For the last seven decades, primary aldosteronism (PA) has been gradually recognized as a leading cause of secondary hypertension harboring increased risks of cardiovascular incidents compared to essential hypertension. Clinically, PA consists of two major subtypes, surgically curable and uncurable phenotypes, determined as unilateral or bilateral PA by adrenal venous sampling. In order to further optimize the treatment, surgery or medications, diagnostic procedures from screening to subtype differentiation is indispensable, while in the general clinical practice, the work-up rate is extremely low even in the patients with refractory hypertension because of the time-consuming and labor-intensive nature of the procedures. Therefore, a novel tool to simplify the diagnostic flow has been recently in enormous demand. In this review, we focus on recent progress in the following clinically important topics of PA: prevalence of PA and its subtypes, newly revealed histopathological classification of aldosterone-producing lesions, novel diagnostic biomarkers and prediction scores. More effective strategy to diagnose PA based on better understanding of its epidemiology and pathology should lead to early detection of PA and could decrease the cardiovascular and renal complications of the patients. The chronicle of primary aldosteronism (PA) commenced in the 1950s when aldosterone was discovered by Simpson and Tait . Conn fiFor the last seven decades, PA has been gradually recognized as a common hypertensive disorder in contrast to expectation of the low prevalence at the dawn of PA ,13. CurrThe current diagnostic process for PA includes a number of strict hurdles between screening and subtyping for accurate decision-making on the treatment . HoweverThe PA prevalence has been estimated as 5–10% in all hypertension based on previous population studies , while gIntriguingly, a number of case reports have documented biochemically overt PA without hypertension since Brook et al. first described a normotensive PA case with aldosterone-producing carcinoma back in 1972 ,43. SeveIn symptomatic PA, more than 90% of all PA are nonhereditary cases. Those acquired PA consists of two clinical subtypes, unilateral and bilateral forms that the Endocrine Society recommends differentiating by AVS . UnilateFor PA subtyping, we must also consider the variable procedures in AVS among institutions. The interpretation of AVS results could be influenced by sampling conditions and respective cut-off values for laterality index . Based oCYP11B2/CYP11B1 chimeric gene, CLCN2, KCNJ5, CACNA1H, and CACNA1D, respectively , ne, ne49], These histological entities were defined in unilateral cases, but only few previous studies provided the detailed histopathological findings of bilateral diseases ,68. BaseHowever, the former study included the cohorts with hyperaldosteronism which did not meet the updated current diagnostic criteria of PA, and the latter study examined unilaterally resected adrenals. Therefore, the details of histopathological findings of bilateral adrenal in bilateral disease and their steroidogenic enzymes’ profiles are required for further clarification.The different expression profiles of some key steroidogenic enzymes, especially those involved in mineralo- or gluco-corticoids such as 3β-hydroxysteroid dehydrogenase types 1 and 2 (HSD3B1/2), 17α-hydroxylase (CYP17A), 11ß-hydroxylase (CYP11B1), and CYP11B2, could also well-characterize the differences of those histological entities. In addition, different profiles of these enzymes have been also recently reported in APAs with different somatic mutations. Therefore, genotype–immunohistochemical phenotype association is also summarized in this paragraph. Representative histological images are illustrated in As mentioned above, APMs and APNs preserved their polarity representing that these cells were functionally differentiated into ZG cells although their morphological features did not necessarily resemble ZG cells ,71. TheyKCNJ5 mutation was detected in more than 70% in East Asian cohorts [CACNA1D was most frequently detected (≈40%) in Afro-America [KCNJ5 mutation and co-immunolocalization of cortisol-biosynthetic enzymes, especially for CYP11B1 [KCNJ5-mutated APAs frequently represent large tumors and are composed of abundant clear tumor cells [KCNJ5-mutated APAs, while a significantly inverse correlation was detected in ATP1A1-mutated APAs [KCNJ5-mutated APAs were deviated phenotype from ZG cells, whereas ATP1A1-mutated APAs were the more differentiating phenotype into ZG cells [KCNJ5-mutated APAs than wild type [On the other hand, aberrant immunolocalization pattern of steroidogenic enzymes was reported to be one of the characteristics of neoplastic aldosterone-producing lesions . In addi cohorts ,78,79,80 cohorts , while C-America . Of part-America ,84. Ono -America . In part CYP11B1 . Hybrid or cells ,88,89. Nor cells . The popor cells . Differeted APAs . Those dZG cells . ImmunolZG cells ,73. HSD3Here, we focus on the diagnostic process for sporadic PA cases. The Endocrine Society has announced the consensus statements on case detection and subtype differentiation in 2016 , followeKCNJ5-mutated APAs [Precise determination of PA subtypes allows clinicians to initiate appropriate treatment, surgery or MRAs, leading to better clinical prognosis. As aforementioned, AVS is the recommended procedure to distinguish unilateral PA from bilateral PA, while the details of the protocol, sequential or simultaneous sampling and cosyntropin stimulated or unstimulated setting, are left to each center . The conted APAs . Thus, tted APAs ,111,112.ted APAs .In addition to the basic process mentioned above, the diagnostic algorithm provides specific conditions where confirmatory testing and/or AVS could be omitted . PatientHowever, the current diagnostic strategy is often considered time-consuming and requires physical burden and expensive cost, particularly in those who undergo AVS . For preFrom the standpoint of clinical subtypes, we could consider several potential approaches which allow us to directly refer the patients for AVS after screening or rapidly induce MRA treatment by skipping the discriminative step B. TheoreSteroid dynamics other than aldosterone, particularly 18-hydroxycortisol (18OHF) and 18-oxocortisol (18oxoF), have been investigated to seek the clinical meaning in PA. Mounting evidence revealed the prominent differences in production of 18OHF and 18oxoF, so-called hybrid steroids, between PA and essential hypertension as well as PA subtypes ,131,132.ATPase-mutated APAs harbor higher peripheral levels of aldosterone, 11-deoxycorticosterone and corticosterone compared with those with wild-type or CACNA1D-mutated APAs [KCNJ5-mutated APAs also had distinct features of higher 18oxoF and 18OHF, compared with other APAs [KCNJ5-mutated APAs represents its impact on steroid profiling as shown in a European cohort [Those gaps of steroid concentrations between bilateral and unilateral PA (BHA and APAs) are recognized as a result from unique expression of steroidogenic enzyme in them. As mentioned in the previous section, APAs express various steroidogenic enzymes not only for mineralocorticoids but also glucocorticoids, while other pathological entities of hyperaldosteronism rarely express the enzymes in the different lineage of the adrenocortical zones ,68,71. Tted APAs . KCNJ5-mher APAs , probablher APAs ,133,134.n cohort .Recently, a European research group has also confirmed the utility of steroid profiling for PA detection. Employing machine learning, a designed steroid panel was validated for prediction of PA with a sensitivity and a specificity of 0.69 and 0.94, respectively . SteroidReassessment of the cut-off values for confirmatory tests also brought an additional meaning in subsequent subtyping. With relatively small number of PA patients, a Japanese group revealed another aspect of SIT as a subtyping tool . Based oBesides, several clinical studies have reported that other basic parameters enhance the subtyping ability of SIT. Kocjan et al. conducted a retrospective study to seek a prediction method for BHA . In addiOverall, existing evidence indicates that refinement of confirmatory tests, particularly SIT, could benefit PA subtype prediction, incorporating with several basic parameters such as serum. However, as previous studies yielded various criteria and results with relatively small cohorts, a further study with large sample size is still required to establish a solid method. Specific focus on either bilateral or unilateral PA, but not both subtypes, may accelerate the development of the alternative approach to avoid AVS for direct induction of MRA treatment or adrenalectomy, respectively.Multiple studies have also attempted to build a prediction score for PA subtypes using baseline characteristics of PA patients ,144,145.Taking advantage of the common availability, a prediction score consisting of baseline parameters could be more practical and useful in PA prediction than subtyping. In the same way as the SPACE score, Burrello et al. constructed a diagnostic scoring system, PACT score, with selected parameters, including sex, antihypertensive medication, serum potassium, the presence of organ damage, renin and aldosterone levels . This 16Based on the easy-to-measure nature and the potential mentioned above, effective use of baseline clinical or biochemical parameters should be further investigated, particularly for skipping the confirmatory step. The prediction model would be cost-effective and could help primary care clinicians with making a decision to refer the patients to tertiary referral centers. Careful consideration of them might also lead to modification of PA screening criteria to increase pretest probability of PA.Over the past decade after the first guideline for PA management was published by the Endocrine Society, countless studies have successively revealed the epidemiological, pathophysiological and biological characteristics of PA, backed by precise evidence from molecular, genetic and pathological examination. This progress enriched our understanding about PA, allowing us not only to redefine PA itself and pathological entities but also to improve the diagnostic strategy. However, current PA work-up still harbors several issues to be addressed: the time-consuming aspect, patients’ physical burden and the low penetration rate. A recent advance we introduced above accelerates the refinement of the diagnostic process, probably leading to more efficient and easier strategy for PA treatment in the future. Considering the regional and racial differences, further development and validation of alternative approach to subtype differentiation or treatment decision should be thoroughly performed in each PA population. A more sophisticated strategy for PA diagnosis is expected to contribute to early detection and optimization of the treatment, leading to longer healthy life expectancy by decreasing the cardiovascular risk.


