Internet of Things (IoT) technology is rapidly expanding the use of its application, from individuals to industries. Owing to this, the number of IoT devices has been exponentially increasing. Considering the massive number of the devices, overall energy consumption is becoming more serious. From this point of view, attaching low-power wake-up radio (WUR) to the devices can be one of the candidate solutions to deal with this problem. With WUR, IoT devices can go to sleep until WUR receives a wake-up signal, which enables a significant reduction of its power consumption. Meanwhile, one concern for WUR operation is the addressing mechanism, since operational efficiency of the wake-up feature can significantly vary depending on the addressing mechanism. We therefore introduce addressing mechanisms for IoT devices equipped with WUR and analyze their performances, such as elapsed time to wake up, false positive probability and power/energy consumption, to provide appropriate addressing mechanisms over practical environments for IoT devices with WUR. Internet of things (IoT) has been a mainstream technology in telecommunications. Currently, IoT devices are utilized on diverse systems, from consumer appliances to industrial applications. To support these various applications, there have been lots of standards-related activities in the IoT industry through various alliances and consortiums and many of them are quite mature in their own realm and territory ,2,3,4,5.On the one hand, raising this kind of platform inevitably causes a fundamental problem; a power consumption issue. On this platform, since large amounts of transmission from lots of applications to the device can occur, this can cause rapid battery exhaustion. This can especially be harmful for wireless devices with small battery capacity, such as mobile phones or smart watches.To deal with the power consumption issue, several approaches to save their consumed power have been proposed. Two typical schemes among them are duty-cycle operation and low-power wake-up radio (WUR). In duty-cycle power saving operation, the radio can reduce its power consumption by periodically turning the transceiver on and off. Duty-cycle power saving operation has the advantage that no additional physical device is required; however, most of the duty-cycle protocols still suffer from overhearing and idle listening, which brings about redundant power consumption. For example, idle listening occurs when a station listens to wireless medium even when there is no communication and overhearing occurs when a station listens for communications destined for another node. These can be a critical aspect in energy-constrained wireless devices.As an alternative to it, WUR has been proposed. In this wake-up radio system, an additional low-power radio is connected to the device along with conventional 802.11 radio. The purpose of WUR is to detect a wake-up signal sent by the wake-up transmitter before the wireless data communication destined for itself. In this way, the conventional radio can be configured to stay in the lowest power mode by default and can selectively listen to the wireless medium only when there is a signal to receive.A representative standard to support wake-up radio is IEEE 802.11ba . A task Some aspects may be required to support the WUR. Since IEEE 802.11ba belongs to the 11 family, primary connected radio must support legacy IEEE 802.11. Additionally, the hardware needs to be newly deployed in order to be capable of the additional radio. However, since they are the world’s most widely used wireless computer networking standards, the main framework of the IoT platform does not need to completely be redesigned. Although it also requires an additional radio, overhearing and idle listening problems can be drastically alleviated. Due to the advantages compared to duty-cycle operation, this paper considers WUR a key solution for solving the power consumption problem of IoT devices and focuses on the detailed performance of WUR.One of the things to consider when applying WUR is ’addressing’. Assuming a transmitter wants to wake up multiple devices, the transmitter may basically transmit a wake-up frame to recipients separately one by one using unicasting, which causes a significant delay in waking up the receivers. Otherwise, the transmitter can wake up all receivers at once using broadcast by risking redundant power consumption. Groupcasting can also be one of the solutions, but it requires a group assigning procedure in advance. The receivers that consistently wake up may be bonded together as a group, but it may be useless if the recipients are selected randomly.Based on these addressing mechanisms, detailed addressing mechanisms, which can be adopted for various environments, have been studied. In Reference , unicastBy changing the way of thinking, a newly developed data structure for addressing is also worth considering. A Bloom filter is a space-efficient data structure, which can be used to test whether or not a certain element is included in a set. One of the most important features of the Bloom filter is that a false negative case does not occur. This means that there is no case where the station to be woken up does not wake up. Because of these characteristics, the Bloom filter has been utilized for various applications, such as content delivery network, blocking malicious URLs and wallet synchronization for cryptocurrencies. In Reference , the autIn this work, we mathematically analyze addressing mechanisms based on IEEE 802.11ba, which is the most cutting-edge protocol for wake-up radio. Expected wake-up time, false positive probability, average throughput and expected power/energy consumption for the mentioned addressing mechanisms are analyzed. We perform extensive numerical analysis and present here our discussion on how to properly use the addressing mechanism in various environments.The remainder of the paper is structured as follows. This section first introduces IEEE 802.11ba, a representative low-power wake-up protocol and its brief operational procedure. We next review a mathematical foundation for the standard Bloom filter for better understanding.IEEE 802.11ba assumes an additional low-power wake-up radio, that is WUR, which aims only to wake up the conventional 802.11 radio. Hence, WUR only needs to receive wake-up frames and forward them to its conventional radio, resulting in very low power consumption. Furthermore, since IEEE 802.11ba is on 11-family, it can be easily adopted to existing wireless local area networks (WLANs).Since the WUR for IEEE 802.11ba is designed to have extremely low power consumption, it has to support a fairly low transmission rate. As a result, the wake-up frame is designed to be transmitted only at 62.5 kbps and 250 kbps. That is why the wake-up frame does not adopt the traditional IEEE 802.11 MAC protocol data unit (MPDU) format with 48-bit address fields. Instead, the Address field supports 12 bits and thus an address named WUR ID (WID) only for the wake-up procedure is newly defined. For the wake-up frames of unicast type, the Address field carries the WID assigned for the one WUR station by the AP to identify one WUR station. For the type of the multicast wake-up frame, the Address field carries the group ID (GID) assigned by the AP to identify one or more WUR stations. For broadcast wake-up frames and types of WUR beacons, the address field carries a transmitter ID (TXID) as it is a frame for all WUR stations. The newly defined IEEE 802.11ba wake-up frame format is shown in A Bloom filter is a data structure used to test whether an element is a member of a set. This property can be used in this paper to determine whether the address of a station is included. For the wake-up operation, the AP can indicate the target wake-up stations to the stations using the Bloom filter.m bits, which initially sets to 0. k independent hash functions are needed, each of which maps an address to one of the m array locations. Hence, to add an element into the Bloom filter, hash it to each of the k hash functions and thus k or less array positions can be drawn. Then the bits at all these positions are set to 1. Naturally, these hash functions must be shared between the AP and the stations associated to it to query its address.An empty Bloom filter can be represented as a bit array of k hash functions to get k indexes, that is, the k hashed values of its address. If all bits are set to 1 for all k bit positions, then the receiver considers itself as an included one.Once the receiver gets the bit array, it will check whether its hashed address is included in the array or not. In order to test whether its address is in the set, the receiver performs the same procedure as the AP. It feeds it to each of the k hash function are 1, then either the element is in the set, or the bits have by chance been set to 1 during the insertion of other elements, resulting in a false positive. This can incur redundant power consumption on the other hand, since a false negative never occurs in a Bloom filter by its inherited characteristics.Since a Bloom filter is a probabilistic data structure, there is a chance that false positives occur, which means that stations that should not be indicated can be indicated by the filter. In particular, in cases when all bits derived from the m is 10 and the number of hash functions, k is 3. All bits are set to 0 in the initialize phase. Each bit is numbered from 1 to 10, so a universe of all hash functions also distributes from 1 to 10. We assume Elements 1 and 2 are inserted into the filter and their hashed values are true negative. On the other hands, although Element 4 is not included in the Bloom filter in fact, the recipient will assume that Element 4 is included since the bits of Bloom filter at hashed values of Element 4, that is false positive and it can cause redundant power consumption.The above-mentioned simple procedures for initializing, inserting and querying a Bloom filter are shown in m, the number of hash functions k and the number of inserted elements n. Assuming hashed values are uniformly distributed among the space of the filter, the probability that a particular bit is not set to 1 by a particular hash function while inserting an element is n elements are inserted, the probability that a particular bit is set to 1 is k array positions computed by the hash function is 1 with above probability. Hence, the probability that the algorithm would incorrectly claim that the element is in the set, even the element is not intended to be inserted, that is, false positive probability, can be represented asThe false positive probability consists of the length of filter m and n are given, the number of optimal hash functions k that minimize the false positive probability can be derived asBased on Equation , assuminp has to be set. Next, in cases when the intended number of inserted elements is n, then the required number of hash functions, k can be calculated as in Equation  unicasting, (2) broadcasting, (3) groupcasting and (4) bloom-filter addressing. The beginning of this section first describes how each addressing mechanism can be designed based on the IEEE 802.11ba wake-up frame format. Next, we analyze some aspects of the mechanisms—wake-up delay, false positive probability and mean power/energy consumption. With wake-up delay, we can present which addressing mechanism is more suitable for delay-sensitive applications. We can also find the