recent study shows that over a median follow-up of 9 years, 33% of patients developed hemodynamically significant VT/VF after their initial ablation and underwent placement of an implantable cardioverter defibrillator (ICD). This could indicate the progressive characteristics of the arrhythmia in patients with MVP .The subsequent ICD-control after 3 weeks did not reveal any arrhythmia. We detected at the 3 months ICD-control a ventricular tachycardia. The VT was detected 3 days after the valve reconstruction. The subsequent ICD-control after 6 weeks did not reveal any arrhythmia. We decided to take a wait-and-see approach based on the preliminary studies on the suppressive effect of mitral valve reconstruction on VT, and the lack of rhythmogenic events in the subsequent ICD-controls. We envisaged ablation in case of VT-recurrence.There is no clear recommendation for a primary prophylactic ICD implantation in patients with MVP and high risk for SCD. Neither the American Heart Association nor the European Society of Cardiology guidelines for ventricular arrhythmias and SCD have specific recommendations for the risk stratification of SCD in MVP. An electrophysiological examination should be considered to clarify the ICD indication. Some center consider implantation of an ICD if sustained monomorphic VT can be induced with up to 3 ventricular extrastimuli or sustained polymorphic VT can be induced with either 1 or 2 ventricular extrastimuli .Due to the lack of prospective studies on this issue, the primary prophylactic ICD implantation remains an individual case decision.MVP is an underdiagnosed entity and is often encountered in asymptomatic individuals. Fibrosis of the papillary muscles and the posterobasal LV segment represents the structural substrate for the development of ventricular arrhythmias. Further more complex mechanisms for the occurrence of VT are reported.Electrocardiographic, echocardiographic and MR-morphological risk features were identified and must be considered for patient stratification. In view of the new studies that have underlined the role of genetic substrate in MVP, genetic testing to determine high-risk individuals will be probably onducted in the future.The current literature regarding the role of mitral valve repair/replacement in reducing ventricular arrhythmias is mixed and comes from isolated case reports or single-center experiences with small sample sizes. The role of electrophysiological exploration and ablation remained controversial. Currently, there are insufficient data supporting the role of primary prophylactic ICD implantation in patients with MVP and high-risk features.In the case of our patient, ICD implantation was performed for secondary SCD prophylaxis.From our point of view, MVP patients are indeed exposed to life-threatening arrhythmia, even SCD, therefore standardized treatment, focusing on primary and secondary prophylaxis is required. In case of unexplained life-threatening ventricular arrhythmias, we do believe that MVP must be considered and screened.


Congenital mitral valve stenosis is a rare and severe disease, usually associated with other heart defects. The appropriate intervention depends on the site and mechanism of valvular obstruction and the aim is to avoid or delay valve replacement since it is associated with significant morbidity and mortality. Early single-stage complete repair is associated with better prognosis. We report the case of a 20-month-old child with a supravalvar mitral ring combined with a ventricular septal defect; pulmonary arterial systolic pressure before the surgery was 79 mmHg. The patient underwent a successful surgical repair with good clinical resolution. Rarely isolated, mitral ring is usually associated with various congenital heart defects, such as interventricular communication, coarctation of the aorta, subaortic stenosis, parachute mitral valve, left superior vena cava draining in the tectum of the left atrium, and cor triatriatum. The variability of the pathology and the defects interfere with the best strategy choice. Supramitral ring is usually associated with a normal valve apparatus. Special emphasis is placed on the differential diagnosis, since early recognition of the lesion may enable the patient to benefit from surgical intervention.Mitral ring is a subtype of congenital mitral valve stenosis (CMS) and is part of a spectrum of obstructive lesions affecting the left heartth percentile. Transthoracic echo evaluation showed a supravalvar mitral ring (SVMR) associated with a large inlet ventricular septal defect , and moderate alkalosis (pH>7.5). The final left atrial pressure to left ventricular pressure (LAP-LVP) gradient was 3 mmHg and the final systolic pulmonary artery pressure was 30 mmHg.The patient was submitted to a surgical resection of the SVMR with closure of the ventricular septal defect . The mitHe was discharged from the hospital with resolution of both mitral stenosis and ventricular septal defect and a lower pulmonary artery pressure, treated ambulatorially with oral sildenafil.. Anatomic treatments for CMS include balloon mitral valvuloplasty, surgical mitral valvuloplasty, and mitral valve replacement. A detailed assessment of the morphology and hemodynamic alteration will define the best treatment strategy. Early recognition of the lesion may anticipate the surgical intervention.Various malformations result in CMS, associated or not with other cardiac defects. It affects 0,4% of patients with congenital heart disease (CHD). It is an abnormal ridge of connective tissue arising from the left atrial wall and ranges from a thin membrane to a thick discrete ridge. It partially obstructs the mitral valve inflow and increases venous capillary pressure and pulmonary artery pressure due to an elevated LAP. Congestive heart failure is expected to occur, as it can be seen in this case. Intervention is indicated in the most severe cases to improve mitral valve function. Among those in which the mitral apparatus is normal, the outcome is better.SVMR is rarely seen in neonates, the ring develops and often progress during infancy. There is a trend toward early single-stage complete repair. Mitral valve replacement and young age are associated with worse survival,10-12.Surgical repair is the preferred treatment for SVMR stenosis, mainly in association with other cardiac lesions. The prognosis in those who require resection within the first 18 months of life is poor due to high mortality and recurrent supravalvar mitral stenosis. The pulmonary vasoreactivity test should be done to define the best candidates for heart surgery among patients with CHD and pulmonary arterial hypertension.In this case, SVMR was associated with ventricular septal defect and pulmonary arterial hypertension. Besides surgical repair, pulmonary arterial hypertension control was the key to success. The distinction between pulmonary vasoconstriction and pulmonary vascular occlusive disease will influence the prediction as to whether a child with PH in association with CHD will respond to the management strategies. In order to avoid rebound PH, NO was careful reduced till the patient was extubated.Endothelial injury associated with cardiopulmonary bypass in patients with CHD predisposes to development of PH. In this patient, left to right shunt and anatomic factors that impose obstruction to pulmonary blood flow (SVMR) were present. After surgical repair, attempts to reduce pulmonary vascular resistance were employed: increased inspire oxygen fraction, moderate hyperventilation, and moderate alkalosis. Pharmacologic interventions were: milrinone, a phosphodiesterase inhibitor, and NO, an endothelium-derived vasodilator with no systemic effect when inhaled. Special attention must be paid to children in risk of PH. Good early survival depends on single-stage repair and postoperative management strategies for PH.Mitral valve repair for congenital supravalvar ring stenosis can be performed successfully. This delicate population of patients should be evaluated looking for other heart defects. Ring resection leads to excellent long-term result