The CardioMEMS pulmonary artery (PA) monitoring system placed in the left lower lobe pulmonary artery is capable of measuring pulmonary artery pressure remotely as a surrogate of intracardiac filling pressures and volume status. The technique is safe and reliable. By using remote PA monitoring for proactive medical interventions, there is a growing body of clinical evidence for a substantial, robust reduction in HF hospitalizations in various populations . This review summarizes the clinical evidence, outlines future perspectives, and aims for remote patient care in heart failure using CardioMEMS. In the last ten years, the field of heart failure has changed quite drastically. Several drugs have been proven more effective in improving prognosis of heart failure (HF) patients . Device Invasive remote monitoring tools are available in HF care and consist of specially developed sensors. One of the holy grails for HF therapy would be to measure filling pressures remotely in a patient with heart failure. The majority of HF drugs, such as diuretics and vasodilators, aim to lower filling pressures. It has been shown that rising filling pressures are the first hemodynamic sign of an upcoming period of decompensation. The rise in filling pressure comes well before the signs of overt clinical congestion . This coThis review will provide an overview of the clinical evidence for the CardioMEMS HF monitoring system in patients with chronic heart failure.The CardioMEMS HF system consists of an implantable wireless sensor, a patient and hospital electronics system and a patient database (Integrated Merlin.net secure website for patient data management). The sensor measures PA pressures using microelectromechanical system technology with a piezoelectrical membrane (wireless)  1,2,3,4,43,4,5. The CardioMEMS PA sensor has no internal power supply and is fully compatible with implantable cardioverter defibrillators (ICDs), (cardiac resynchronization therapy) CRT devices and left ventricular assist devices (LVADs). Furthermore, the sensor is MRI (magnetic resonance imaging) compatible. Potential complications are mostly related to the implant procedure, which is of very low risk as will be discussed extensively in this review. Patients who are already on anticoagulants are restarted on treatment after sensor implantation. Patients who are not yet receiving anticoagulants should start treatment with aspirin (81 mg/day or 325 mg/day) and clopidogrel (75 mg/day) concomitantly for 1 month after implant, after which aspirin monotherapy is to be continued lifelong . The neeThis article provides an overview of the latest promising information on using CardioMEMS for telemonitoring of heart failure in New York Heart Association (NYHA) class III patients. The increasing body of evidence for this technique suggests exciting opportunities to improve future heart failure management.Currently, multiple studies have investigated the safety and clinical efficacy of the CardioMEMS PA sensor in chronic HF patients. All studies are discussed in detail below, and an overview of the study characteristics and their results is provided.p < 0.0001). During the entire follow-up of 15 months, the treatment group had a 37% reduction in HF-related hospitalizations as compared to the control group (The CardioMEMS Heart Sensor Allows Monitoring of Pressure to Improve Outcomes in NYHA Class III Heart Failure Patients (CHAMPION) trial, published in 2011, was the first clinical trial confirming that implantable hemodynamic monitoring systems can reduce the number of HF hospitalizations as a landmark study . The CHAol group . Considep < 0.0001) compared to admission rates during randomized access which confirms the demonstrated benefit of the CardioMEMS HF system monitoring (p < 0.0001). These extended follow-up findings are important as they confirm the significant long-term benefit of remote monitoring by the CardioMEMS HF system with even slightly more pronounced effects. The authors showed that the medication changes over time were mainly related to changes in diuretic dose and vasodilators ..p < 0.00p < 0.0001) [The PAS was a multicenter prospective open-label study performed in 1200 chronic HF patients with a prior HF admission within 12 months from 104 sites from the United States and published its main results in 2020. Patients were selected irrespective of their HF subtype and ejection fraction percentage. Again, the hospitalization rates during the first 12 months post CardioMEMS implantation were compared to the hospitalization rates during the 12 months prior to CardioMEMS implantation. These patients had a mean age of 69 years and 62% were men. Background HF therapy  and ICD therapy) in HFrEF patients was contemporary and adequate . The rat 0.0001) . The fre 0.0001) . The rat 0.0001) . No prev 0.0001) .In Europe, another post-marketing surveillance study is currently ongoing and some of the first-year results have been published in 2020. The CardioMEMS Post-Market Study (COAST) study aims to investigate the effectiveness of the CardioMEMS system in a post-marketing setting in Europe . It inclp < 0.001) [Several studies have examined the effectiveness of ambulatory hemodynamic monitoring by the CardioMEMS HF system in reducing HF hospitalization outside strict clinical trials or prospective study settings ,10. Desa< 0.001) . In thos< 0.001) .A second matched-cohort study from the Medicare beneficiaries’ claims database between 1 June 2014 and 31 March 2016 studied 1087 patients who received an implantable PA sensor and 1087 matched control patients [An overview of the study characteristics and their results is shown in In the United States, the GUIDE HF trial is currently enrolling and intends to test the efficacy of the CardioMEMS HF system in an expanded population, including patients outside the current indication of NYHA III but at risk of future HF events  . The triIn the Netherlands, the MONITOR HF (Hemodynamic Monitoring In Heart Failure) trial started enrollment on 1 April 2019 and is currently enrolling patients in NYHA functional class III with 1 HF hospitalization within 12 months, defined as an admission for HF longer than 6 h and/or use of i.v. diuretics or emergency ward visit for HF resulting in i.v. diuretic therapy, independent of EF%  . The MONIntuitively, the use of a remote hemodynamic monitoring tool provides unique opportunities for further research. For example, the effects of newer drugs like sacubitril-valsartan or sodium-glucose co-transporter-2 inhibitors prescribed in the outpatient clinic can be evaluated daily based on direct hemodynamic feedback, whereas this is conventionally assessed by judging patient status, laboratory values and echocardiography parameters which do not always accurately reflect hemodynamic status. Valvular heart disease, such as mitral regurgitation and aortic regurgitation, may generate volume overload and an increase in PA pressures without causing actual signs of congestion in the patient. In these cases, CardioMEMS may help assess the need for valvular intervention based on hemodynamic parameters, especially when drug interventions are unsuccessful in reverting pulmonary hypertension. After valvular intervention, CardioMEMS can accurately assess the hemodynamic effects of the intervention on a daily basis, which was not possible before. Furthermore, the PA pressure measurements can help titrate HF drugs as described in an example case report . FinallyIn 2021, several updates to the European Society of Cardiology and U.S. HF guidelines are expected, with a potential change in recommendations on CardioMEMS after the MEMS-HF and PAS data as well as real-world experiences. Additional research is needed to assess which patients are most likely to benefit from a PA sensor. In the upcoming years, the CardioMEMS HF system will most likely be upgraded with a CardioMEMS app, which is already being used in the United States. With increasing numbers of CardioMEMS implantations, over 20,000 in the USA in 2020, efforts need to be made to improve infrastructure for large-scale programs to maximize efficiency. A management-by-exception approach focusing on patients who are above their pressure threshold and reducing monitoring time in those patients within normal PA pressure range would be ideal. Currently, there are no structured treatment algorithms. Constructing such algorithms is a very complex issue, because they should provide therapy suggestions on an individual basis considering differences in treatment tolerance, blood pressure, renal function and many other comorbidities. Hospitals need to assess their telemonitoring platform or infrastructure in order to derive maximum benefit from ambulatory hemodynamic monitoring as well as reduce resource utilization and healthcare costs.For patients with chronic heart failure in NYHA functional class III and a previous HF admission, the CardioMEMS HF system is a safe, reliable and proven clinically effective monitoring strategy to prevent HF hospitalizations. The benefit of remote monitoring using PA pressures has been shown across all EF ranges, including HFrEF and HFpEF. Monitoring of heart failure status by CardioMEMS is based on filling pressures instead of symptoms or bodyweight, and interventions mainly consist of remote optimization of diuretic or vasodilator doses. Clearly, by preventing HF hospitalizations using hemodynamic sensors such as CardioMEMS, future heart failure care can be optimized and healthcare resources better utilized for patients in need. In addition, costs of medical care can be reduced by preventing HF admissions via proactive early interventions.