proper addressing mechanism for those applications that require a high data rate with an achievable data rate. False wake-up probability and mean power/energy consumption let us know the lifetime for the stations.In the case of unicasting, two addressing methods are available. One is to use the Address field, which is mandatory for all APs and stations, and the other is to use Frame Body field, which can be optionally implemented. In the former case, the Address field of the wake-up frame contains a WID, which is negotiated between the AP and the station in advance, which identifies the station. In the latter case, the wake-up frame has a list of identifiers in the Frame Body field where one of the identifiers identifies the station. Since the maximum length for the Frame Body field is defined as 128 bits and the length for one WID is 12 bits, one wake-up frame can contain up to 10 individual addresses.For broadcasting, an AP can wake up all stations using transmit ID, which is the address of the AP itself, which means that the wake-up frame is broadcasted, with a broadcasting wake-up frame. The AP may transmit this broadcasting wake-up frame to stations to indicate that a crucial update to the conventional 802.11 radio’s parameters is available via the radio for the stations.A group ID is used for groupcasting. A group ID identifies a group of one or more stations. A wake-up frame with this group ID in the Address field is a group addressed wake-up frame that is addressed to all the WUR stations identified by that group ID. Although this groupcasting can be an efficient way for addressing, allocating group ID should be negotiated in advance and is actually defined as an optional feature in IEEE 802.11ba.n, and the false positive probability To use a Bloom filter, an appropriate length of the filter needs to be calculated. Once the AP determines how many stations it wakes up, denoted as Equation . MeanwhiEquation  divided For unicasting wake-up, every station is woken up one by one. When the station’s WUR receives a wake-up frame assigned to it, it wakes up the conventional 802.11 radio in preparation for receiving a data frame. In the case of a broadcasting wake-up case, since the wake-up frame is received by all stations, the unscheduled station also wakes up the conventional 802.11 radio just like the scheduled station. In the groupcasting case, a station can also have group ID in addition to its own WID. If a station receives a wake-up frame which includes its WID or group ID, the station wakes up the conventional 802.11 radio. When the Bloom filter is used for the addressing method, a station should indicate how many hash functions are used. This information can be included in the wake-up frame. The station can query the existence of its address with this information. If the query proves that the address is in the filter, it wakes up the conventional 802.11 radio. Finally, it is assumed that the data frame and the (block)ack frame are transmitted to the recipients at the same time using MU-MIMO or OFDMA since these schemes are currently used in IEEE 802.11ax. These brief wake-up procedures for the addressing mechanisms described are illustrated in n stations. It also assumes that the wake-up frame follows the format of In this subsection, wake-up delays are analyzed for each addressing method. We define the wake-up delay as the elapsed time from the first wake-up frame transmission to the completion of the ack frame transmission when the AP wants to wake up n stations, Referring to In broadcasting, since all the stations will wake up at once, average wake-up delay, n stations, n targeting stations. We derive the expected value of n is the same among the cases, the number of groups may vary depending on which stations in which group are subject to wake-up. To derive In the case of groupcasting, the average wake-up delay to wake up So, the number of groups becomes n becomes 2, We can express Thus, a recurrence relation between Let Equation  can be eMultiplying both sides of Equation  by 1∏k=0Assuming With Equations  and 12)12), the n stations can be represented as follows: Hence, the general form of the expected number of wake-up frames to wake up As a result, the average wake-up delay for groupcasting can be expressed with Equations  and 14)14).n stations, n stations for the Bloom filter addressing. Similar to the case of groupcasting, In the case of the Bloom filter, the average wake-up delay to wake up n stations and As shown in Equation , the optAs a result, average wake-up delay for Bloom filter can be expressed with Equations  and 17)17).In this subsection, false positive probabilities are analyzed for addressing mechanisms. Since the above-mentioned four addressing mechanisms do not suffer from false negative probability unless there is a transmission failure, only false positive probabilities are addressed in this section. In this paper, false positives are defined as the probability that a station wakes up even if it is not actually marked in received wake-up frames. This probability can particularly be important for the amount of power consumption.n’s.In the case of unicasting, since wake-up frames are transmitted only to the corresponding stations, false positive probabilityn’s.For broadcasts, the address field of a wake-up frame indicates that the station receiving the frame should wake up, so all stations wake up. In that sense, false positive probabilityFor groupcasting, the probability of false positives can vary depending on whether other stations in the group to which the station belongs should wake up. By the pigeonhole principle,n target stations are not associated with the group that the particular station is associated with. For example, if the particular station belongs to Group 1, false positive does not occur only if the groups on the n target stations are not all of group 1. Hence, what is mentioned above can be represented asOn the other hand, if ented aspfalse,grn stations are indicated, For the Bloom filter, the difference between the other mechanisms is that the target false positive probability is set in advance, and then the actual false positive probability is calculated based on that probability. As defined earlier in Equation , let theWith Equations , 2) and and2) anIn this subsection, the expected energies for one station per one cycle are analyzed. The expected power can be calculated by the expected energy divided by the expected wake-up delay. We evaluate these values considering the ‘true positive’ stations as well as the ‘false positive’ ones by using the equations calculated above.n, as shown in n stations are subject to wake up, In common, by the law of total expectation, the expected energy per one cycle when the number of wake-up stations is quations , 19), n, as shon can be expressed as follows: After that, the expected power for one station when the number of wake-up stations is Referring to quations , 27), E[energybEquation , the expFor groupcasting, the expected consumed energy if the station is decided to wake up, Consequently, Hence, with Equations , 30) an an30) anIn the case of the Bloom filter, the expected consumed energy if the station is decided to wake up, Consequently, Hence, with Equations , 25), ,  and 33)33) with In this simulation, we omit channel contention between wake-up frames and data frame since the channel contention does not affect the result of the wake-up procedure. Hence, the elapsed time to contend for the channel is excepted from this simulation. We assume the length of the data frame and ack frame from conventional 802.11 radio to be 3000 Bytes and 32 Bytes, respectively. We also assume the length of Frame Body field for the Bloom filter to be 128 bits. Data rates of conventional 802.11 radio and WUR are 8.6 Mbps and 250 kbps, respectively. Transmit and receive power consumption , time paHereafter, the target stations mean that the station is subject to wake up by wake-up frame. It is straightforward that the expected delay for unicasting linearly increases. This is because, as the number of target stations increases by one, the elapsed wake-up time also increases by With the elapsed time and the frame length, we assumed 3000 Bytes, the average data throughputs can also be analyzed. As the number of target stations exceeds 100, the false positive probability for groupcasting becomes nearly 1 since almost all groups are indicated. As mentioned earlier, even if only one station is subject to be woken up, all stations in the group to which it belongs must wake up. This is why the curve of groupcasting converges on 1 as the number of target stations increases. For Bloom filters, the probability of false positives increases until the number of target stations reaches 80. It can be seen that the probability drastically drops when the number of target stations is 100 because the number of wake-up frames increases by 1, which lengthens the length of the Bloom filter. As shown in Equation , the falPower consumption is one of the good criteria to decide an appropriate addressing mechanism especially for the power-insufficient devices, such as mobile phones or small sensors. In From these analyses, unicasting wake-up is relatively inferior to other addressing mechanisms because unicasting not only takes longer to wake up, but also consumes more energy than other mechanisms. The unicasting wake-up can be a good option when the number of target stations is very small. Broadcasting wake-up is appropriate for stations that use applications requiring high data rates but have sufficient battery power, especially when there are lots of target stations. Groupcasting can be one of the addressing options, however, its false positive probability gets high when the target number is large. It can be solved by delicate grouping in advance; however, if the wake-up stations are randomly chosen, it becomes hard to adopt groupcasting. Using the Bloom filter, the expected wake-up delay is quite short while data throughput is relatively high. Hence, the Bloom filter can be a good addressing mechanism under ordinary environments.In In this paper, we give intensive mathematical analysis among four addressing mechanisms which can be used for IoT devices with low-power wake-up radio are analyzed. Through the performance analyses, unicasting wake-up is a relatively inferior to other addressing mechanisms because unicasting not only takes longer to wake up but also consumes more energy than other mechanisms. The unicasting wake-up can be a good option when the number of target stations is very small. Broadcasting wake-up is appropriate for stations that use applications requiring high data rates but have sufficient battery power, especially when there are lots of target stations. Groupcasting can be one of the addressing options, however, its false positive probability is high when the target number is large. It can be solved by delicate grouping in advance; however, if the wake-up stations are randomly chosen, it becomes hard to adopt groupcasting. Using the Bloom filter, the expected wake-up delay is quite short while data throughput is relatively high. Further, by adjusting the target false positive probability, Bloom filters can be fine tuned for specific traffic and application conditions. Hence, the Bloom filter can be a good addressing mechanism under ordinary environments. According to our study, an appropriate addressing mechanism can be selected depending on the application characteristics.


