High‐quality healthcare is essential to ensuring maternal and newborn survival. Efficient measurement requires knowing how long measures of quality provide consistent insight for intended uses.We used a repeated health facility assessment in Senegal to calculate structural and process quality of antenatal care (ANC), delivery and child health services in facilities assessed 2 years apart. We tested agreement of quality measures within facilities and regions. We estimated how much input‐adjusted and process quality‐adjusted coverage measures changed for each service when calculated using quality measurements from the same facilities measured 2 years apart.Over 6 waves of continuous surveys, 628 paired assessments were completed. Changes at the facility level were substantial and often positive, but inconsistent. Structural quality measures were moderately correlated (0.40–0.69) within facilities over time, more so in hospitals; correlation was <0.20 for process measures based on direct observation of ANC and child visits. Most measures were more strongly correlated once averaged to regions; process quality of child services was not (−0.32). Median relative difference in national‐adjusted coverage estimates was 6.0%; differences in subnational estimates were largest for process quality of child services (19.6%).Continuous measures of structural quality demonstrated consistency at regional levels and in higher level facilities over 2 years; results for process measures were mixed. Direct observation of child visits provided inconsistent measures over time. For other measures, linking population data with health facility assessments from up to 2 years prior is likely to introduce modest measurement error in adjusted coverage estimates. The premise of universal health coverage (UHC), enshrined in the Sustainable Development Goals and adopted as national policy by many countries, is essential health service delivery with financial protection. Health systems must be high quality for service coverage to yield better population health outcomes , 2. GiveHealth facility assessments are infrequent but typically detailed surveys of service availability, readiness and quality of care that can provide unique value beyond more frequent methods such as routine health information systems . In low‐Measurement stability may vary by type of quality measure. Health facility assessments typically produce measures of structure, or inputs to care, and those with clinical observations also generate measures of processes of care , 22. WhiPlan National de Développement Sanitaire et Social (PNDSS) 2019–2028 [The state of health system measurement in Senegal provides a unique opportunity to assess stability of quality measures. A health facility assessment has been conducted annually in Senegal since late 2012, capturing standardised information on a representative sample of the entire health system. At the same time, the government of Senegal has embedded the steps towards UHC in the 019–2028 , 28 and 019–2028 . Materna019–2028 .The aims of this analysis are to define structural and process measures relevant to quality of care for maternal and child health across the continuous SPA surveys, to assess stability of such measures at the facility and sub‐national levels based on assessments conducted 2 years apart and to quantify the effect of any instability on effective coverage measures.We used data from the Service Provision Assessment (SPA), a standardised cross‐sectional survey designed to measure health service availability, readiness and quality . The SPAWe used the household surveys conducted annually by ANSD and the DHS Program from 2015 to 2019 to define the populations in need and utilisation of care as part of the calculations of quality‐adjusted coverage .Health services in Senegal are organised within the 14 regions and are offered by hospitals, health centres, health posts staffed by 2 salaried providers and health huts staffed by volunteer community health workers . For thePatients were selected for observation using systematic random sampling from a list of those presenting for services on the day of the visit. Survey data include sampling weights for each facility, provider and client visit.The DHS household surveys used multistage sampling, first selecting census districts by probability proportional to size and then households with systematic random sampling. Women 15 to 49 years old were approached and interviewed . These sWe included SPA data from the facility audit of service availability and readiness, from provider interviews, and from direct observations of curative consultations for children under 5 years  as well as of antenatal care (ANC) visits . We extracted covariates to characterise the sample and consider continuity of providers within facilities over time: location, facility tier, ownership type, number and tenure of staff providing care for the maternal and child health (MCH) services of interest – ANC, delivery and/or curative care for sick children – and number of observations conducted during the assessment. Provider interview data were weighed using within‐facility sampling weights in summarising to facilities.We analysed measures of structural and process quality for maternal and child health services. For structural quality, we defined service readiness scores based on the WHO Service Availability and Readiness Assessment  for geneFor process quality, we defined adherence to global guidelines: the 2016 WHO‐focused ANC model  and the To assess stability at the subnational level, we used the 4 major regions defined by the DHS survey . We averaged scores based on all facilities or all direct observations of care in each of the major regions within the analytic sample of paired assessments of the same facilities, yielding 4 sets of regional measures . Observations were weighted based on the facility or client weight when averaging.To test the impact of instability in quality measures on effective coverage, we considered 2 steps of the effective coverage cascade: input‐adjusted coverage  based on structural quality measures and quality‐adjusted coverage  based oWe calculated adjusted coverage as the product of contact coverage and quality. We defined the reference period for health facility assessments as 1 year prior for maternal health (women interviewed in 2018 regarding pregnancies in the past 2 years would be matched to the 2017 SPA data) and in the same year for child health. We calculated adjusted coverage nationally and within major region, accounting for type of facility and incorporating stratified sampling and survey weights  following established procedures , 38. AdjIn this analysis, we (1) describe the analytic sample of paired assessments to explain the basis of analysis and how it differs from a full SPA and (2) assess stability over 2 years for facilities, regions and in adjusted coverage estimation. We used descriptive statistics to summarise the pooled sample of hospitals, health centres and health posts assessed between 2012/2013 and 2018. We compared facilities included in the repeated assessment to those excluded using descriptive statistics and, for continuous characteristics, ANOVA tests incorporating clustering due to repeated inclusion of facilities assessed three times. This comparison is unweighted; pooled data and the analytic sample of repeated facilities are not representative of a predefined target population.To define stability of quality measures for description and benchmarking, we assessed continuous quality measures. We quantified the magnitude of change in quality measures as the absolute value of the difference between time points for each facility; to capture overall (net) difference, we averaged observed difference by facility tier and by region. We calculated Pearson correlation coefficients for quality scores for facilities and