To investigate changes in tricuspid annulus (TA) and tricuspid valve (TV) morphology among chronic thromboembolic pulmonary hypertension (CTEPH) patients before and 12 months after pulmonary thromboendarterectomy (PEA) and compare these findings to normal control subjects.20 CTEPH patients and 20 controls were enrolled in the study. The patients were examined with echocardiography, right heart catherization and cardiac magnetic resonance imaging prior to PEA and 12 months after.2, p < 0.005). TA annular area in systole remained unchanged (p = 0.11) and was comparable to controls. The leaflet area, tenting volume and tenting height in systole were significantly increased at baseline but decreased significantly with comparable values to controls after 12 months (p < 0.005). There was correlation between the changes of right ventricular-pulmonary artery coupling and changes of TV tenting height , TV tenting volume  and TV leaflet area  from baseline to 12 months after PEA. Tricuspid regurgitation jet area/RA area was significantly (p < 0.01) reduced from baseline (30 ± 13%) to 12 months after PEA (9 ± 10%).Right atrium (RA) volume was significantly reduced from baseline to 12 months after PEA (30 ± 9 vs 23 ± 5 ml/mIn CTEPH patients selected for PEA, TV tenting height, volume and valve area are significantly increased whereas annulus size and shape are less affected. The alterations in TV morphology are fully reversed after PEA and correlates to improvements of right ventricular-pulmonary arterial coupling. Functional tricuspid regurgitation (TR) develops as a consequence of geometrical distortion in the anatomical structures situated in relation to the tricuspid valve (TV) causing leaflet tethering and tricuspid annular (TA) dilatation . FunctioIn the present study, we aimed to investigate the changes of TA and TV morphology assessed by CMR with relation to changes in pulmonary arterial pressures by right heart catherization (RHC) in CTEPH patients before and 12 months after PEA and compare these findings to normal control subjects.Between December 2014 and January 2017, we enrolled 20 CTEPH patients and 20 controls in the study at Aarhus University Hospital, Denmark. In total, 47 consecutive patients were evaluated for CTEPH during the study period. After clinical and diagnostic evaluation 20 patients were identified to fulfill the inclusion criteria for participation in in the study, which included: Established CTEPH diagnosis, age ≥ 18 years and indication for PEA , 11. TheThe CTEPH diagnosis was defined in accordance with the World Health Organization classification as PH with a mean PA pressure (mPAP) ≥ 25 mmHg, a pulmonary capillary wedge pressure ≤ 15 mmHg, and specific angiographic signs at least 3 months after effective anticoagulation . The CTEThe PEA procedure was performed on cardiopulmonary bypass in deep hypothermia and periods of circulatory arrest. None of the patients underwent concomitant coronary artery bypass grafting or valve interventions.CMR was performed using a Philips Achieva dStream 1.5 T whole body MR scanner . Cine scanning (time-resolved imaging) was used to assess right atrium (RA) and ventricle and left atrium and ventricle volumes and geometry. An integrated 4-electrode electrocardiogram (ECG) was used to synchronize data acquisition. A survey scan was followed by an ECG-triggered temporally resolved cine scan using a balanced steady-state free precession sequence during breath-hold. The following imaging parameters were used: repetition time 2.9 ms, echo time 1.46 ms, flip angle 90°, 160 × 136 acquisition matrix, 30 phases within one cardiac cycle, slice thickness 8 mm and field of view 319 × 319 mm.A stack of 3 long-axis slices was acquired for 4-chamber view, and for short-axis view 10–12 slices were acquired covering the entire right and left ventricle. For tricuspid valve analysis a special focused stack specifically designed for this study consisting of 6–8 long-axis slices and 10–12 slices in short-axis were acquired covering the entire tricuspid valve and right ventricle. Pulmonary flow measurements were obtained using a free-breathing, ECG-triggered phase contrast sequence. The image parameters for the phase contrast sequence were: slice thickness 7 mm, 301 × 301 mm field of view, 128 × 96 acquisition matrix, 35 cardiac frames, velocity encoding 150 cm/s and scan duration 1:43 min. Image analysis of the heart chambers and pulmonary flow were performed using Segment v.2.2 R6274 . Tricuspid valve analyses were performed in an inhouse software originally developed for detailed mitral valve analyses as described previously   and RV length in end-diastole. RV volumes were calculated from the short-axis cine images. From the stack of parallel short-axis images, end-diastolic volume (EDV), end-systolic volume (ESV), and stroke volume (SV) and ejection fraction were calculated. RV mass was measured in systole. Cardiac output (CO) was measured as pulmonary flow. CO was indexed to body surface area as cardiac index (CI).Transthoracic echocardiography was performed using a Vivid E95 ultrasound system  equipped with an M5S transducer.Color Doppler imaging was used to assess severity of the TR, and the transvalvular gradient was measured using continuous‐wave Doppler. Quantification of TR severity was done in accordance with guidelines using the proximal isovelocity surface area method and estimation of TR jet area/RA area .The echocardiographic data were blinded to invasive measurements and clinical status and examined by a single investigator. Data were analyzed offline using dedicated software .Standard RHC was performed using a standard 7.5F triple-lumen Swan-Ganz catheter . The following parameters were measured: mean RA pressure (mRAP), systolic, diastolic and mPAP, mean pulmonary capillary wedge pressure (PCWP), CO, CI and systemic blood pressure. PCWP was measured at end expiration. CO was measured according to the Fick principle. RV contractility was also quantified by maximum/end-systolic elastance (Ees) and RV afterload with arterial elastance (Ea). Ees was calculated as (RV maximum pressure − mPAP) divided by SV , 15. Ea Data are presented as mean ± standard deviation, unless otherwise specified. Histograms and Q-Q-plots were used to check for normality. Between-group differences were assessed by t-test for normally distributed data and Mann–Whitney U-test for non-normally distributed data. Baseline versus 12 months differences were assessed by the paired sample t-test and Wilcoxon signed-rank test for non-normally distributed data. Pearson's correlation coefficient was calculated for normally distributed data and Spearman correlation coefficient for non-normally distributed data. Categorical variables were compared using the chi-square test. Analyses were performed using Stata .Baseline characteristics of 20 CTEPH patients and 20 control subjects are shown in Table p < 0.0001). A significant reduction in Nt-ProBNP was also observed: preoperatively 890  ng/l to 239  ng/l at 12 months (p < 0.005). Mild TR was noted in 60% and moderate-severe TR was noted in 40% of the patients at baseline with an average effective regurgitant orifice (ERO) of 0.30 ± 0.30 cm2 and a TR jet area/RA area of 30 ± 13% for all patients. After 12 months only two patients had moderate-severe TR with an ERO of 0.38 cm2 and 0.47 cm2 whereas 18 patients only had trace or mild TR. The TR jet area/RA area was reduced to 9 ± 10%, (vs baseline p < 0.01) whereas the ERO, due to very mild regurgitation, was not satisfactory obtainable in 15 patients.At baseline, CTEPH patients were highly symptomatic with the majority in New York Heart Association (NYHA) class III. NYHA class improved 12 months after PEA (NYHA class I-II (n = 19) and III-IV (n = 1)) . TA height in systole was increased at baseline but decreased significantly during follow-up and was comparable to controls. The difference between height of TA in systole and diastole changed significantly. At baseline the difference was 0.2 ± 5.1 mm compared to − 5.8 ± 7.0 mm at 12 months, p = 0.028. The systole-diastole difference was comparable to controls (− 4.3 ± 3.8 mm) at 12 months.The TV size by annular area and circumference did not change significantly even though a tendency towards lower annular area was noted. The SL/AP ratio in systole and diastole remained unchanged during follow-up  but normalized at follow-up. Increased tenting volume has been reported in patients with functional TR in two previous 3D echocardiographic studies showing a tenting volume of 4.2 cm3 in 17 chronic PH patients with significant TR and of 3.2 cm3 among 53 patients with severe TR and PH of different etiology, respectively [17. A dramatic RV remodeling was shown after PEA as RV volume, and the sphericity index normalized during follow-up. Dilatation and changes of RV geometry are known to affect the position and function of the papillary muscles (PM) resulting in increased tethering of the TV [Preoperatively 40% of our patients demonstrated a moderate-severe functional TR in accordance with observations in PH in which severe TR varies between 10–30% of cases , 17. As ectively , 20. Desf the TV . Distortf the TV .Previous two- and three-dimensional echocardiographic studies of functional TR in PH patients have reported various degree of TA dilation depending on the severity of the regurgitation –21.Among the present patients no significant increase in annular area or circumference were noted and the annulus size was comparable to control subjects. One important reason for this finding could be that the TR severity of the present population was preoperatively only moderate and thereby contributing less to RA volume overload with subsequent dilatation of the RA as well as the annulus. The potential pathophysiological mechanism in the present patient population is likely to be initiated by the remodeling of the RV and tethering of the TV as seen in other etiologies of PH , 22. In Preoperatively, our CMR data demonstrated classic RV remodeling as seen in PH with increased.Beyond reporting serial data on RV volume and systolic function, we were able to measure and characterize the TA and TV morphology in CTEPH patients and normal subjects by CMR. The CMR technique seems promising for TV evaluation. The benefit of CMR in the initial diagnosis of CTEPH is probably limited. However, in terms of RV characterization CMR provides very accurate estimates of RV volumes, RV function and TV regurgitant volumes. In addition, LGE and T1-mapping will probably provide insights on RV damage among CTEPH patients in the near future.In terms of medical treatment for CTEPH there is no clear support for treatment with specific PH active drugs before PEA. Furthermore, the only approved drug in CTEPH, riociguat, is only registered for use in inoperable cases or in persistent PH after PEA .Some limitations have to be considered in the present study. First of all, the number of patients studied is small but the examinations were performed prospectively and consecutively combining CMR techniques with invasively assessed hemodynamic parameters during a complete one year of follow-up. Despite the small number of patients studied as compared to other observational studies of TR and TV in PH patients, we had the opportunity to study the valve morphology in a situation where the hemodynamic conditions were reversed and thereby being able to study the associations between RV remodeling, hemodynamic and morphological TV changes.The number of PH patients with severe TR varies considerably in line with the present findings which limits the possibility to study to what extent the observed changes in TA and TV has on the patients with severe TR.TV tenting height, volume and valve area are significantly increased whereas annulus size and shape are less effected in CTEPH patients selected for PEA when assessed by CMR. The TV morphology alterations were fully reversed and correlated to the demonstrated improvements of RV-PA coupling after PEA during 12 months of follow-up. The present data calls for further studies to evaluate the surgical strategy in CTEPH patients scheduled for PEA, as it may be possible to refrain from annuloplasty in selected cases.