Myocardial infarction (MI) healing occurs in 2 phases: first an inflammatory phase, where clearance of necrotic debris occurs, followed by a reparative phase characterized by angiogenesis, granulation tissue formation, and attempts to repair the extracellular matrix. While efficient healing relies on coordinated mobilization of monocytes to the damaged myocardium, with resolution of the acute inflammatory response by ∼10 to 14 days, excessive inflammation impairs myocardial salvage and promotes adverse cardiac remodeling.In ischemic heart failure, pro-inflammatory macrophages persist long after the formation of healed scar in remote and border zones of the infarcted, remodeled heart because of maladaptive changes in the mononuclear phagocytic network and spleen 68Ga-DOTATATE, a somatostatin receptor subtype-2 positron emission tomography (PET) ligand, could identify pro-inflammatory macrophages within atherosclerotic plaques 68Ga-DOTATATE could reveal residual post-infarction myocardial inflammation.We previously demonstrated that Patients with an MI within 3 months treated by percutaneous coronary intervention , and patients with a past history of MI and echocardiography data available from after their event , were included. Patients with equivocal culprit arteries, and those managed medically or with coronary artery bypass grafting surgery, were excluded.max) and tissue-to-blood ratios (TBRmax), normalized for blood pool activity in the superior vena cava, were derived blinded to clinical details in each of the 16 myocardial segments.ECG-gated PET imaging was performed as previously described 68Ga-DOTATATE and 18F-FDG PET signals were compared: 1) within infarcted and noninfarcted segments; 2) to each other; and 3) to tracer activity in the thoracic vertebral bone marrow as an experimental marker of systemic inflammation, using standard nonparametric statistical tests ] unless stated). Recently infarcted myocardial segments were defined by clinically adjudicated (treated) culprit artery territories, with individual anatomical variation verified by angiography. In patients with old MI, infarcted myocardium was determined by echocardiographic wall motion abnormalities (hypokinesia/akinesia), assessed independently of the study and prior to enrollment.Myocardial 68Ga-DOTATATE and 18F-FDG scans.Demographics were similar for recent MI  and old MI  patients. There were 3 ST-segment elevation MIs, which were all old MIs. PET imaging occurred 35 days (range 21 to 80 days) after recent MIs, and 7 years (range 1.8 to 22 years) after old MIs, with 2 days (range 1 to 21 days) in between 68Ga-DOTATATE signals were higher in infarcted compared with noninfarcted myocardium in patients with both recent MI  and old MI .68Ga-DOTATATE, which exhibited very low background myocardial binding in all patients, avid myocardial 18F-FDG uptake  rendered 5 (42%) scans uninterpretable despite 6-h pre-scan fasting. In the readable scans, the 2 tracers showed reasonable agreement in the myocardium . Despite high liver and spleen 68Ga-DOTATATE activity, focal myocardial signals were clearly distinguishable in all 5 patients with inferior infarcts.Unlike 68Ga-DOTATATE signals were highly correlated with both infarct-related myocardial inflammation detected by 68Ga-DOTATATE , and metabolic bone marrow activity measured by 18F-FDG .Bone marrow 68Ga-DOTATATE identified active inflammation in recently infarcted myocardium, as well as old ischemic injury. Our observations agree with existing clinical data 68Ga-DOTATATE binding in chronically damaged myocardium, particularly at the infarct border (SSTR2 is not expressed in these cell types.We found that t border , likely 68Ga-DOTATATE could represent an important prognostic biomarker to study disease mechanisms and test novel therapies for the inflamed, failing heart.Residual myocardial inflammation detected by


The pathogenesis and cardiovascular impact of type 2 diabetes (T2D) may be different in South Asians compared with other ethnic groups. The phenotypic characterization of diabetic cardiomyopathy remains debated and little is known regarding differences in T2D-related cardiovascular remodeling across ethnicities. We aimed to characterize the differences in left ventricular (LV) diastolic and systolic function, LV structure, myocardial tissue characteristics and aortic stiffness between T2D patients and controls and to assess the differences in T2D-related cardiovascular remodeling between South Asians and Europeans.1H-MRS). Differences in cardiovascular parameters between T2D patients and controls were examined using ANCOVA and were reported as mean (95% CI). Ethnic group comparisons in the association of T2D with cardiovascular remodeling were made by adding the interaction term between ethnicity and diabetes status to the model.T2D patients and controls of South Asian and European descent underwent 3 Tesla cardiovascular magnetic resonance imaging (CMR) and cardiac proton-magnetic resonance spectroscopy , P = 0.017], whereas global longitudinal strain and aortic pulse wave velocity were similar. South Asian T2D patients had a higher LV mass  (P for interaction by ethnicity = 0.005) with a lower extracellular volume fraction  (P for interaction = 0.114), whilst European T2D patients had a higher myocardial triglyceride content  (P for interaction = 0.002) than their control group.A total of 131 individuals were included  and 77 Europeans ]. The ratio of the transmitral early and late peak filling rate (E/A) was lower in T2D patients compared with controls, in South Asians [− 0.20 , Diabetic cardiomyopathy was characterized by impaired LV diastolic function in South Asians and Europeans. Increased LV mass was solely observed among South Asian T2D patients, whereas differences in myocardial triglyceride content between T2D patients and controls were only present in the European cohort. The diabetic cardiomyopathy phenotype may differ between subsets of T2D patients, for example across ethnicities, and tailored strategies for T2D management may be required. Type 2 diabetes (T2D), independent of other cardiovascular risk factors, is associated with an increased risk of heart failure . South ABy using cardiovascular magnetic resonance (CMR), the impact of T2D on the left ventricle (LV) can be characterized on a functional, structural and myocardial tissue level. Strain echocardiography studies have shown that not merely LV diastolic function, which may be most susceptible to myocardial energy depletion, but also LV systolic function might be impaired . The intThis is a single-center, cross-sectional study. The data of the T2D patients of European and South Asian origin  were derived from the baseline measurements of two previous randomized controlled trials  was ≥ 52.5 and < 86.5 mmol/mol (≥ 7.0 and ≤ 10.0%) and ≥ 47.5 and < 96.5 mmol/mol (≥ 6.5 and ≤ 11.0%), systolic and diastolic blood pressure was < 150/85 mmHg and < 180/110 mmHg, estimated glomerular filtration rate (eGFR) was > 60 mL/min/1.73 m2 and > 30 mL/min/1.73 m2, no history of significant coronary artery disease for the European T2D group (significant coronary artery disease was defined as: a history of coronary artery bypass grafting and/or percutaneous coronary intervention or significant coronary artery stenosis proven by coronary angiography or non-invasive imaging), and no acute coronary accident in the preceding 30 days for the South Asian T2D group. Main exclusion criteria were: any contra-indication for contrast-enhanced CMR and heart failure New York Heart Association class III–IV. All T2D patients were screened for abnormalities on rest echocardiography (ECG). For the present study, all T2D patients with significant coronary artery disease or valvular disease were excluded.All T2D patients were obese }, abnormalities upon physical examination, laboratory assessment  or rest ECG.The healthy controls were recruited by advertisements in Leiden University Medical Center  and in local newspapers. Individuals aged 40–70 years without a history of cardiovascular disease, no medication use and no contra-indications for contrast-enhanced CMR were eligible for participation in the healthy control group. Exclusion criteria were: prediabetes or diabetes , metabolic syndrome {≥ 2 of the following criteria: systolic and diastolic blood pressure blood pressure ≥ 140/90 mmHg; triglycerides ≥ 1.7 mmol/L; HDL-cholesterol < 0.9 mmol/L for men or < 1.0 mmol/L for women; obesity . Smoking status was self-reported and was categorized as currently vs. previously or never. Blood pressure was measured in seated position on the right arm after rest, using a validated automatic oscillometric device  and was the mean of two consecutive measurements. HbA1c was examined with ion-exchange high-performance liquid chromatography . Lipid levels were assessed on a Modular P800 analyzer  with calculation of low-density lipoprotein (LDL)-cholesterol according to the Friedewald formula. The total body fat percentage was derived from bioelectrical impedance analysis .CMR scans were acquired using a 3 Tesla MR scanner with a dStream Torso anterior coil and a FlexCoverage posterior coil, with up to 32 coil elements for signal reception .2, acquired voxel size 1.60 × 1.70 mm2, slice thickness 4 mm, slice gap − 2 mm, number of slices 140). VAT and abdominal SAT were quantified as the mean area in squared centimeters of all three slices .Visceral and abdominal subcutaneous adipose tissue  were assessed on 2-point Dixon water-fat separated transverse images of the abdomen. VAT and abdominal SAT were semi-automatically measured based on pixel intensity thresholding on three reformatted transverse slices at the level of the fourth and fifth lumbar vertebrae, with slice thickness of 10 mm and slice gap of 12 mm (repetition time (TR) 3.5 ms, first/second echo time (TE) 1.19/2.3 ms, flip angle (FA) 10°, field of view (FOV) 500 × 365 mm2 (4-chamber) and 400 × 352 mm2 (short-axis), acquired voxel size 2.0 × 1.6 mm2 (4-chamber) and 1.5 × 1.5 mm2 (short-axis), slice thickness 8 mm, number of phases 30 (4-chamber) and 35 (short-axis)] and free-breathing ECG-gated whole-heart gradient-echo 4D velocity-encoded MR .LV function was examined on breath-hold ECG-triggered short-axis and 2-, 3- and 4-chamber long-axis cine balanced steady-state free precession   . Startin by 100%  . Post-contrast T1 mapping was acquired 20–25 min after administration of 0.15 mmol gadoterate meglumine  per kilogram of body weight. Because of ongoing optimization of the T1 mapping protocols throughout the study, native and post-contrast MOLLI acquisition schemes were adjusted (for the European T2D patients: 3b(3b)3b(3b)5b and 3b(3b)3b(3b)5b; for the European controls: 3b(3s)3b(3s)5b and 3b(3s)3b(3s)5b; for the South Asian T2D patients and controls: 5s(3s)3s and 4s(1s)3s(1s)2s, respectively). T1 relaxation times were measured in the mid-ventricular septum, after manual correction for motion .Myocardial diffuse fibrosis was quantified using native and post-contrast modified Look-Locker inversion recovery (MOLLI) T1 mapping, obtained in short-axis orientation at the mid-ventricular level .Clinical characteristics, adiposity and cardiovascular parameters were presented for the T2D and control group, for Europeans and South Asians separately, and were expressed as mean ± SD, medians (interquartile ranges) or numbers (percentages). We assessed the differences in clinical characteristics and cardiovascular parameters between T2D patients and controls, for Europeans and South Asians, using the Student’s t-test or the Fisher’s exact test, and reported the differences in adiposity parameters as means (95% CI). Differences in cardiovascular parameters between T2D patients and controls, for South Asians and Europeans, were further examined using ANCOVA with adjustment for age, sex, systolic and diastolic blood pressure and smoking status (currently vs. never or formerly). Ethnic group comparisons in the association of T2D with cardiovascular remodeling were made by adding the interaction term between ethnicity and diabetes status to the model . We asseIn the present study, 48 of the 50 European T2D patients who participated in the trial NCT01761318 . The European and South Asian control groups were similar regarding smoking status (P = 0.297), systolic and diastolic blood pressure , triglycerides (P = 0.582), total cholesterol (P = 0.285), LDL-cholesterol (P = 0.848) and HbA1c (P = 0.925), except that high-density lipoprotein (HDL)-cholesterol was lower among the South Asians (P = 0.010). For the South Asian as compared with the European T2D patients, diabetes duration was longer (P = 0.012), the daily insulin dose tended to be higher (P = 0.056), the urinary albumin/creatinine ratio was higher (P = 0.045) and total cholesterol was lower (P = 