During the last years, post-mortem imaging has gradually been assumed within research in the field of forensic pathology. This role appears to be clearly and simply applied in the trauma field with the use of conventional radiography or Post Mortem Computed Tomography (PMCT). Recently, particular attention was paid to cardiovascular imaging using Post Mortem Magnetic Resonance Imaging (PMMRI). The present experimental study aims to: (i) confirm the efficacy of a Post Mortem Cardiac Resonance Imaging (PMCRI) study protocol for the study of human hearts collected during the autopsy; (ii) apply the defined protocol on subjects who died of “SCD (sudden cardiac death)”, to identify alterations that could guide subsequent sampling. Two hearts of healthy subjects , who died from causes other than SCD were collected and compared to hearts that belonged to SCD individuals . The exams were performed on a 1.5 T scanner  on hearts collected during autopsy and after a 30-day formalin fixation. Two readers analyzed the obtained images blindly and after randomization. From the comparison between the data from imaging and the macroscopic and histological investigations carried out, the present study proved the effectiveness of a PMMRI protocol to study ex-situ hearts. Moreover, it suggested the following semeiology in post-mortem SCD cases: the hyperintense area with indistinct margins in the Short Tau Inversion Recovery (STIR) sequence was linked to edema or area of pathological fibers, whereas the hypointense area in the T2-FFE sequences was linked to fibrosis. PMMRI can provide a valuable benefit to post-mortem investigations, helping to distinctly improve the success rate of histological sampling and investigations, which remains the gold standard in the diagnosis of sudden death. It has not been long since Flach et al. exclaimed “Times have changed!” , to undeAmong all the areas of interest, cardiovascular imaging plays a central role in the research of PMMRI (Post-Mortem Magnetic Resonance Imaging), although there is no universally shared standardized protocol. Therefore, the present experimental study aims to: (i) confirm the efficacy of a PMMRI study protocol for the study of human hearts collected during the autopsy; (ii) apply the defined protocol on subjects who died of SCD (sudden cardiac death), to identify alterations that could guide subsequent sampling.The full characteristics of the selected cases are shown in Two hearts of healthy subjects  who died from causes other than SCD were collected. The family and personal cardio-pathological history were nil, and no cardiovascular risk factors were known at the time of death.Subsequently, during the second phase, two hearts that belonged in life to deceased individuals “within one hour of the onset of symptoms in an apparently healthy subject”   on hearts collected during autopsy (performed 24 h after death without the corpses staying in the cold room) and placed in a polymer container with 10% formalin solution . The entire disposal was then fitted in the center of a 16-channel TORSO XL coil and placed in the MRI scanner, as in our previous study . FirstlyBalanced Turbo Field Echo (b-TFE) survey:  450 mm, Time of Echo (TE) 1 ms, Time of Repetition (TR) 3 ms);Turbo Field Echo (TFE) T1-3D sequence weighted in axial:  862 ms);T1 Spin Echo (SE) Spectral pre-saturation inversion recovery (SPIR) sequence weighted in axial: ;T2-3D VISTA (Volume Isotropic Turbo-Spin Echo Acquisition) sequence weighted in axial plane: ;Short Tau Inversion Recovery (STIR) sequence weighted in axial plane: ;T2 (Fast Field Echo) FFE in the axial plane ;3D b-FFE in the axial plane .The exams were performed on a 1.5 T scanner  equipped with a gradient system enabling 33 mT/m maximum amplitude and a slew rate of 80 mT/m/ms. The examination protocol included the following sequences:3D b-FFE was included in the present protocol to visualize coronary arteries without a contrast agent. Indeed, a coronary angiogram was indirectly obtained with this 3D sequence using the artificial contrast made by coronary filling with formalin solution.Total examination time lasted less than 40 min. This protocol was elaborated according to the need to study the signal behavior of fixed tissues, investigating mainly T1 and T2 weighted imaging, edema, and calcification. 3D isotropic imaging was preferred to bi-dimensional images due to the possibility of post-processing reconstructions.The study of the images was performed blindly  and after randomization by two readers with experience in cardiac radiology to evaluate the presence/absence of alterations and their localization.CMR, with morphological study and tissue characterization;Coronary-MR of coronary arteries, with segmental characterization, according to American Heart Association (AHA) ,9.In order to minimize individual variability in the study of cardiac magnetic resonance (CMR) images, it was decided to proceed with the preparation of a structured report for each sample:All hearts were sampled in compliance with the “Guidelines for autopsy investigation of sudden cardiac death”  and maxiIn cases A and B, both evaluators agreed upon the high technical quality of PM-CMR and coronary imaging. Moreover, no focal, patchy, or diffuse signal alterations were noticed. No significant restrictions of molecular diffusion were detectable in the DWI and ADC maps. Coronary analysis revealed no pathological defect of the lumina, with regular anatomical origin and course. Area of altered signal, with blurred edges and hyperintense in the long TR sequence fluid-sensitive (STIR), was appreciated in the mid-cardiac level, at the sub-endocardial area of the LV septum .Microscopic analysis demonstrated foci of myocells characterized by sarcorexis, with transverse hypereosinophilic bands and contiguous stretched fibers, separated from each other by the presence of amorphous eosinophilic material.At the same endocardial side of the mid-cardiac level, more evident along the left ventricle (LV) lateral and posterior wall, a hemi-circumferential in-homogeneously hypointense area of the altered signal was highlighted in the T2-weighted and T2-FFE sequences, finding compatibility with extensive areas of fibrotic substitution of myocardial tissue . AnotherThere are no clear areas of restriction of diffusivity in the DWI sequences and the corresponding coronary artery disease (CAD) map.The overall assessment of coronary vessels is shown in An abundant and widespread representation of the epicardial adipose tissue. The LV presents an irregular wall thickening, with posterior and lateral walls of greater thickness. The average diameter of the LV was about 11.14 mm.The large area of the altered signal, with sub-endocardial-transmural extension, blurred edges, and hyper-intense in STIR sequence, was appreciated in the mid-cardiac level of the posterior and lateral LV walls .In the mid-basal area, on the epicardial side, along the anterior wall of the LV, there was an area of altered signal, hemi-circumferential and in-homogeneously hypo-intense in the T2-weighted and T2-FFE sequences. Other areas of similar signal and significance were appreciated, again in the meso-cardiac area, at the septal level, and the postero-septal angle .No clear areas of diffusivity restriction were appreciated in DWI sequences with high values of band in the corresponding CAD map.The overall assessment of coronary vessels is shown in Besides abundant epicardial adipose tissue, the heart appeared globally hypertrophic, with an average LV diameter of about 18.35 mm. The RV also looked thickened. An area of altered signal, with indistinct margins and hyperintense in the STIR sequence, was appreciated in the mid-cardiac area at the sub-endocardial level of the LV postero-lateral site, referable to clinical edema/hypercellularity . AnotherIn the T2-FFE sequences, a global reduction of the myocardial signal was documented; this in-homogeneously hypointense finding was more accentuated at the level of the LV lateral and posterior walls in the mid-basal cardiac region .There were no clear areas of restriction of diffusivity in the DWI sequences and the corresponding ACD map. No clear areas of diffusivity restriction were appreciated in DWI sequences with high values of band in the corresponding ACD map.The overall assessment of coronary vessels is shown in Heart and coronary samples taken from cases A and B did not show pathological results, apart from the presence of autolysis of myocells in some fields.The heart measured 11.8 × 12 × 4.5 cm and weighed 460 g, with a regular representation of the subepicardial fat. The study of the coronary arteries  made it After dissection according to the semi-conservative technique, the left ventricular chamber showed: an anterior wall of 1.2 cm; a lateral wall of cm 1.45; a posterior wall of 1.4 cm; a thickness of the interventricular septum equal to 1.2 cm.There was nothing to report on the endocardium, which appeared translucent. There was also nothing to report to the right ventricular chamber, with walls 0.6 cm thick and regular volume. The atrial chambers appeared to be of regular volume. The atrio-ventricular valves had thickened valvular laces, as well as pulmonary and aortic semilunar valves.left ventricle: in multiple fields, the myocardial architecture is altered by the presence of extensive areas of fibrotic substitution of the myocardial tissue and by interstitial and perivasal fibrosis that interrupt myocardial continuity, a characteristic mostly represented at the second section and the lateral and posterior walls, above all if compared to the anterior wall at the same section A,C.septum: second section, immediately below the endocardium pertaining to the left ventricle, foci of myocells characterized by sarcorexis, with transverse hypereosinophilic bands and contiguous stretched fibers, separated from each other by the presence of amorphous eosinophilic material B; fragmeThe second pattern associated with the previous one was represented by a unique band of 10–20 hypercontracted sarcomeres close to the intercalated disc with a typical aspect of paradiscal lesion F. In thiIn correspondence with the areas identified on the magnetic resonance examination, it was possible to observe:The heart measured 12 × 11 × 3 cm and weighed 415 g, with an abundant representation of sub-epicardial fat. Absence of alterations in the coronary vessels .The histological examination showed in the mid-cardiac section of the left ventricle, a polymorphous pathological picture in the heart, characterized by areas of edema and fiber segmentation.The heart was of normal shape and size, regular consistency, measured 12 × 11.5 × 7 cm and weighed 550 g, with an abundant representation of subepicardial fat. The coronary study confirmed the PMMRI results .The macroscopic evaluation of cardiac walls showed an anterior wall equal to 1.5 cm, a lateral wall equal to 1.9 cm, a posterior wall equal to 1.8 cm, and a thickness measured in all correspondence of the interventricular septum equal to 1.6 cm.At the lateral wall of the left ventricle, the fibers appeared separated by amorphous eosinophilic material, as well as interested by the recurrence of foci of myocardial cells characterized by sarcorexis, with transverse hypereosinophilic bands and contiguous stretched fibers, both in the subepicardial and in the subendocardial area. In particular, the samples were conducted in correspondence with the lateral and posterior walls of the left ventricle. The same findings were found at the middle third of the septum at the same level.The death of C is attributable to sudden cardiac death on an arrhythmic basis, according to the contribution provided by: the circumstantial and clinical-anamnestic data; the autoptic results, which highlighted the presence of three-vassal coronary heart disease with significant stenosis of the coronary lumen; the evidence of myocardial and coronary imaging which identified the presence of suspected areas, subsequently confirmed by the histological examination, and significant stenosis of coronary vessels. In addition, the toxicological investigation excluded causal/co-causal inference from toxic substances  in the death determinism.The death of D is attributable to sudden cardiac death on an arrhythmic basis because the integration of all evidence came from: the circumstantial data of death following a sudden pain; the results of the sectoral and macroscopic examination of the heart, which highlighted obesity, with an increase in visceral and subepicardial fat, as well as thickening of the LV lateral and posterior walls, in the absence of significant coronary stenosis; the myocardial and coronary imaging which identified the presence of anomalous areas and widespread irregularity in the context of the myocardial muscle, in the absence of significant coronary stenosis; from the results of histopathological examinations, which allowed us to document a polymorphic pathological picture, characterized by areas of edema and fiber segmentation and confirming the absence of significant coronary stenosis. Even in this case, the toxicological tests resulted negative.The death of E is due to sudden cardiac death on an arrhythmic basis, following the analysis of the complete pattern: the circumstantial and clinical-anamnestic data of a hypercholesterolemic and hypertensive subject; the cardiac macroscopic inspection which showed an increase in subepicardial fat, with significant stenosis affecting the three main epicardial vessels; the presence of pathological areas at PMMRI and significant stenosis at coronary-RM; the histopathological examinations, which allowed to confirm the significant coronary stenosis already evident on macroscopic and radiological examination, associated to necrosis with contraction bands of quantitatively significant extent; and the negativity at the toxicological investigation.The present study had as its objective, first of all, the evaluation of the application of studying the heart following evisceration and, subsequently, proving its “effectiveness” in post-mortem diagnostics in cases of sudden death.PMMRI, indeed, among the other techniques, is still the least studied and of rare application to forensic pathology, and the first reason is certainly the complexity of its technology ,14. In fNevertheless, its applicability has already been demonstrated in other studies for the diagnosis of hypertrophic cardiomyopathy  and myocIn continuity with the previous ones, the present study proposed a protocol for PMMRI that has demonstrated its applicability, with images that were evaluated as being of excellent quality. Furthermore, by the presence of the formolic solution, it was possible to obtain a visualization of the coronaries without having to resort to dynamic sequences.Potentially, however, in addition to high-contrast resolution and anatomical details, PMMRI could be used to identify specific tissue characteristics, such as in the case of hemorrhage, to establish the temporal evolution of a pathological process. On this basis, PM-CMR is a field of recent growing interest due to its role in distinguishing acute, sub-acute, and chronic infarction, as demonstrated by the studies of Jackowski et al. ,20. SwisHowever, the histological morpho-structural findings typical of cardiopathology do not coincide only with the signs of an “infarct” necrosis, or of myocardial flaccid paralytic tissue with stretching of the necrotic myocardial fibers ,23,24,25These different histopathological substrates, however, are not all identifiable recurring to imaging, as far as interpretable with current data. On the other hand, not all the information coming from PMCMR have found, to date, a histopathological equivalent or interpretation, such as diffusion-weighted imaging (DWI) or spectroscopy for the chemical study of tissues . FurtherIn the present study, although in a few cases examined, the proposed PMCMR-protocol was able to identify areas of altered signal, helping to distinctly improve the success rate of histological sampling and investigation (which remain the gold standard in the diagnosis of sudden cardiac death). Conversely, even if conducted by the guidelines, the pathological areas could not have been sampled, due to a random method. In this regard, another problem raised using PMCMR is the absence, to date, of a codified semeiology to give the correct meaning to the alterations detected with this method in a post-mortem context. From this study, it seems reasonable to link the hyperintense area with indistinct margins in the STIR sequence to edema or the area of pathological fibers and the hypointense area in the T2-FFE sequences to fibrosis. These findings offer new perspectives in this field that can integrate with new developments that will occur in the coming years with the main objective of developing shared and standardized protocols.