0.046), whereas HbA1c was similar (P = 0.801).In total, the present study comprised 131 individuals . In the European cohort (n = 77), 48 patients  and 29 controls  were included. The South Asian study population (n = 54) consisted of 33 patients  and 21 controls . Baseline characteristics are presented in Table 2  and 6.2 kg/m2  for BMI, 24 cm  and 19 cm  for waist circumference, 0.15  and 0.10  for waist-hip ratio, 9.8%  and 5.0%  for total body fat percentage, 146 cm2  and 96 cm2  for abdominal SAT and 131 cm2  and 79 cm2  for VAT, respectively.In both the European and South Asian populations, obesity and adipose tissue parameters, blood pressure, cholesterol and glycemic levels were higher in the T2D compared with the control group Table . DiffereIn univariable analyses, for both Europeans and South Asians, T2D patients as compared with controls had LV structural alterations (higher LV concentricity), with impairments in LV diastolic function (lower E/A ratio and higher LV filling pressure) and aortic stiffness (higher aortic pulse wave velocity) Tables . The E dP = 0.095 and 0.008 for interaction by ethnicity, respectively). In European T2D patients the stroke volume was reduced, with a slight decrease in cardiac index, whereas in South Asian T2D patients cardiac index was preserved in comparison with their control groups (P = 0.012 for interaction by ethnicity). In European T2D patients the LV concentricity was increased in parallel with lower end-diastolic volumes (P = 0.001 for interaction by ethnicity), whereas in South Asian T2D patients the increased LV concentricity was in parallel with a higher LV mass (P = 0.005 for interaction by ethnicity). In South Asian but not in European T2D patients compared with their controls, the myocardial cell and extracellular volumes were higher . Because of a larger increase in the myocardial cell volume than in the extracellular volume, the extracellular volume fraction was slightly lower in the South Asian T2D patients than in the controls (P = 0.114 for interaction by ethnicity). In European but not South Asian T2D patients, the myocardial triglyceride content was higher and native T1 was lower in comparison with their controls .In multivariable analyses, in both European and South Asian T2D patients the E/A ratio remained lower and LV concentricity persisted to be higher compared with controls, but there were no differences in the E dec peak, GLS or aortic pulse wave velocity Table . FurtherIn both Europeans and South Asians, the E/A ratio was lower in relation to T2D, whereas global systolic and diastolic strain parameters and aortic pulse wave velocity were similar in the T2D patients and controls in multivariable analysis. Furthermore, South Asian T2D patients had a higher LV mass with a lower extracellular volume fraction, whilst European T2D patients had a higher myocardial triglyceride content than their control group.In our study, in both the European and South Asian population, T2D was associated with reduced LV diastolic function and increased LV concentricity. LV diastolic function in T2D may be impaired due to disturbances in myocardial substrate utilization and myocardial energetics , 27. MorThe prevalence of diastolic dysfunction in asymptomatic T2D patients has been reported to be at least 50% . NotablyImportantly, the increased LV concentricity in European T2D patients was due to a reduction in LV end-diastolic volume, whereas the higher LV concentricity among South Asian T2D patients was related to an increase in LV mass. These observations imply that the higher LV concentricity in T2D may be the result of impaired LV diastolic function  and/or LV hypertrophic remodeling . In the A previous community-based study reported that T2D may be more detrimental for cardiac function among South Asians compared with other ethnic groups . NeverthBoth in imaging studies in T2D patients and in histological studies in diabetic mice, T2D has been demonstrated to be associated with myocardial steatosis , 43–45. Previously, myocardial diffuse fibrosis as indicated by an increased extracellular volume fraction has been demonstrated in obese adolescents with or without T2D, independent of blood pressure . InteresDue to the cross-sectional design of our study, we cannot address issues of causality in the association of T2D with cardiovascular parameters. Our work should be considered a hypothesis-generating study and larger prospective studies are required to confirm the differential impact of T2D on LV structure and myocardial tissue characteristics between Europeans and South Asians. Due to the relatively low sample size, we could not perform subgroup analyses, for example by sex. It has been recognized that T2D in women may be more detrimental for cardiac function as compared with men . The SouLV diastolic dysfunction was identified as a common characteristic of diabetic cardiomyopathy among South Asians and Europeans. Importantly, increased LV mass was solely observed among South Asian T2D patients, whereas differences in myocardial triglyceride content between T2D patients and controls were only present in the European cohort. This study comprised detailed phenotyping of cardiovascular remodeling in T2D patients, in both South Asians and Europeans. Our results suggest that the diabetic cardiomyopathy phenotype may differ between subsets of T2D patients, for example across ethnicities. Therefore, further research on tailored strategies for T2D management may be warranted.


Transthoracic echocardiography (TTE) plays a fundamental role in the management of patients supported with extra-corporeal membrane oxygenation (ECMO). In light of fluctuating clinical states, serial monitoring of cardiac function is required. Formal quantification of ventricular parameters and myocardial mechanics offer benefit over qualitative assessment. The aim of this research was to compare unenhanced (UE) versus contrast-enhanced (CE) quantification of myocardial function and mechanics during ECMO in a validated ovine model.2), end systolic area , fractional area change , endocardial global circumferential strain , myocardial global circumferential strain , endocardial rotation  and global radial strain  were evaluated for UE-TTE and CE-TTE.Twenty-four sheep were commenced on peripheral veno-venous ECMO. Acute smoke-induced lung injury was induced in 21 sheep (3 controls). CE-TTE with Definity using Cadence Pulse Sequencing was performed. Two readers performed image analysis with TomTec Arena. End diastolic area . Mean CE EDA and ESA were significantly larger than in unenhanced images. Mean FAC was almost identical between the two techniques. There was no significant difference between UE and CE EGCS, MGCS and ER. There was significant difference in GRS between imaging techniques. Unenhanced inter-observer variability was from 0.48–0.70 but significantly improved to 0.71–0.89 for contrast imaging in all echocardiographic parameters.Semi-automated methods of myocardial function and mechanics using CE-TTE during ECMO was feasible and similar to UE-TTE for all parameters except ventricular areas and global radial strain. Addition of contrast significantly decreased inter-observer variability of all measurements. Extra corporal membrane oxygenation (ECMO) is a specialised form of pulmonary or cardiopulmonary support in critically unwell patients , 2, 3. IAssessment of ventricular function ranges from a qualitative visual evaluation to more formal quantification such as volumes, ejection fraction and tissue Doppler parameters , 18. MorThis research was performed at the Medical Engineering Research Facility at The Prince Charles Hospital, Brisbane, Australia. Approval had been obtained from the Animal Ethics Committee of the Queensland University of Technology  and the University of Queensland . Unenhanced and contrast-enhanced echocardiographic imaging was performed in our validated veno-venous (VV) ECMO ovine model. This research conformed to the National Health and Medical Research Council (NHMRC) Code of Practice for the Care and Use of Animals for Scientific Purposes . AnaesthWith the sheep in a sternal recumbent position, transthoracic echocardiography was performed by a single operator (DGP) in all sheep, using a Siemens Sequoia C512 scanner and 4V1 transducer. TTE imaging was performed following 20 h of ECMO support in 23 sheep and after 2 h of ECMO support in 1 sheep. Conventional parasternal short axis views, using ECG gating, were obtained initially. Due to the external morphology of a sheep chest wall, conventional apical TTE views cannot be obtained. Immediately after the unenhanced TTE images were acquired, the contrast-enhanced TTE images were recorded. Activated Definity contrast  was diluted to 50 mL with normal saline and administered via an Alaris GH Plus infusion pump into an internal jugular central venous line. The infusion rate was varied to optimise image quality and was in the range 200–300 mL/h. A low mechanical index, proprietary imaging technique called Cadence Contrast Pulse Sequencing was used for all contrast-enhanced TTE images . The ima2), end systolic area (ESA) (cm2), fractional area change (FAC) (%), endocardial global circumferential strain (eGCS) (%), myocardial global circumferential strain (mGCS) (%), endocardial rotation (ER)  and global radial strain (GRS) (%). FAC was defined as the EDA minus the ESA divided by the EDA. eGCS was defined as the strain derived from the deformation of the endocardium in the circumferential direction in the left ventricular short axis. mGCS was defined as the strain derived from the deformation of the mid wall of the myocardium in the circumferential direction. ER was defined as the absolute rotation in the endocardium at the single defined parasternal short axis view . GRS was defined as the strain derived from the whole thickness of the myocardium in the radial direction. This analysis was then repeated for a matching contrast-enhanced parasternal short axis image. All images were interpreted by two readers, one experienced in strain analysis (KJ) and one inexperienced in performing strain analysis (DGP). Each reader was blinded to the other reader’s analysis but the same unenhanced and contrast-enhanced images were assessed by each reader.All images were transferred to a separate workstation and analysed using TomTec-Arena . Unenhanced and then contrast-enhanced parasternal short axis (mid-left ventricular level) images were assessed. Following selection of an appropriate parasternal short axis clip, the endocardium at end diastole was tagged at three anatomic points, which then enabled the programme to automatically track endocardial motion. The epicardial border was automatically generated but could be manually adjusted. Veracity of tracking was then visually assessed and manually adjusted as required. In those images with poor tracking, analysis was not performed. Data collected were end diastolic area (EDA) (cmt test. Inter-observer variability was assessed using the intra-class correlation coefficient (ICC). A P value of <0.05 was considered as statistically significant. Statistical analysis was performed using MedCalc version 10.0 .Continuous variables are expressed as mean ± one standard deviation. Comparison between the continuous variables was performed using a paired P < 0.05).Twenty-four sheep underwent unenhanced and contrast-enhanced TTE during VV ECMO and were included in this study. Of the 48 sheep datasets evaluated, three were excluded (two unenhanced and one contrast enhanced) due to poor endocardial tracking that resulted in negative FAC values. This resulted in a total of 22 sheep (92%) with paired evaluable unenhanced and contrast-enhanced images for final analysis. Mean ECMO flow during TTE imaging was 2.76 ± 0.58 L/min (range 1.46–3.79). Mean pump speed was 2668 ± 496 RPM (range 1460–3290). Mean contrast infusion rate was 247.9 ± 42.9 mL/h (range 200–300 mL/h). There was no significant difference between heart rate (98.8 ± 17.4 vs 103 ± 21.3 BPM) for unenhanced versus contrast-enhanced images respectively.) Frame rate for contrast-enhanced TTE was slower than unenhanced imaging , end systolic area (cm2), fractional area change (%), endocardial global circumferential strain (%), myocardial global circumferential strain (%), endocardial rotation (degrees) and global radial strain (%), both for unenhanced and contrast-enhanced TTE by an experienced reader are shown in Results for the end diastolic area cm, end sysVideo 1http://movie-usa.glencoesoftware.com/video/10.1530/ERP-18-0071/video-1.Example unenhanced imaging endocardial tracking. View Video 1 at Download Video 1Video 2http://movie-usa.glencoesoftware.com/video/10.1530/ERP-18-0071/video-2.Example contrast-enhanced imaging endocardial tracking. View Video 2 at Download Video 2The mean contrast-enhanced EDA and ESA were significantly larger than the unenhanced images. However, the mean FAC was almost identical between the two techniques. There was no significant difference between unenhanced and contrast-enhanced mean endocardial global circumferential strain, myocardial global circumferential strain and endocardial rotation. However, there was a significant difference in global radial strain between the two techniques. Using the intra-class correlation coefficient, the inter-observer variability between the experienced and inexperience user was fair to good for unenhanced imaging (range 0.48–0.70) but good to excellent for the contrast enhanced images (range 0.71–0.89).The main findings of this study are threefold. Firstly, semi-automated quantification of myocardial function and myocardial mechanics in the parasternal short axis view was technically feasible in the majority of unenhanced and contrast-enhanced images. Second mean fractional area change, endocardial global circumferential strain, myocardial circumferential strain and endocardial rotation were not significantly different between unenhanced and contrast-enhanced imaging. However, there were significant differences in end diastolic area, end systolic area and global radial strain. Third, the addition of contrast to the TTE imaging resulted in significantly less inter-observer variability, with the inexperienced reader results more closely approximating that of the experienced reader compared to unenhanced images.Our research showed that unenhanced TTE areas (end diastolic and end systolic) were significantly less than contrast-enhanced areas but the final product  was similar. This finding is consistent with an extensive evidence base demonstrating that endocardial borders are better defined using contrast , 28, 29.Circumferential stain in both the endocardium and myocardium was not significantly different between unenhanced and contrast-enhanced imaging in our study. In our study, circumferential strain was evaluated at both the endocardial and myocardial layers off the left ventricular wall. Circumferential strain, whilst not currently utilised in routine clinical practice, can be used to detect regional myocardial dysfunction and has been shown to be a useful predictor of prognosis in cardiac failure , 35, 36.Left ventricular rotation at the mid cavity level was assessed in our study. Rotation is defined as the rotational displacement around the long axis of the left ventricle and is measured in degrees . There wThe results of our study showed that there was a significant difference between unenhanced versus contrast-enhanced global radial strain. There were very wide limits of agreement and the contrast-enhanced images provided significantly higher values than the unenhanced images. This wide variation in radial strain is a well-recognised limitation of this directional aspect of STE , 41. OurTo our knowledge, there are few substantiated data in the literature that can confirm the feasibility of strain imaging during contrast administration. There is even less data on the evaluation of myocardial strain during ECMO. The calculation of myocardial strain parameters during contrast-enhanced echocardiography has traditionally been considered as not feasible with wide limits of agreement , 47. ThiAccurate evaluation of cardiac function during a dynamic clinical course typical of ECMO support is fundamental in the management of such patients. For this to occur, clear identification of the cardiac structures, especially the endocardial borders is required. Ventricular function can be qualitatively measured using a semi-subjective visual evaluation. This typically grades ventricular function as normal, mild, moderately or severely impaired, along with a quoted estimate of ejection fraction. Systolic thickening of the myocardium is also an important component of evaluating myocardial function. Serial monitoring of ventricular function however requires more formal quantification of function , 52. Formal quantification of ventricular volumes and function can be performed using several methods. The conventional and most widely used technique is to calculate the ejection fraction using two dimensional TTE, usually by employing the stacked method of discs, or Simpson’s biplane method . This teContrast microspheres are hydrodynamically fragile structures and an ECMO circuit would represent an adverse environment for their stability and durability. The main sites for increased microsphere destruction are the oxygenator and within the ECMO pump rotor housing . ComplexOur ECMO circuit utilised a ROTAFLOW  ECMO pump which did not have a built in venous bubble detector. Newer ECMO pumps, such as the CardioHelp (Maquet), have an integrated ultrasonic bubble detector. There has been some work to suggest that contrast microspheres may result in ECMO bubble detectors reading this as air within the circuit and critically impacting on ECMO circuit functionality . These uEvaluation of ventricular function has now progressed beyond just ejection fraction calculation. Myocardial deformation (which may be independent to ejection fraction) can be measured using simple tissue Doppler imaging or more advanced speckle tracking echocardiography , 18, 19.This research was performed during ECMO support in a validated ovine model. These sheep do not have an apical window and as such, the clinically relevant and well-validated technique of global longitudinal strain could not be analysed. Whilst within the accepted workflow of our software programme, the frame rates were relatively low for STE and this may have had an impact on data analysis. Additionally, the frame rates for contrast-enhanced images were lower than with unenhanced imaging. Inter-vendor variability in measurement has been seen as a limitation of STE and work is on-going to determine the optimal work flow strategy to address this . FeasibiThe results of our study show that semi-automated processing methods of myocardial function and mechanics using contrast-enhanced echocardiography during ECMO support is both feasible and similar to conventional unenhanced imaging for FAC, endocardial rotation and circumferential strain. Ventricular area measurement followed the well-recognised trend seen in the ventricular volume assessment, where unenhanced values were significantly lower than contrast enhanced values. Finally, the addition of contrast significantly decreased the inter-observer variability of all measurements. Translation of these results to the clinical environment suggest that in those patients supported with ECMO, contrast enhanced imaging in those with non-diagnostic echocardiograms may be a feasible technique for evaluation of myocardial function and deformation mechanics.David Platts is a Medical Liaison Officer for Lantheus Medical Imaging Australia. The other authors have nothing to disclose.This research was supported in part by funding from the National Health and Medical Research Council (grant no. 1010939) and The Prince Charles Hospital Foundation. John Fraser holds a Health Research Fellowship awarded by the Office of Health and Medical Research, Queensland, Australia. The Siemens Sequoia scanner used for this research was obtained with a research grant awarded to David Platts from the Private Practice Fund, The Prince Charles Hospital.D P designed the experiment, acquired the images, performed the analysis and composed the manuscript. K S performed analysis of the images and critically reviewed the manuscript. J C oversaw analysis using TomTec and critically reviewed the manuscript. D B and G M S critically reviewed the manuscript. J F F designed the ovine ECMO model and critically reviewed the manuscript. All institutional and national guidelines for the care and use of laboratory animals were followed.


Novel fully automated left chamber quantification software for three-dimensional echocardiography (3DE) has a potential for reliable measurement of left ventricular (LV) volumes and ejection fraction (LVEF). However, the optimal setting of global LV endocardial border threshold has not been settled.A.I., Philips Medical Systems) in 65 patients who had undergone both 3DE and cardiac magnetic resonance (CMR) examinations on the same day. We recorded LV end-diastolic volume (LVEDV) and LV end-systolic volume (LVESV) according to the change in LV global border threshold settings from 0-point to 100-point with each increment of 10-point. These values were compared to the corresponding values of CMR with disk-area summation method and feature tracking (FT) method. Coverage probability (CP) was calculated as an index of accuracy and reliability. Fully automated software provided LV volumes and LVEF in 57 patients (Feasibility: 88%). LVEDV and LVESV increased steadily according to the increase in border threshold and reached minimal bias when border threshold setting was 80 against CMR disk-summation method and 90 against CMR FT method. Corresponding CP of LVEF was 0.74 and 0.84 against disk-area summation method and FT method.We performed LV volumes and LVEF analysis using fully automated left chamber quantification software (Dynamic HeartModelWith CMR values as a reference, LV endocardial border threshold value can be set around 80 to 90 with the same number of LV end-diastole and end-systole threshold to approximate LVEDV, LVESV and LVEF with clinically acceptable CP values of LVEF. Left ventricular (LV) ejection fraction (LVEF) using transthoracic two-dimensional echocardiography 2DE) is still one of the most important cardiac metrics to quantify LV function. Several cut-off values of LVEF has been used to select candidates for implantable cardiac defibrillator  and to dDE is stiA.I.) for left heart chamber quantification with three-dimensional echocardiography (3DE) have been shown promising to quantify LV volumes and LVEF in a routine clinical setting [A.I.) has been released, and it now provides LV volume curve using 3DE speckle tracking technology.Recent advances in fully automated software  and end-systole (ES) using Dynamic HeartModelWe retrospectively searched patients who had clinically indicated CMR examination and also agreed to undergo 3DE examination on the same day in University of Occupational and Environmental Health Hospital from January 2017 to July 2018. Among 107 patients for potentially eligible patients, a total of 65 patients who had one-beat 3DE datasets acquisition with specific ultrasound machine that were required for fully automated left chamber quantification software analysis was finally selected for the analysis. All study patients were ethnic Japanese. The ethics committee of the University of Occupational and Environmental Health Hospital approved the study protocol, and informed consent was waived due to the retrospective nature of the analysis.Real-time 3DE full-volume datasets were acquired from the apical window with the patient in the left lateral decubitus position using EPIQ 7G scanner  equipped with a fully sampled matrix-array transducer (X5-1). The depth and sector angle were adjusted to include the entire left and right chambers. Specific one-beat acquisition mode (3D HMQ) was used to acquire 3DE datasets. Several one-beat acquisitions were performed. These datasets were stored digitally for offline analysis.A.I., QLAB, version 10.5, Philips Medical Systems) that detects LV endocardial surfaces using an adaptive analytical algorithm that consists of knowledge-based identification of initial global shape and LV chamber orientation, followed by patient-specific adaptation [One-beat 3DE full-volume data sets were analyzed using fully automated quantification software  incorporates 3DE speckle tracking technology. It provides LV volume curve during one cardiac cycle. Like HeartModel analysis, we adjusted ED and ES endocardial border threshold with each increase of threshold value from 0-point to 100-point via 10-point increment and obtained LVEDV and LVESV at each increment. Again, we did not perform manual editing. LVEF was calculated as the same process.In contrast to HeartModel that provides LVEDV and LVESV, the new software  with a phased-array cardiovascular coil. In each patient, retrospective electrocardiographically-gated localizing spin-echo sequences were used to identify the long axis of the heart. Steady state fully precession (SSFP) dynamic gradient-echo cine loops were acquired using retrospective electrocardiographic gating and parallel imaging techniques during 10-sec to 15-sec breath-holds, with a following general parameters: slice thickness of the imaging planes 8 mm, field of view 40×40 cm, scan matrix 200×160, flip angle 50°, repetition/echo times 3.8/1.7 ms, views per segment 20, number of reconstructed cardiac phases 20.CMR LV volumes were measured from