The use of Kampo medications  is common in Japan. However, some Kampo medications may cause heart failure. Given that the incidence of heart failure has increased in past decades, investigating the prevalence of the use of Kampo medications that may cause heart failure in patients with acute heart failure is important.A retrospective cross‐sectional study was conducted. All 437 consecutive hospitalized patients with acute heart failure from April 2017 to October 2019 were included. The primary outcome was the use of Kampo medications, including ephedra, licorice, aconite, or ginseng, which were defined as those that may cause heart failure. The causality between these medications and the index of acute heart failure was determined by clinical pharmacists based on the Naranjo criteria.The mean patient age was 81.1 years old, and 199 (54.5%) were women. Kampo medications that may cause heart failure were used in 30 patients (6.9%), and in four of these patients, acute heart failure was judged to be caused by Kampo medications. In the multivariable analysis, the number of non‐Kampo medications used regularly (OR 1.13) and female sex (OR 2.23) were the only independent predictive factors for the use of Kampo medications that may cause heart failure.A substantial proportion of acute heart failure patients in Japanese hospitals use Kampo medications that may cause heart failure. Further study is warranted to investigate the causal link between the incidence of acute heart failure and the use of these herbal medications. Kampo medications composed of ephedra, licorice, aconite, or ginseng may cause or exacerbate heart failure. Our findings suggest that acute heart failure may be caused by these herbal medications in a substantial proportion of patients hospitalized with acute heart failure in a Japanese hospital. The causal link between the use of CEHF Kampo medications and acute heart failure was also investigated.22.1A retrospective, single‐center, cross‐sectional study using electronic medical records was conducted to investigate the prevalence of the use of CEHF Kampo medications among hospitalized patients with acute heart failure. Our hospital is an acute care hospital. This research was approved by the institutional medical ethical committee.2.2All consecutive patients aged 18 years old or older who were hospitalized due to acute heart failure from April 2017 to October 2019 were included. Patients with missing information about medications before the index admission were excluded. Acute heart failure was defined as either new‐onset heart failure or decompensation of chronic established heart failure with symptoms sufficient to lead to hospitalization based on recent guidelines.2.32 for 3 months were also judged to have chronic kidney disease even if chronic kidney disease was not documented in the medical records. Information about prescribed drugs, including Kampo medications, was obtained from a comprehensive medication list compiled by pharmacists during the course of routine care. Information about triggers of acute heart failure was collected from medical records documented by the physicians caring for the patients.Information on patient age, sex, Charlson Comorbidity Index score.2.4The primary outcome was the proportion of all acute heart failure patients who used CEHF Kampo medications. Based on a recent scientific statement,In acute heart failure patients who used CEHF Kampo medications, causality was assessed according to the Naranjo criteria Table . Three p2.5There were no past studies reporting the prevalence of CEHF Kampo medications among patients hospitalized due to acute heart failure. Therefore, assuming that the proportion of patients who used CEHF Kampo medications was 6%, based on a previous study to determine the prevalence of potentially inappropriate use of Kampo medications among elderly patients in outpatient settings,Descriptive statistics were used to report the baseline characteristics of the study population. To identify the independent risk factors associated with the use of CEHF Kampo medications, multivariable analysis with binary logistic regression was conducted. We examined the associations between the primary outcome and age, sex, past medical history, and number of regular non‐Kampo medications. Then, the variables that had p‐values of 0.2 or more were removed using the backward method. The level of statistical significance was set at 5%. These analyses were performed with STATA software, version 15 .3The baseline characteristics of the 437 patients who were hospitalized due to acute heart failure are shown in Table Kampo medications that can cause or exacerbate heart failure were used in 30 patients . Among these patients, the most common prescribed herbal medication was licorice , followed by ginseng  and ephedra  (Table In the univariable analysis, increased age, female sex, dementia, and use of a large number of regular non‐Kampo medications were significantly associated with increased risk for the use of CEHF Kampo medications, while a past history of heart failure was significantly associated with a decreased risk Table . However4This study was the first to determine the prevalence of the use of herbal medications that can cause or exacerbate heart failure in patients hospitalized with acute heart failure. The prevalence of the use of Kampo medications containing ginseng in the present study was 2.7%, which was similar to the prevalence of the use of ginseng among patients with chronic heart failure in past studies conducted outside of Japan.Female sex and the use of a large number of regular non‐Kampo medications were the only independent risk factors associated with the use of CEHF Kampo medications in the present study. This result was similar to that of studies of Western medications reporting that female sex and number of regular medications were significant factors associated with potentially inappropriate medication for elderly patients.In the current study, the most common CEHF Kampo medications were Kampo formulations containing licorice. Given the sodium retention caused by licorice,Based on the Naranjo criteria, most of the CEHF Kampo medications used in this study were relatively less likely to cause acute heart failure. However, this result should be interpreted cautiously. Triggers of acute heart failure are often multifactorial.mokuboito, which is a Kampo medication containing ginseng and sinomenine, on heart failure symptoms, although its beneficial effect is believed to be attributed to sinomenine, not ginseng.The strength of our study is that we included all consecutive hospitalized patients with acute heart failure. Therefore, our findings represent a real‐world situation. In addition, more than two pharmacists independently assessed the causal link between the use of CEHF Kampo medications and heart failure according to the standard criteria. However, our findings should be interpreted with caution. First, our study was a retrospective, observational study. Therefore, the data extracted for use in this study might not be accurate. Second, given that the attitude toward prescribing Kampo medications is different between Japanese physicians,In conclusion, one in every 14 patients hospitalized in a Japanese hospital with acute heart failure used CEHF Kampo medications. Most were Kampo medications that contained licorice. Given the limited generalizability due to the single‐center design, our findings must be confirmed in other Japanese hospitals. Moreover, further studies are warranted to investigate the causal link between the use of these herbal medications and the incidence of acute heart failure.The authors have stated explicitly that there are no conflicts of interest in connection with this article.App S1Click here for additional data file.


In patients of chronic thromboembolic pulmonary hypertension undergoing pulmonary endarterectomy, veno-arterial extracorporeal membrane oxygenation (VA-ECMO) provides full haemodynamic support. However, during a rescue treatment of VA-ECMO for patients with difficulty weaning from cardiopulmonary bypass, a significantly increase left ventricular afterload through retrograde infusion of arterialized blood into the descending aorta may occur.We report a 70-year-old man who suffered severe residual pulmonary hypertension following pulmonary endarterectomy for chronic thromboembolic pulmonary hypertension. Preoperative echocardiogram showed a dilated and poorly functioning right ventricle, as well as a small left heart with normal function , while postoperative echocardiography revealed a significant decrease of whole ventricular function on postoperative day 1, indicating the patient developed severe secondary left ventricular dysfunction on the basis of right ventricular dysfunction, during VA-ECMO support. Then comprehensive measures were adopted, such as down-regulating VA-ECMO flow rate, adjusting respiratory parameters, using vasoactive drugs, as well as prostacyclin. Eventually, the pulmonary hypertension decreased to moderate degree, and the heart function improved gradually.In the face of severe residual pulmonary hypertension and sencondary left ventricular dysfunction associated with VA-ECMO, comprehensive measures described above may facilitate recovery. ECMO flow titration to maintain relatively low flow rate is very important to not only maintain systemic perfusion, but also reduce left ventricular afterload and ensure pulsatile perfusion of pulmonary artery. In patients of chronic thromboembolic pulmonary hypertension (CTEPH), there can be an impaired right and left ventricular function . While iA 70-year-old male, diagnosed with CTEPH, was hospitalized for PEA. He had post-exercise exhaustion and shortness of breath for almost 2 years, and experienced a sudden dizziness with visual rotation and syncope. Despite the medical therapy, the clinical symptoms gradually worsened. Echocardiogram showed a dilated and poorly functioning right ventricle, as well as a small left heart with normal systolic and diastolic function Fig. -A1, A2(T2) range from 60 to 65%. After median sternotomy, the ascending aorta and both vena cava were cannulated regularly, and CPB was initiated. After the initiation of CPB, the mean PAP (mPAP) decreased to the range from17 to 31 mmHg. Aortic cross-clamping and blood cardioplegia were administered during pulmonary arteries dissociation. Then, the removal of thickened arterial intima and old organized thrombi was completed under deep hypothermic (22 °C) low flow (DHLF) and deep hypothermic circulatory arrest (DHCA). NIRS fluctuates from 55 to 60% during DHLF and DHCA. After the surgical procedures, full flow was restored, heart rebeated, and the patient was gradually rewarmed to normal. Norepinephrine (0.05μg/kg.min), epinephrine (0.02μg/kg.min), and isoproterenol (0.02μg/kg.min) were used to maintain stable hemodynamics. Transesophageal echocardiogram (TEE) showed good systolic and diastolic heart function.After the patient was induced, the initial pulmonary arterial pressure (PAP) was 93/46(63) mmHg, and preoperative right radial artery blood pressure (ABP) was 120/88 mmHg. Near infrared spectroscopy (NIRS) monitoring presented the basic cerebral regional oxygen saturation (rSO2O) was initiated to achieve lung protective ventilation. Oxygen flow rate was increased from 2 L/min to 6 L/min, with oxygen concentration raised to 47% for myocardial oxygen supply improvement. Moreover, atrial septostomy was carried out to decompress the right ventricle, so as to reduce the PAP. Consequently, mPAP decreased to 10 mmHg gradually, and the cardiac function improved slowly.However, during the first attempt to discontinue CPB, the PAP increased rapidly to 63/35(43) mmHg, with unstable hemodynamic (ABP 70/40 mmHg), and TEE suggested right heart insufficiency, accompanied with normal left ventricular function. Then, CPB was resumed immediately. After assisting for another 45 min and increasing the dosage of vasoactive drugs , the separation failed again, just the same as the first time. Considering that severe residual PH combined with right heart dysfunction are the main reasons for the failure of CPB weaning, ECMO was adopted. Consequently, 19F arterial cannula and 22F venous cannula were inserted into the right femoral vessels, and femoral VA-ECMO was initiated with a flow of 3.0 ~ 3.5 L/min. On arrival at the intensive care unit, ECMO flow rate was 3.5 L/min, and severe PH (PAP 56/25 mmHg) persisted with low ABP (70/55 mmHg). Echocardiography revealed significant decrease of biventricular function  should be kept below the diastolic ABP during intraoperative ABP control. And the “Rule of 70s” is useful for controlling ABP: age > 70, diastolic ABP > 70, Heart rate = 70, and PP < 70 . BesidesAs to the ECMO mode chosen after PEA, veno-venous ECMO (VV-ECMO) is a good option for patients with only respiratory failure but preserved heart function, while VA-ECMO is crucial to heart failure cases with or without hypoxemia . Given tIn conclusion, comprehensive measures such as down-regulating ECMO flow rate, adjusting respiratory parameters, using vasoactive drugs, as well as atrial septostomy may facilitate recovery, in the face of severe residual PH and sencondary heart dysfunction associated with ECMO. ECMO flow titration to maintain relatively low flow rate is very important to not only maintain systemic perfusion, but also reduce left ventricular afterload and ensure pulsatile perfusion of pulmonary artery.


Glial tumors in the cerebellopontine angle (CPA) are uncommon and comprise less than 1% of CPA tumors. We present four cases of pilocytic astrocytoma of the CPA (PA-CPA) that were treated in our department. Patients who received surgical treatment for PA-CPA from January 2004 to December 2019 were identified by a computer search of their files from the Department of Neurosurgery, Tübingen. Patients were evaluated for initial symptoms, pre- and postoperative facial nerve function and cochlear function, complications, and recurrence rate by reviewing surgical reports, patient documents, neuroradiological data, and follow-up data. We identified four patients with PA-CPA out of about 1500 CPA lesions (~ 0.2%), which were surgically treated in our department in the last 16 years. Of the four patients, three were male, and one was a female patient. Two were adults, and two were children (mean age 35 years). A gross total resection was achieved in three cases, and a subtotal resection was attained in one case. Two patients experienced a moderate facial palsy immediately after surgery (House–Brackmann grade III). In all cases, the facial function was intact or good (House–Brackmann grades I–II) at the long-term follow-up (mean follow-up 4.5 years). No mortality occurred during follow-up. Three of the patients had no recurrence at the latest follow-up (mean latest follow-up 4.5 years), while one patient had a slight recurrence. PA-CPA can be safely removed, and most complications immediately after surgery resolve in the long-term follow-up. Pilocytic astrocytomas (PA) comprise 6% of all intracranial tumors and are the most (in some studies the second most ) common Pilocytic astrocytomas of the cerebellopontine angle (PA-CPA) are rare  and mighPA-CPA are a formidable challenge from neurosurgical perspective, and different strategies are necessary to protect surrounding neurovascular structures.The goal of this retrospective study is to analyze the surgical management of exophytic PA of the brainstem with invasion of the CPA, especially with focus on the clinical presentation, surgical strategy, the extent of resection, and early and late treatment outcomes.Patients who had undergone surgery for PA-CPA from January 2004 to December 2019 were identified through a computer search of the patients’ medical files at our neurosurgery department. Four patients with PA-CPA of > 1500 CPA lesions (0.2%) had undergone surgery in our department. The patients were evaluated for presenting symptoms, preoperative and postoperative facial nerve function , cochlear function , extent of resection, recurrence rate, survival rates, and complications by reviewing patient documents, surgical reports, neuroradiological data, and follow-up data. Furthermore, the surgical strategy was analyzed. PA-CPA had been confirmed histopathologically in each case.The study was approved by the ethics committee.Three patients had been positioned under general anesthesia in supine position and one in semisitting position according to our standards. The anesthesiologic setup in the case of semisitting position included transesophageal echocardiography for early detection of air emboli. All patients underwent a retrosigmoid craniectomy. Intraoperative monitoring included motor evoked potentials (MEP) and electromyography (EMG) recordings of the facial nerve and the lower cranial nerves, and auditory evoked potentials and MEP and sensory evoked potentials of the upper and lower extremities.Clinical examination for facial nerve  and hearing function  was performed in all cases 3 days after surgery and was repeated at the 3-month follow-up. Postoperative MRI-examinations were performed 3 months after surgery. Further follow-up examinations have been performed every 6 months for at least 1 year.Four patients  with PA-CPA were included in this study. Two were adults (ages 53 years and 71 years), and two were children (ages 7 years and 10 years). Three PA-CPA were located on the right side, and one was on the left side.Three patients had secondary PA-CPA arising from the cerebellum 1/4) and the cerebellar peduncle (2/4), and one patient had a primary PA-CPA . MRI exams showed cystic PA-CPA in two cases Fig.  left and/4 and thThis 7-year-old male presented with slight facial palsy (H+B grade II), nausea, vomiting, and nystagmus for 2 months.This 10-year-old female with a history of dyspnea for 2 years presented in our outpatient ambulance with slight facial palsy (H+B grade II), disturbance in walking, nausea, vomiting, and mild hemiparesis for 1 month.This 71-year-old male presented with disturbance in walking, urinary incontinence, and slight dementia for many months.This 53-year-old male with a history of a testicular carcinoma, which had been treated by surgery and chemotherapy, presented with disturbance in coordination and sensitivity of the left arm for 10 days.All presenting symptoms were related to the compression of the brainstem or cranial nerves, or to hydrocephalus.The most common symptoms were facial palsy (2/4) on the side of the PA-CPA (H+B II), disturbance in walking (2/4) , and vomiting and nausea (2/4).Other symptoms included slight hemiparesis (1/4), disturbance of coordination and sensitivity of the left arm (1/4), dyspnea (1/4), and nystagmus (1/4).Cystic and non-cystic PA-CPA:2.Primary and secondary PA-CPA:In case of large cystic PA-CPA Fig.  left a dIn the case of primary PA-CPA (with arising from the root entry zone of the vestibular nerve), the vestibular nerve had to be sacrificed. In secondary PA-CPA, the extent of resection depends on the infiltration of the brainstem, cerebellar peduncle, and cerebellum (see below).A gross total resection (GTR) of the PA-CPA was achieved in three cases (3/4) Table  Fig. 1b middle. Three of the patients had no recurrence at the latest follow-up  Table . PediatrPA was histologically confirmed in each case Table  with typNone of the patients received radiotherapy or chemotherapy before or after surgery Table . One patAnatomical facial nerve preservation was achieved in all four patients Fig. . ImmediaIn two of the four cases, no functional impairment of the facial nerve (H+B grade I) was detectable at the 3-month follow-up examination. In the two other cases (cases 1 and 3), there was a slight palsy of the facial nerve (H+B grade II) at the 3-month follow-up and long-term follow-up Table .None of the patients had a cochlear dysfunction (GR grade I) before surgery Table . AnatomiFurther complications  immediately after surgery included palsy of the VI (1/4) and XII (1/4) cranial nerves (case 2), dysphagia (1/4) (case 3), and hemiparesis (2/4) (in case 1 a new hemiparesis and in case 2 worsening of a previously known hemiparesis). All these symptoms recovered in the long term, except for a slight remnant hemiparesis in one case (case 2). No mortality occurred during follow-up.Most common lesions in the CPA are vestibular schwannoma (70–80%) , meningiCPA gliomas are rare , 16 and Primary CPA glioma arises from the root entry zone  of the cranial nerves in the CPA , 16. CraThe glial segment is histologically identical in structure to the central nervous system (the nerve axons are supported by neuroglia: astrocytes and oligodendrocytes), while the peripheral segment structure is similar to a peripheral nerve (nerve fibers are insulated by Schwann cells) , 16.Between glial and peripheral segments lies a transitional or intermediate zone. Various studies analyzed the differences in length of different segments in different cranial nerves , 39, 41.In 1904, Panse  was the Arnautovic et al. were the first who reported a case of glioma from the proximal portion of the trigeminal nerve. Arnautovic et al.  concludeIn