multiple short-axis SSFP images using an analytical software , and the disk-area summation method was used for the calculation of the LVEDV and LVESV. LVEF was measured by standard formula.CMR images were analyzed using commercial FT software , which is a vector-based analysis tool based on a hierarchical algorithm –15. Usinth to 75th percentile according to data distribution. All statistical analyses were performed using commercially available software . Freedman analysis with post-hoc comparison was performed to compare LVEDV, LVESV, and LVEF among different border settings and CMR. Linear correlations and Bland-Altman analysis were performed between the two methods. Since Dynamic HeartModel and CMR FT provide LV volume curves, we determined the reliability of the curves from Dynamic HeartModel against that obtained from CMR FT. Data were extracted using plots digitalization (WebPlotDigitizer), and each curve was digitized and interpolated 100 points during one cardiac cycle. A linear correlation was performed using 100 plots between the two methods, and r-values from linear correlation analysis were calculated in each patient. We calculated coverage probability (CP) as the percentage of the number of measurements whose difference fulfilled pre-defined criteria. Regarding LVEDV and LVESV, the cut-off value was 30 mL between 3DE and CMR measurements [Continuous variables are expressed as mean ± SD or as median and 25urements –18. Regaurements –18.th to 75th percentile: 0.80 to 0.93) in 55 patients.This is the first systematic study to investigate optimal endocardial border threshold values for determination of LV volumes and LVEF using 3DE fully automated left chamber quantification software (Dynamic HeartModel) and its earlier version (HeartModel) against CMR as a reference. Our results showed that the bias between both Dynamic HeartModel and HeartModel determined LVEDV and LVEDV were smallest when the border threshold value was set to 80-point against CMR disk-area summation method, or 90-point when compared to CMR FT method. Dynamic HeartModel could improve measurement accuracy over previous version of the software because the former was yielded with higher values of CP with equivalent border setting.The importance of cardiac chamber size and function in cardiac imaging cannot be over-emphasized. The limitations of 2DE have been inexorably mentioned in previous studies, including foreshortening and geometric assumptions –21. The Fully automated left chamber quantification software with knowledge-based technology utilizes 3DE datasets with less technical demanding steps, and the time required to analyze 3DE LV volumes and LVEF is only less than 30 seconds without any manual editing , 7. TimeIn this study, feasibility of LV volumes and LVEF measurements was 88%, and the values were in agreement with the previous studies , 6. FullThe Dynamic HeartModel performs 3DE speckle tracking on the LV endocardial border in each frame over the entire cardiac cycle, resulting in the generation of LV volume curves. We determined its reliability against corresponding LV volume curves derived from CMR FT method. Median r -values by linear regression analysis from the whole subjects (r = 0.87) supported its accuracy and reliability.In summary, this is the first study to perform systematically the determination of optimal border threshold by fully automated left chamber quantification software for the quantification of LV volumes and LVEF compared to the standard CMR disk-area summation method and the novel CMR FT method. The fully automated quantification software with appropriate border threshold value setting has a potential for the evaluation of LV function with confidence.There were several limitations that should be acknowledged in this study. First, the software was not associated with 100% feasibility. In this study, there were 2 cases of incorrect LV casts that could not be edited, and other 6 patients were excluded due to very poor image quality rejected 3DE datasets acquisition, resulting in overall feasibility of 88%. The number however, was similar to previously performed feasibility studies . It may We concluded that LV endocardial border threshold value can be set around 80 to 90 with the same number of LV ED and ES threshold to approximate LVEDV, LVESV and LVEF with clinically acceptable CP values of LVEF as CMR values as a reference.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.


N = 85); the left atrial diameter (LAD) was positively and the left ventricular ejection fraction (LVEF) was negatively associated with AC in DCM patients (N = 65); age was negatively associated with DC in healthy controls (N = 85); and the LAD was negatively and the LVEF was positively associated with DC in DCM patients (N = 65). In females, only age was associated with either AC or DC in healthy controls (N = 117). Kaplan–Meier analysis revealed that male DCM patients with greater LADs (≥46.5 mm) , an elevated AC (≥-4.75 ms) , and a lower DC (≤4.72 ms)  were at higher risk of cardiac death within 60 months of follow-up. In conclusion, in males, DCM significantly affected both the AC and DC; a higher AC or a lower DC increased the risk of cardiac death.The effects of dilated cardiomyopathy (DCM) on cardiac autonomic regulation and electrophysiology, and the consequences of such changes, remain unclear. We evaluated the associations between heart rate acceleration capacity (AC) and deceleration capacity (DC), heart structural and functional changes, and cardiac death in 202 healthy controls and 100 DCM patients. The DC was lower and the AC was higher in DCM patients . Multivariable, linear, logistic regression analyses revealed that in males, age was positively associated with AC in healthy controls ( Dilated cardiomyopathy (DCM) is a progressive disease of the heart muscle characterized by the presence of left ventricular dilatation and systolic dysfunction . DCM is In clinical practice, some DCM patients had concomitant supraventricular arrhythmias or conduction disease; and such electric instability could not be explained reasonably by existing pathophysiological principles of DCM . The heaThe phase-rectified signal averaging (PRSA) technique detects and quantifies quasi-periodic oscillations that masked by non-periodic components, artifacts, and/or ectopic beats . Using tThe review board of the First Affiliated Hospital of Soochow University approved this study, which adhered to all principles of the revised Declaration of Helsinki. Written informed consent  was obtained from all patients as dictated by the guidelines of the Chinese National Ethics Regulation Committee. All participants and their immediate relatives, caregivers, or legal guardians were told that they could withdraw consent at any time.Dilated cardiomyopathy patients treated between January 2013 and June 2016 were enrolled. DCM was diagnosed when the ejection fraction was < 0.45 and/or a fractional shortening < 25% was apparent, combined with a left ventricular end-diastolic dimension (LVEDD) > 112% of the predicted value after correction for age and body surface area . ExclusiA total of 202 healthy controls who underwent physical examinations in our hospital served as normal controls . All controls were confirmed to not have DCM, atrial fibrillation, atrial flutter, pacemakers, sick sinus syndrome, an atrioventricular block, hypertension, coronary heart disease, even limited cardiomyopathy, pulmonary heart disease, myocarditis, valvular heart disease, congenital heart disease, any neuromuscular disease, any liver or kidney dysfunction, and diabetes.As we reported previously Figure  Zou et , a PRSA As previously described in detail , transthThe distributions of all variables were first assessed by drawing histograms; correlations between variables were then calculated using scatter plots and Pearson’s correlation coefficient analysis. All analyses were performed separately for either gender.t-test was used for comparisons within groups and the non-paired Student’s t-test for comparisons between groups; all tests were two-sided. Next, the associations between the AC/DC and echocardiographic indices and age were subjected to univariate linear logistic regression, and factors associated with P-values < 0.1 underwent further multivariable linear logistic regression. Pearson’s correlation revealed a close link between AC and DC, and we thus performed linear logistic regression using either AC or DC as a dependent variable. Third, we performed Kaplan–Meier analyses with log-rank testing to calculate survival rates over the 60 months of follow-up and to compare survival rates between groups. The LAD, DC, and AC cutoffs were selected by reference to the areas under the receiver operating characteristic (ROC) curves (AUCs). P-values < 0.05 were deemed to reflect statistical significance. All statistical analyses were performed with the aid of SPSS software version 17.0 .We used three progressive analysis strategies to evaluate associations between AC, DC, and DCM. First, we compared the AC, DC, and echocardiographic indices between DCM patients and healthy controls. The paired Student’s In males, the average AC, LAD, LVEDD, and LVESD were significantly higher in DCM patients than controls; conversely, the average DC and LVEF were significantly lower than in controls Table . In femaTo explore correlations between AC, DC, age, and echocardiographic parameters, we drew scatter plots and calculated Pearson’s correlation coefficients. AC was positively and DC was negatively associated with age in both male and female controls  associated with the LVEF  and LVEF associated with AC increased with a B value of -8.632  (Table P = 0.026); the association of LVEF with AC increased with a B value of -14.791 ; and the LAD was also positively associated with the AC with a B value of 0.107  ; a multivariable linear logistic regression analysis was thus not performed  and 7.063  respectively  and -0.058  respectively; and LVEF was associated with DC with a B value of 13.342   and 8.428 , respectively ; a multivariable linear logistic regression analysis was thus not performed , a higher AC , and/or a lower DC  were at higher risk of cardiac death , 0.359 , and 0.754 (0.637 ∼ 0.871), respectively Figure . The cutOur number of female patients was small and we could not identify any parameter predicting survival; we thus did not perform a Kaplan–Meier analysis of female DCM patients.Adult patients with DCM generally have a 1-year mortality rate of 25–30% and only 50% survive to 5 years . CurrentHeart rate is modulated by both the sympathetic and vagal nervous systems: the former accelerates and the latter decelerates the rate . PRSA caIt has been very difficult to identify and quantify the roles played by the vagal and sympathetic nervous systems in terms of cardiac electrophysiology, not only because effective methods are lacking, but also because both types of nerves are complex in structure, containing mixtures of neural types . Few stuOur results are consistent with a prior report focused on the associations between AC/DC and HF  at the fWe enrolled only 35 female DCM patients, and only 5 died during the 5 years of follow-up, so it was not possible to analyze female survival. This is a limitation of our report. Additionally, mutations in genes encoding cytoskeletal, sarcomere, and nuclear envelope proteins are known to account for up to 35% of all DCM cases ; mutatioCZ and XY conceived and designed the work. YY, FW, HD, XH, BZ, and XL performed the experiments, and acquired, analyzed, and interpreted the data for the work. CZ and XY drafted the work and revised it critically for important intellectual content. YY, FW, CZ, HD, XH, BZ, XL, and XY approved the final version of the manuscript to be published.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


BACKGROUND: Chemokines are critical mediators in controlling and monitoring the healing and ventricular remodeling after myocardial infarction (MI). They proved to be valuable targets for therapeutic measures to reduce the scar formation and to preserve heart function in patients suffering MI. In the present study, the role of CCR3 in myocardial ischemia/reperfusion was established.
METHODS AND RESULTS: One week after infarct induction in a mouse coronary ligation model, the functional and morphological parameters of the heart were analyzed. Isolated-heart Langendorff perfusion showed no significantly differences in heart function, infarction size and post infarction angiogenesis after CCR3 blockade. Apoptotic, proliferation signals as well as collagen synthesis were not affected in CCR3 antagonist treated mice. Notably, CCR3 inhibition was accompanied by massive neutrophil infiltration, while leaving the presence of other immune cell subsets in heart unaffected.