addition, malignant primary CPA gliomas had also been described so far. Breshears et al.  and KaslArnautovic  concludeSecondary CPA gliomas are exophytic tumors arising from the brainstem or the cerebellum with a secondary invasion of the CPA .Choux et al.  describeBrainstem gliomas may show complex growth patterns  and typiIn 1947, Revilla  publishePA are typically intraparenchymal in origin and are rarely exophytic . In the In addition, other gliomas of the CPA (except PA) have been described in the literature. Non-pilocytic glioma of the CPA (NPG-CPA) included among other things anaplastic astrocytoma  and GBM Matsuda et al.  summarizOther cases of CPA glioma, which are not more precisely classified, are described by Gentry et al.   were similar to our study.One interesting finding in our study was that both patients with cystic PA-CPA were much younger when compared with both patients with solid PA-CPA (mean age 8.5 years versus 62 years).Similar to Guillamo et al.  results,In the series by Guillamo et al.  of 48 adTo the best of our knowledge, the largest single institutional series of adult PA was published by Theeler et al.   presents a formidable challenge. In 2004, Yousry et al.  demonstrIn our opinion, also intraoperative monitoring  during surgery is of high importance and helps the surgeon to preserve cranial nerve functions.Furthermore, it is essential to recognize that the surgical strategy in cystic and non-cystic PA-CPA is different. In the case of large cystic PA-CPA, a decompression of the cyst should be, in most cases, the first step  and theIn the case of primary PA-CPA, there is a further important decision: Should one sacrifice or preserve the cranial nerve from which the tumor arose? In our study, we decided to sacrifice it, because the loss of cranial nerve VIII function on one side is compensable. Most authors, with similar cases of PA-CPA of cranial nerve VIII, made the same decision , 30, 45.In a case of secondary PA-CPA, the extent of resection depends on the infiltration of the brainstem, the cerebellar peduncle, and the cerebellum.In our study, three CPA gliomas were totally removed, and one CPA glioma was subtotally removed. At the same time, the facial nerve was anatomically preserved in all cases and showed good functional outcome in all cases in the long term. The patient with the incomplete resection of the PA-CPA demonstrated a slight progression of residual tumor tissue 1 year after the resection. On further follow-up, no further progression was observed.In a case of clear further progression or recurrence, a future second surgery, radiotherapy, or chemotherapy should be discussed, in our opinion (according to our tumor board).Similar to our results, most authors concluded that, in cases of exophytic brain stem gliomas, a gross total or subtotal removal with a favorable prognosis is possible in most patients .Regarding the clinical outcome and complications, it is difficult to find clear analyses in the literature. While primary PA-CPA are only described in single case reports, secondary PA-CPA are only described as part of other gliomas of CPA or PA of other locations .The series by Walter Dandy  focused Farmer et al.  focused To best of our knowledge, there is no study about PA-CPA in literature.The main limitation of this study is the small number of patients, due to the rare prevalence of PA-CPA.In summary, CPA gliomas can be classified into primary and secondary CPA gliomas depending on their site of origin.Two different subtypes of PA-CPA exist: (1) cystic PA-CPA in young patients and (2) non-cystic PA-CPA in older patients.A PA-CPA can be safely removed, and most complications that occur immediately after surgery have resolved in the long-term follow-up. Nevertheless, the treatment of such a rare tumor remains a challenge.


Sudden cardiac death (SCD) from ventricular fibrillation (VF) can occur in mitral valve prolapse (MVP) in the absence of other comorbidities including mitral regurgitation, heart failure or coronary disease. Although only a small proportion with MVP are at risk, it can affect young, otherwise healthy adults, most commonly premenopausal women, often as the first presentation of MVP. In this review, we discuss arrhythmic mechanisms in MVP and mechanistic approaches for sudden death risk assessment and prevention. We define arrhythmogenic or arrhythmic MVP (AMVP) as MVP associated with complex and frequent ventricular ectopy, and malignant MVP (MMVP) as MVP with high risk of SCD. Factors predisposing to AMVP are myxomatous, bileaflet MVP and mitral annular disjunction (MAD). Data from autopsy, cardiac imaging and electrophysiological studies suggest that ectopy in AMVP is due to inflammation, fibrosis and scarring within the left ventricular (LV) base, LV papillary muscles and Purkinje tissue. Postulated mechanisms include repetitive injury to these regions from systolic papillary muscle stretch and abrupt mitral annular dysmotility (excursion and curling) and diastolic endocardial interaction of redundant mitral leaflets and chordae. Whereas AMVP is seen relatively commonly (up to 30%) in those with MVP, MVP-related SCD is rare (2–4%). However, the proportion at risk  is unknown. The clustering of cardiac morphological and electrophysiological characteristics similar to AMVP in otherwise idiopathic SCD suggests that MMVP arises when specific arrhythmia modulators allow for VF initiation and perpetuation through action potential prolongation, repolarization heterogeneity and Purkinje triggering. Adequately powered prospective studies are needed to assess strategies for identifying MMVP and the primary prevention of SCD, including ICD implantation, sympathetic modulation and early surgical mitral valve repair. Given the low event rate, a collaborative multicenter approach is essential. Mitral valve prolapse (MVP) refers to the systolic displacement of the mitral valve leaflet(s) of at least 2 mm above the annular plane into the left atrium . Dr. JohIn his early description of the condition, Dr. Barlow stated, “The prognosis of this syndrome is uncertain, and sudden death may occur” . AlthougThe proportion of MVP patients who have AVMP or MMVP and their proportional risk of developing SCD remains to be established. Published reports allow for an estimation of the annual risk of MVP-related SCD between 0.2% and 1.9% . KligfieComparative studies have identified certain characteristics common to MVP patients with SCD or significant ventricular arrhythmia. These include complex and frequent ventricular arrhythmia on ECG or ambulatory monitoring, ECG T-wave inversion, bileaflet prolapse, mitral annular disjunction or dehiscence (MAD), rapid systolic movement of the lateral mitral annulus (Pickelhaube sign) and myocardial scarring on CMR ,10,16,17MVP has been shown to have sex-differences in its presentation and outcomes, with women being more likely to have bileaflet prolapse with a greater degree of valve thickening and less likely to undergo valve surgery . The latAssociations between the genetic substrate and MVP have been considered. Delling et al. described familial clustering with the prevalence of a family history of MVP in a large cohort of patients to be 20.4% and suggested that MVP has an autosomal dominant inheritance with variable expression . A genetEvents leading up to arrhythmic SCD are frequently described as an interplay of the following three factors: substrate, trigger and transient modulator (transient initiating event) . In MVP,Premature ventricular complexes (PVCs) and non-sustained ventricular tachycardia (NSVT) have been described in 43% of patients with MVP and may trigger VF, yet only about 6% of MVP patients develop SCD ,20. GeneIn addition to PVCs that originate from the papillary muscles, PVCs arising from the Purkinje tissue have also been implicated as a trigger for VF . SeveralA critical role for the Purkinje-papillary muscle complex has been shown through catheter ablation studies of VF triggers in MVP. In one study, Purkinje origin of the VF trigger was present in all 6 patients undergoing catheter ablation, of which 4 were from Purkinje tissue located on papillary muscles . FurtherMyocardial tissue abnormalities can result in arrhythmia from triggering and re-entry ,49. The Myocardial inflammation and fibrosis affecting the left ventricle has been demonstrated in AMVP by both autopsy studies as well as clinical imaging, both within the papillary muscles as well as at the basal posterolateral segment of the left ventricle ,52,53. SMyocardial remodeling can be seen as secondary to significant MR as well as a PVC-induced cardiomyopathy . An incrAutonomic dysfunction may contribute to arrhythmogenesis in MVP patients. A sympathetic tone plays an important role in both triggering arrhythmias and initiating scar-related reentrant arrhythmia and has been proposed as playing a role in MVP-associated ventricular arrhythmias . Among tRhythm disturbances frequently seen in AMVP patients include repolarization abnormalities and complex ventricular ectopy. Inferolateral T-wave inversions (TWI) are the most frequent repolarization abnormality observed ,18. MoreAbnormalities of repolarization may also account for the increased incidence of AMVP associated SCD in women. It is well known that torsades de pointes (TdP) is more frequently seen in women ,61,62. IComplex ventricular ectopy in AMVP generally refers to the presence of one or more of the following: ventricular bigeminy, PVC couplets, nonsustained ventricular tachycardia (NSVT) and sustained VT. The dominant PVC morphologies are those arising from the papillary muscle region or outflow tract , mitral annular disjunction or dehiscence (MAD), the Pickelhaube sign and global longitudinal strain (GLS). In particular, the echocardiographic presence of MAD and the Pickelhaube sign have become popular in the risk assessment, owing to their ability to serve as predictors of scars.Bileaflet morphology has frequently been identified as a high-risk feature of SCD. Among a cohort of 24 patients with an implantable cardioverter-defibrillator (ICD) who experienced idiopathic out-of-hospital cardiac arrest without an identified etiology after comprehensive workup, 10 (42%) were found to have bileaflet MVP . HoweverMR is often seen in conjunction with MVP and represents an important consequence of the disorder. In a cross-sectional population-based study by Freed et al., 70% of MVP patients were found to have some degree of MR . Howeverp < 0.0001) and 3.85 , respectively . Su. Su86]. The autonomic nervous system is known to play a central role in the genesis and maintenance of arrhythmias . NeuromoThe role of circulating biomarkers and genetic testing in risk stratification is still unknown. As mentioned previously, mechanical stress-induced fibrosis is believed to be play a central role in the pathophysiology. This may involve the upregulation of transforming growth factor-β1 (TGF-β1) and other growth factors. The soluble suppression of tumourigenicity-2 (sST2) and TGF-β1 has been studied as a potential marker of ventricular arrhythmia in patients with MAD. Circulating sST2 levels were higher in patients with MAD and ventricular arrhythmia compared with arrhythmia-free patients . MicroRNThe association of fibrosis on imaging with the risk of sudden cardiac death continues to be investigated. In a recent study by Lee et al., the presence of LGE on CMR was found to be an independent predictive factor for SCA or VA in MVP patients . HoweverMiller et al. recently described the use of a hybrid PET-MRI system in a cohort of 20 patients with AMVP . Focal oThere may be a role for artificial intelligence in better identifying patients with AMVP and MMVP when applied to existing investigational approaches. Recently, such an approach was able to predict the presence of complex ventricular ectopy on ambulatory monitoring from a resting 12-lead ECG with an area under the curve (AUC) of 0.81 . The extEarly surgical intervention may also serve a role by modifying the underlying electrophysiologic substrate and warrants further study. MVP is a common, heterogenous disorder comprised of a spectrum of many low-risk patients on one end but also a high-risk subset on the other end (MMVP). The incidence of SCD in patients with MVP is not clearly established. It is usually due to VF and associated with excessive leaflet mobility inducing mechanical stretch of the inferobasal wall and papillary muscles and diastolic interaction of the leaflets or chordae with the ventricular endocardium, leading to inflammation and scarring. Fibrosis in these areas along with MAD and systolic curling of the mitral leaflets are the proposed pathophysiologic mechanisms for SCD. Not only has the identification of those with MMVP, who are at a high risk of SCD, proven challenging, but the management of MMVP also remains uncertain. This is especially true for determining appropriate ICD placement as well the utility of early mitral valve repair and prophylactic catheter ablation. Based on our current understanding, patients with high-risk features such as bileaflet involvement, complex ventricular ectopy, MAD, systolic curling, ventricular fibrosis and increased ventricular mass should undergo further risk stratification in order to mitigate the risk of SCD. The implementation of a multimodality approach with multicenter RCTs will be paramount in achieving this.


Cyclic variation of heart rate (CVHR) associated with sleep‐disordered breathing reflects cardiac autonomic responses to apneic/hypoxic stress. However, the association of CVHR with cardiac function is unclear.We investigated a total of 181 patients who underwent both 24‐hour Holter electrocardiography (ECG) and quantitative gated single‐photon emission computed tomography (SPECT) myocardial functional imaging, excluding patients with atrial fibrillation, myocardial infarction, structural heart disease, and implantable devices, from January 2017 to July 2018. The number of CVHR per hour (CVHR index) in sleeping‐time Holter ECG was compared with the parameters of left ventricular (LV) systolic and diastolic functions assessed by cardiac SPECT functional imaging, peak filling rate (PFR), first‐third mean filling rate (1/3 MFR), and time to peak filling rate (TTPF).P < .05) and 1/3 MFR  but positively correlated with TTPF  and was not correlated with LV ejection fraction. Multivariate linear regression analysis revealed that high CVHR index was independently associated with LV diastolic dysfunction, even after adjusting for the relative wall thickness and LV mass index assessed by echocardiography.In all patients, the CVHR index was not associated with any parameters of cardiac functions. However, in a propensity score–matched subgroup of patients without ischemia (N = 39), the CVHR index was negatively correlated with PFR (r = −0.35, These results indicate that the high frequency of CVHR in sleeping time is associated with LV diastolic dysfunction in nonischemic patients, irrespective of LV geometry. Previous studies demonstrated that apnea‐hypopnea index (AHI) in patients with obstructive sleep apnea (OSA) was correlated with left ventricular (LV) diastolic dysfunction evaluated by echocardiography.Furthermore, myocardial ischemia itself causes not only LV systolic dysfunction but only LV diastolic dysfunction.22.1We retrospectively investigated a total of 181 hospitalized patients who underwent Holter ECG, echocardiography, and quantitative gated single‐photon emission computed tomography (SPECT) from January 2017 to July 2018, after excluding patients who met the following criteria: age <20 years, atrial fibrillation and complete atrioventricular block at night, implantable devices, myocardial infarction, and structural heart disease. Since the LV diastolic function is impaired in an ischemic heart, to examine the impact of ischemia on cardiac function, we divided the 181 patients into the ischemic heart disease (IHD) group and nonischemic heart disease (non‐IHD) group  identified all R‐wave positions and excluded abnormal beats, such as ventricular and supraventricular ectopic complexes and artifacts. The algorithm to detect CVHR automatically was prepared as previously reported.2.3All patients underwent transthoracic echocardiography  by a technician. LV and left atrial internal dimensions and LV wall thickness were measured at end‐diastole and end‐systole in accordance with the recommendations of the American Society of Echocardiography (ASE) and the European Association of Cardiovascular Imaging (EACVI).2.4ECG‐gated single‐photon emission computed tomography (SPECT) was performed at rest and during sinus rhythm using thallium‐201 chloride (111 MBq) or technetium‐99 m tetrofosmin (740 MBq) as a tracer. At 60 minutes after intravenous tracer injection, ECG‐gated SPECT data were obtained for 60 seconds per projection from 30 projections during a 180° rotation using a two‐headed gamma camera with a low‐energy, high‐resolution parallel‐hole collimator. A cardiac cycle was divided into 16 frames. The data were stored in a 64 × 64‐word matrix nuclear computer system, and no attenuation or scatter correction was applied to this protocol. For the data analysis, the quantitative gated SPECT program  was applied to process short‐axis tomograms to determine the LV end diastolic volume, LV end‐systolic volume, and LV ejection fraction (LVEF). Peak filling rate (PFR), first‐third mean filling rate (1/3 MFR), and time to peak filling rate (TTPF) were also obtained as the diastolic functional parameters.2.5t‐test for two‐group comparisons. Categorical variables were compared using the chi‐square test. Pearson's correlation analysis was used to evaluate the correlations between the parameters. The multivariable linear regression analysis was employed to identify the independent parameter for impaired LV diastolic function. A propensity score was used to match the subgroups in a 1:1 ratio and calculated using logistic regression. Covariates with a P‐value <.20, as determined by univariate analysis, were used to generate the propensity score, which included age, body mass index (BMI), hypertension, and diabetes. In addition, sex was included in the matching variable, considering the possibility of imbalance after propensity score matching. A P‐value <.05 was considered to indicate statistical significance. Statistical analyses were performed using GraphPad Prism 6 statistical software  and EZR , which is a graphical user interface for the R software program .Normally distributed continuous variables were presented as mean ± standard deviation (SD) for each group unless stated and analyzed by unpaired 3The flowchart of this study is shown in Figure There were statistical differences in some parameters of clinical backgrounds between the non‐IHD group and IHD groups Table . To avoiThe univariate analysis Table  demonstr4The major findings of this retrospective study are as follows: (a) CVHR index was negatively correlated with the parameter indicating LV diastolic function evaluated using gated SPECT imaging in patients without ischemia. (b) Multivariate linear regression analysis revealed that high CVHR index was independently associated with LV diastolic dysfunction, after adjusting for the LVMI and RWT.Heart failure with preserved ejection fraction (HFpEF) is a clinical syndrome in which patients have symptoms and signs of heart failure with normal or near‐normal LVEF. Now, it accounts for 56% of patients with heart failure, and its prevalence is increasing.OSA has been associated with diastolic dysfunction and increased LVMI, which is the result from episodes of repetitive hypoxia during sleep and increases in afterload.The central sleep apnea (CSA) is another class of sleep‐related breathing disorder. Like the OSA, the CSA also tends to be accompanied with HFpEF.Definite diagnosis of OSA requires all‐night laboratory polysomnographic examination, which is occasionally inconvenient to perform. Thus, the Holter ECG‐based screening for sleep apnea could be an easy supportive method. CVHR index in sleeping‐time Holter ECG was reported to be closely correlated with AHI in full polysomnography.The LV diastolic dysfunction of the local myocardium exposed to ischemia due to organic coronary artery stenosis, now on, in the past, is thought to persist regardless of the presence of OSA.ECG‐gated SPECT can quantitatively and objectively assess LV systolic (LVEF) and diastolic  function. Echocardiography is noninvasive and frequently used for evaluation of LV function; however, the intra‐ and interoperator variation in measurement tend to be larger. In contrast, PFR, 1/3 MFR, and TTPF obtained from gated SPECT have been highly correlated with LV end diastolic pressure (LVEDP), which was measured using the invasive method of cardiac catheterization.5The present study has several limitations. First, this study collected single hospital‐based samples, and the number of study sample became relatively small. Therefore, the existence of referral bias should be considered. Second, CVHR index was less certain than AHI because the sleeping time was self‐reported and was not judged by electroencephalographic findings. Third, patients with atrial fibrillation or implanted pacing devices are not applicable because of the loss of the physiological significance of the CVHR index. Fourth, it is unclear whether CVHR index is related to heart failure caused by the diastolic dysfunction, as few patients had moderate to severe heart failure in our population. Fifth, the e′ value and left atrial volume index (LAVI) evaluated by echocardiography were missing in many cases, which made it difficult to classify them into the severity of LV diastolic function (grade I‐III) recommended by the ASE/EACVI guideline.6High frequency of CVHR in sleeping time is associated with LV diastolic function in nonischemic patients, irrespective of LV geometry. CVHR determined by Holter ECG may be a useful screening index that reflects early LV diastolic dysfunction in patients without structural and ischemic heart disease.The authors have no conflict of interest.Conceptualization: Takanori Yaegashi.Formal analysis: Takanori Yaegashi.Investigation: Takanori Yaegshi.Methodology: Takanori Yaegshi.Supervision: Manabu Nakano and Yoshiharu Murata.Writing—original draft preparation: Takanori Yaegashi.Writing—review and editing: Manabu Nakano.All authors have read and approved the final version of the manuscript.Dr Takanori Yaegashi had full access to all of the data in this study and takes complete responsibility for the integrity of the data and the accuracy of the data analysis.Takanori Yaegashi affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned  have been explained.Table S1. Clinical characteristics of total and subgroups.Click here for additional data file.