CONCLUSION: Since neutrophils represents one of the most widely explored therapeutic targets in the treatment of cardiac disease, this study may open a new perspective for a better understanding of the physiology and homeostasis of neutrophils and points out new directions for intervention in acute MI. In this regards, the efforts of scientific community are focused on finding new therapeutic strategies based on a better understanding of the molecular and cellular events.Despite extensive research in the last decades, myocardial infarction (MI) still remains the first cause of death in developed countries. The acute blockage of a coronary artery leads to a complex inflammatory response, to the cellular debris, as well as to start healing processes and restore the functional integrity of the heart as soon as possible2-4, but also as potential and valuable pharmacological targets5. CC chemokines are mostly involved in the recruitment of monocytes and macrophages, while CXC family of chemokines have essential roles in neutrophil, B- and T-cell recruitment6. During healing after myocardial infarction, neutrophils were seen to be recruited mainly through CCR17 and CXCR48 and to a lesser extent through CXCR29,10. Inflammatory monocytes are responsive to CCR211 ligands but not to CCR1 and CCR512-14 while later on the inflammatory cascade non-classical monocytes will be recruited via CX3CR112. T cells were reported to exert their regulatory functions and reduce adverse remodeling of the infarcted heart via CCR515. Post infarct neoangiogenesis, which supports the scar formation, depends on the recruitment of endogenous endothelial progenitor cells to ischemic myocardium by CCR3- and CXCR4-mediated interactions16.Chemokines are critical mediators in controlling and monitoring all these events and therefore, they have been established not only as predictors of heart injury17, which all are relevant to MI, and as it bind a wide range of ligands, such as CCL5, CCL2, CCL7, CCL11, CCL13, CCL15, CCL24 or CCL2618, its contribution to post-MI inflammation has not yet been addressed. In this study, we have dissected CCR3’s role in healing after MI, using a pharmacological CCR3-antagonist in a mouse model of myocardial ischemia/reperfusion.Although CCR3 is expressed by variety of immune cells, such as eosinophils, basophils, mast cells, lymphocytes or monocytes and macrophages19. Briefly, mice were intubated under general anesthesia and positive pressure ventilation was maintained using a mouse ventilator. Hearts were exposed by left thoracotomy and MI was produced by suture occlusion of the left anterior descending artery (LAD) over a silicon tube. The ligature was removed after 30 min to permit reperfusion. The ribs, muscle layer and skin incision were closed, and morphine  was administrated until full recovery. The mice were treated orally with a CCR3 antagonist  or vehicle, one day before MI and 3 times per week. All animal experiments and study protocols were approved by local authorities, complying with German animal protection laws .).Eight weeks-old male C57Bl/6J mice underwent coronary occlusion and reperfusion as describedSeven days after MI, heart function was analyzed using a Langendorff apparatus with Isoheart software (Hugo Sachs Elektronik-Harvard Apparatus) under constant perfusion pressure and electrical stimulation (600/min constant heart rate). Coronary flow, left ventricular developed pressure (LVDP), increase (dP/dtmax) and decrease (dP/dtmin) in LV pressure were measured without and with dobutamine. Finally, hearts were embedded in paraffin and cut into 5 mm serial slices.8,19. The infarcted area was determined in all ten sections and expressed as percentage of total LV area, using Diskus software (Hilgers). Cell content was also analyzed in serial section of hearts after MI. Sections  were stained for neutrophils , macrophages , lymphocytes , vessels , and Collagen (Gomori’s 1-step trichrome stain). Cells were numbered in six different fields inside the infarcted area in each section and expressed as cells/mm² using DISKUS . Apoptotic cell  or proliferation  indexes were expressed as percentage of positive cells from total nuclei (DAPI).Ten serial sections per mouse  were stained using Gomori’s 1-step trichrome stain, as previously describedStatistical analysis was performed with Prism5 software (GraphPad Prism) using Student t test. P-values of <0.05 were considered significantTable 1. Moreover, we were unable to detect any significant differences in the degree of neo-angiogenesis, as well as in coronary flow compared with control group (Table 1).One week after ischemia/reperfusion induction in mock or CCR3 antagonists (GW-766994) treated mice, the functional parameters of the heart were recorded using isolated Langendorff heart perfusion. Interestingly, GW-766994 treatment did not affect or improve significantly the heart function or the infarction size, as shown in Figure 1 [A]). Since apoptotic signals were not amplified , this suggests that neutrophils are retained within the infarcted areas unable to migrate or to die. Other immune subsets, such as monocytes/macrophages  and lymphocytes  were not affected by the GW-766994 treatment. The proliferation  and the collagen deposition (Table 1) inside the infarcted area remain comparable between the groups.Notably, one week after MI, we observed massive neutrophil infiltration in the GW-766994 treated group, while isolated neutrophils were barely observed in control mice at this time point (In this study, we were able to demonstrate that the neutrophils trafficking into the infarcted area was significantly affected by the anti-CCR3 treatment, while morphological and functional parameters of the heart after MI were not changed. These findings are not only novel, but also very surprising, since the negative remodeling after MI was always connected with the neutrophil infiltration. Neutrophils are the first cells to be recruited to the infarction site, releasing inflammatory mediators, proteolytic enzymes and reactive oxygen species, which directly injure the surrounding living cells.10 which suggest that in some cases, impairing the neutrophil recruitment do not have any influence on later healing and repairing processes after MI. A specific and selective therapeutic intervention by blocking only IL-1 pro-inflammatory signals was also proposed as a more valuable and feasible alternative20.Neutrophil depletion in animal models led to a marked decrease in infarct size and therefore, impairing the neutrophil infiltration into the infarcted area represents one of the most discussed therapeutic strategies inside the cardiology community. However, the present study confirms other previous data21. In our model, the neutrophils are trapped inside the infarcted area and are unable to activate the apoptotic pathways, which demonstrates the crucial role of CCR3 in the fate of neutrophils during the healing after MI. Although this finding is interesting and surprising, further investigations are necessary to elucidate the entire mechanisms and connections until we will be able to adjust the current therapeutic strategies for the benefit of patients.On the other hand, the fast disappearance of the neutrophils from the infarcted area was always attributed to their programmed death. However, the triggers and the mechanisms of these processes are far from being understood. Mice lacking CCR3 showed defective eosinophil and mast cells trafficking, accumulating into lung parenchyma, being unable to migrate outside the subendothelial space16. We did not find any significant differences between the groups in the angiogenesis and coronary flow after MI, probably due to the sufficient compensatory mechanisms22.The last surprising finding of our study is the lack of effect on angiogenesis after MI. There are reports demonstrating the role of CCR3 in the recruitment of CD34 positive progenitor cells from bone marrow to ischemic, but not to normal myocardiumIn conclusion, despite the lack of effects on heart function of the CCR3’s pharmacological blockade, this study opens a new perspective in better understanding the physiology and homeostasis of neutrophils, which have the crucial role in initiation and progression of the healing and scar formation after MI. Only knowing their precise role, fate and the interaction with all other involved players, we will be able to propose and develop new therapeutic strategies to reduce the complications after MI and to increase the life quality of the patients.


Even in the era of percutaneous reperfusion therapy, left ventricular (LV) remodeling after myocardial infarction (MI) leading to heart failure remains a major health concern. Contractile dysfunction of the infarcted myocardium results in an increased pressure load, leading to maladaptive reshaping of the LV. Several percutaneous transcatheter procedures have been developed to deliver devices that restore LV shape and function. The purposes of this review are to discuss the spectrum of transcatheter devices that are available or in development for attenuation of adverse LV remodeling and to critically examine the available evidence for improvement of functional status and cardiovascular outcomes. Despite continuous improvements in acute and long-term treatment of myocardial infarction (MI) over recent decades, the resulting myocardial injury remains an important cause of adverse left ventricular (LV) remodeling, which over time progresses into the clinical syndrome of heart failure . TypicalIn the early stages after MI, influx of inflammatory cells leads to the destruction of collagen and regional thinning of the infarcted area . The heaSigns of LV remodeling can already be seen in the early stages after MI, within hours to days . ContempShort-term effects of drugs and devices on (reverse) LV remodeling are associated with reduced longer-term mortality rates . ConsequN = 1000), CABG and surgical ventricular reconstruction reduced LV end-systolic volume by 19%, compared with 6% by CABG alone, but had no significant effect on mortality, hospitalization for cardiac events, and 6-min walk test (6MWT) distance [The first surgical attempt at LV restoration was the aneurysmectomy with a linear suture, first described by Cooley et al. in 1958  and devedistance . A possip = 0.05), but no significant change in peak oxygen consumption or cardiac index [N = 300), the implanted device named the CorCap™  had no significant effect on 3- and 5-year mortality but did significantly reduce LV end-diastolic volume (LVEDV) up to 5 years after implantation, consistent across strata with and without mitral valve replacement [Several surgical LV restoration techniques have been investigated in patients with dilated cardiomyopathy, including not only ischemic but also idiopathic etiologies. In 1985, the first successful dynamic cardiomyoplasty procedure was performed, which was the surgical wrapping of an autologous latissimus dorsi muscle around the heart, which was activated by an external cardiomyostimulator for 10 weeks to gradually transform muscle fibers from type II to type I . A prospac index . The carlacement –34. It hN = 11) demonstrate a stable reduction in LV volumes up to 12 months [As an alternative to the invasive surgical ventricular reconstruction method, a minimally invasive surgical technique was designed to exclude the nonviable part of the LV in patients with LV dilatation and anteroseptal scarring. The Revivent™ myocardial anchoring system , previously named the PliCath HF™, is composed of polyester-covered titanium anchors (5 × 25 mm) mounted on a polyethylene-ether-ether-ketone tether, which are placed on the right side of the interventricular septum and on the LV wall. The anchors are drawn together to allow apposition of the LV free wall to the septum, thereby excluding the nonviable anteroseptal scar. Initial results in humans  system, also receiving CE marking. The upgraded system is not completely transcatheter-based, still requiring a less invasive left thoracotomy. From outside the LV, a needle is used to puncture the LV wall, cross the LV, and puncture the interventricular septum. The needle position is monitored using fluoroscopy, and a Swan-Ganz catheter is introduced in the right jugular vein to monitor ventricular pressures. After reaching the right ventricle, the needle is replaced with a sheath and a guidewire. The guidewire is captured in the right ventricle by a snare from the Swan-Ganz catheter and connected with the internal anchor. The external anchor is placed from outside the LV wall. If necessary, additional pairs of anchors (2–3) are placed to achieve the desired line of apposition. Injection of contrast in the LV is used to confirm whether successful exclusion of the nonviable LV segment has been achieved. The Revivent-TC system has been successfully implanted in six sheep, successfully reducing LVESV, improving LVEF, and improving strain in border and infarct regions . Study rThe umbrella-like Parachute® device  is intended to partition off the akinetic or aneurysmatic portion of the LV in patients with ischemic heart failure. The device is comprised of a fluoropolymer (ePTFE) membrane stretched over a self-expanding nitinol frame, ranging between 65 and 95 mm in diameter when expanded. It is deployed into the LV apex and stabilized by 2-mm anchors at the end of each strut of the umbrella. The device provides efficacy by regional unloading of the akinetic LV region and global reduction of wall stress by reducing LV dimensions. Before implantation, LV anatomy has to be evaluated carefully, preferably by computed tomography imaging (CT), because anatomical characteristics such as prominent trabeculation or a “LV moderator band” are unsuitable for device implantation. The Parachute device has received CE marking for commercial use in Europe but is only approved for investigational use in the USA.N = 39), which took place in Europe and the USA simultaneously, demonstrated safety and feasibility of the Parachute device in heart failure patients with LVEF between 15 and 40% and a dilated LV with an akinetic or dyskinetic anterior-apical wall [p < 0.01). During 12-month follow-up, cardiac mortality was 8.4%, device-related major adverse cardiac cerebral events (MACCE) occurred in 7.0%, heart failure hospitalizations in 24.1%, and stroke in 3% of subjects. Even though patients were given low-dose aspirin and warfarin for at least 12 months post device implant, the echo core lab identified thrombus on the device in 3.3% of the subjects at 12 months. The PARACHUTE IV was the first randomized controlled trial, aiming to include 478 patients with NYHA class III–IV, LVEF between 15 and 35%, LV motion abnormalities, and LV anatomy appropriate for Parachute implantation assessed by CT imaging and randomize to optimal medical therapy or Parachute implantation [clinicaltrials.gov≠NCT01614652) and it is unclear whether investigation of the device will be continued.The device has been investigated in several PARACHUTE trials Table . The PARcal wall . There wantation . The priE/E′), and this reduction was correlated with improvement in NYHA functional class [N = 3) and at autopsy after deaths that were not device related (N = 4) [N = 2) showed evidence of microscopic calcification, which could in theory lead to fatigue and rupture of the membrane on the long term.In addition to the primary study results, there have been some interesting post hoc analyses. Hemodynamic assessment after Parachute implantation demonstrated an acute increase in stroke volume and mean aortic pressure . A CT stal class . Anotheral class . A patho (N = 4) . The devThe aforementioned study findings suggest that the Parachute device could be beneficial by reducing cardiac dimensions and end-diastolic wall stress and improving cardiac output. However, 3-year results demonstrate a reduction of LVEF and stroke volume. Results from the PARACHUTE IV trial will have to demonstrate the added benefit of the Parachute device in addition to optimal medical therapy. It is unclear whether the investigation and development of the device will be continued.Several surgical LV techniques have been attempted to treat ischemic FMR before the use of a transcatheter delivery route. The Coapsys™  device was designed to treat annular dilatation and papillary muscle displacement in patients with FMR by connecting an anterior and posterior epicardial pad with a subvalvular chord through the LV cavity and subsequently reducing the anteroposterior diameter by bearing load during the diastolic phase. The RESTOR-MV randomized controlled study was initiated, including patients referred for CABG with the presence of FMR . ParticiA transcatheter variant of the Coapsys, the iCoapsys™ repair system, was designed for the same patient category with ischemic FMR. The device consisted of the same elements as the original Coapsys  but was implanted using transcatheter delivery. It was successfully implanted in 12 adult sheep, with no complications reported . Prior t3 System™ has a bridge element inside the LV cavity, but instead of being attached on the epicardium, its anchors are placed on the right side of the atrial septum and in the great cardiac vein. It has been investigated in an ovine tachycardia model (N = 19), successfully improving cardiac output and reducing FMR grade and septolateral diameter [Similar to the iCoapsys repair system, the percutaneous septal sinus shortening system or PSdiameter . First-idiameter .Transcatheter interventions targeting the mitral apparatus such as percutaneous edge-to-edge mitral valve repair, percutaneous annuloplasty, and percutaneous mitral valve replacement are being reviewed elsewhere in this issue. A retrospective analysis of percutaneous edge-to-edge repair with the MitraClip  in 106 patients with ischemic FMR showed a significant reduction of left atrial volume at 1 year after implantation but no effect on LV volumes . In the A transcatheter mitral annuloplasty by implantation of a device in the coronary sinus (transvenous annuloplasty) has the advantage that no atrial septum puncture is required to gain access to the left heart. However, the coronary sinus is anatomically at a distance from the mitral annulus, and in some cases, the great cardiac vein passes over a coronary artery, which can be compressed or occluded by the device. The Monarc (previously Viking) system  uses an implant with two self-expanding anchors and a spring-like “bridge,” which was investigated in 72 patients of which 57% had a prior MI . It was The AccuCinch  transcatheter direct mitral valve annuloplasty (or ventriculoplasty) system is designed to place anchors in the subannular space . CinchinLV reconstruction techniques are intended to  revert the changes to LV mechanical properties caused by myocardial injury. Ideally, this should be done during the early stages after MI, when scar formation, regional thinning of the myocardium, and LV dilatation can still be prevented. Most of the aforementioned studies, however, exclude patients within 90 days after MI. The reasoning behind this is that adverse LV remodeling can largely be reversed due to myocardial hibernation. Early assessment of myocardial viability by late enhancement CMR could be used to assess the risk of progressive LV remodeling and the need for an early intervention  Fig. 1)1).Fig. 1As stated earlier, MI induces degradation of extracellular matrix, which reduces elasticity of the myocardium. A proposed option to restore the mechanical properties of the myocardium is by injecting biomaterials into the myocardium, which could serve as an artificial extracellular matrix. Biomaterial scaffolds incorporating stem cells were not included in this review, because we considered cellular products to be a different category. Several types of biomaterial injections have been tested in animal studies. The effect of calcium hydroxyapatite microsphere (CHAM) injections in infarcted myocardium was investigated in 31 sheep and appeared to limit LV dilatation and improve LVEF up to 4 weeks after ligation of the left anterior descending coronary artery . A folloAnother widely investigated biomaterial is injectable myocardial matrix hydrogel, which is produced by decellularizing porcine myocardial tissue and processing it to form a myocardial matrix with the ability to gel upon injection. Myocardial matrix hydrogel injections have been investigated in 58 rats undergoing ischemia reperfusion followed by injection of either the hydrogel or saline 2 weeks later . The hydA less frequently investigated type of hydrogel that has been investigated in animal studies post-MI is injectable hyaluronic acid-based hydrogel, which appears to reduce myofiber stress and limit adverse LV remodeling , 67.As a less invasive alternative to intramyocardial injections, biomaterials can also be administered by intracoronary infusion. In 27 post-MI patients, the intracoronary administration of 2 ml of 1% sodium alginate plus 0.3% calcium gluconate within 7 days after MI was feasible and tolerated well . The infStudy endpoints of clinical trials investigating the effect of LV restoration or enhancing devices should be carefully considered. Because LV dimensions are artificially altered, they should be seen as independent variables. Parameters of LV remodeling such as LVESVi and LVEDVi have to be used to assess the efficacy of the procedure and should not be interpreted as a proxy variable for patient outcome. Preferable outcome measures to be considered for large pivotal trials are (cardiovascular) mortality, major adverse cardio- and cerebrovascular events, and (non-)heart failure hospitalizations . Other  were entered into force . The newPatient selection could be very important in determining which patients could have clinical benefit from implantation of a LV restoration device. As the potential benefit of LV restoration at early stages after MI is theoretically larger, early assessment of myocardial viability after MI could be a tool for risk stratification and determining the need for an early intervention. In patients with heart failure, an elementary requirement to be considered for device implantation is that medical therapy has been optimized according to heart failure guidelines, as this has been proven to promote reverse LV remodeling. A potential predictor of poor outcome could be pre-existing diastolic dysfunction, as using a device to artificially reduce the LV volume might further increase LV myocardial stiffness. The lack of consensus on the definition of diastolic dysfunction makes investigating this very challenging. A post hoc analysis of the association between pre-existing diastolic dysfunction and survival in earlier randomized controlled trials on surgical LV restoration could provide more insight.Improvements in safety and efficacy of mechanical circulatory support devices such as left ventricular assist devices (LVAD) might reduce the need for LV restoration devices in the future. The 6-month results of the HeartMate 3 Left Ventricular Assist System  demonstrate a survival free of any nonsurgical bleeding, thromboembolic event, pump thrombosis, or neurological event in 69% of patients . ProgresBoth surgical and transcatheter LV restoration techniques consistently demonstrate improvements in quality-of-life measures and functional status but currently fail to demonstrate a clear survival benefit. Study designs for surgical LV restoration techniques are limited to patients that are already planned for surgery with thoracotomy, such as CABG. The noninvasive nature of transcatheter procedures allows for easier patient selection and identification of independent device-related effects. Selection of suitable study endpoints and the use of a sham control procedure is essential in clinical trial design. Transcatheter LV restoration devices show promising results in both animal and in-human studies at different stages of adverse LV remodeling after MI. The Parachute device could be beneficial in heart failure patients with a recent anterior MI, poor systolic function, and a suitable LV anatomy by reducing cardiac dimensions and end-diastolic wall stress. The PARACHUTE IV randomized controlled trial will have to demonstrate additional benefit on top of optimal medical therapy, but it is uncertain whether investigation of the device will be continued. Most of the benefit of LV restoration devices is theoretically gained at early stages after MI, using devices that can alter LV mechanical properties, such as transcatheter injection of biomaterials in the infarcted region. This will require proper selection of patients at risk of adverse LV remodeling. In the near future, it will prove to be challenging for small medical device manufacturers to comply with requirements of the 2017 European medical device regulations.