regions at measured 2 years apart  [To quantify the stability of quality measures used to identify relatively better or worse performing facilities, we calculated percent agreement and Cohen's kappa for categorical measures.To assess the impact of instability in quality measures on adjusted coverage of health services, we calculated differences for each adjusted coverage metric  to 0.18  on average, with some facilities changing as much as ±0.50 out of 1.0 Figure . Net chaStructural quality measures were weakly to moderately correlated over 2 years, more strongly so in higher level facilities and particularly for general readiness and readiness for child care services Figure . Across Process quality measures showed weak or negligible correlation across health facility types except for performance of signal functions in hospitals Figure .Across all measures, categorical classification showed over 50% agreement only for general and child service readiness and signal functions Table . Kappa sResults were robust for all measures when using sampling weights from the second wave Table .Averaging across facilities with unstable quality measures resulted in relatively small net change in quality measures at the regional level, with the largest differences for adherence to guidelines in sick child care Figure . AdherenAdjusted coverage could be compared for 28 estimates at the national level . Eighty‐three of the possible 112 regional estimates had ≥1 facility per type and could be included for analysis. Adjusted coverage estimates can be conceptualised as weighted averages of facility quality based on the proportion of those in need choosing that facility type. Health posts were the most commonly used facilities across all services, capturing 71% of ANC 1 users, 66% of ANC 4 users, 56% of deliveries and 80% of sick child visits across the years of DHS surveys. A data file of all adjusted coverage estimates is available as Supplemental Material.Figure We used the continuous health facility assessments in Senegal to test the stability of quality measures over 2 years for use at the facility level, regional level and in adjusted coverage calculations. We found substantial change in measures of quality of care over 2 years within overall positive trends. Facility measures of structural quality and on performance of BEmONC signal functions were moderately stable as continuous scores, particularly among hospitals. Direct observation of primary care did not provide stable information on level or classification of facility quality. Regional quality measures were at least moderately stable for structural quality and direct observation of ANC. Instability in quality estimates resulted in a median relative difference of ±6% across national adjusted coverage estimates and as much as 20% for regional estimates of adjusted coverage based on direct observation of child services. Careful consideration is required of the types of measure, facility and summary method in using health facility assessment information more than a year after data collection, with generally greater stability in structural measures and in aggregate measures pooling across multiple facilities.Facility‐level findings suggest a hierarchy of measures in terms of consistency: general and child service readiness were at least moderately consistent in all facility types as continuous measures for description/benchmarking; ANC service readiness, basic obstetric service readiness and reported performance of obstetric signal functions were moderately consistent only in hospitals; adherence to guidelines in ANC and sick child care were not consistent at any level of facility. Kappa statistics were low for all measures: classification can exacerbate error in underlying measures  and may For most measures, facility instability averaged out within regions, resulting in strong or moderate correlation of regional measures over time. The exceptions were obstetric signal functions and direct observation of sick child care, which was negatively correlated despite being based on similar numbers of providers and patient visits as for ANC. Prior research has also found unexplained variation in direct observation of child visits ; these fThe assessment of adjusted coverage in this work provides an empirical estimate for the expected measurement error when using an older health facility assessment to link with population data in settings like Senegal. . We fouAspects of this study design should be considered in extrapolating the findings. This study was conducted on the subset of facilities that could be linked over a 2‐year period in Senegal from 2012/2013 to 2018, which included most hospitals and health centres included in the SPA and a subset of health posts . The findings should be generalisable to facilities of these types within Senegal and potentially in similar health systems, particularly within health facility tier and for higher level facilities better represented in this study. Findings on adjusted coverage are limited to the particulars of these data: simulation studies would be needed to further detail expected differences for a range of sample sizes and levels of stability. Due to the nature of the resampling, we are not able to assess stability of measures over a shorter duration or to consider all facilities over 3 or more surveys. Application of these findings to other settings or times must also consider potential external changes to health services, whether a policy reform or a systemic shock such as the Covid‐19 pandemic, that may produce much greater change than observed here.Health facility assessments conducted in Senegal have yielded a range of important insights into the health system and the quality of maternal and child health services , 46, 47.Dr. Leslie discloses research funding from ICF International, the World Bank, the World Health Organization and the US National Institutes of Health unrelated to the conduct of this research. Dr. Nimako reports being a consultant for the Bill & Melinda Gates Foundation during the conduct of the study. The authors declare no conflicts of interest.Supplementary MaterialClick here for additional data file.Supplementary MaterialClick here for additional data file.AppendixClick here for additional data file.


These differences were primarily driven by a significantly greater mean severity of hip/groin, and foot/toe injuries on artificial surfaces. This is the largest study to date to examine the relationship between surface type and injury risk in rugby union. The average severity and burden of injuries sustained on artificial surfaces was significantly greater compared with those sustained on hybrid/natural grass surfaces. This study can inform those involved in selection of surface for elite sport, weighing up the positive and negative elements of the varying surface types.The use of artificial playing surfaces in professional rugby union is growing, but their effect on the injury risk profile remains unclear. The aim of this study was to examine the effect of playing surface on match injury risk in men's professional rugby in England. Six seasons of injury data (2013/14–2018/19) were collected from 15 professional English, men's rugby teams participating in domestic and European competition. The incidence, severity, and burden of match injuries were compared across playing surfaces. The dataset included 3351 injuries from a combined European and domestic data set  and 2675 injuries from a domestic only dataset . There were no differences in incidence rates between surface types on combined European and domestic match data, but injury burden was significantly greater on artificial  in comparison with natural/hybrid surfaces (2364 days/1000 h, 95% CI 2277–2454,  Hybrid playing surfaces are made of predominantly natural grass but also contain synthetic material in various forms to aid in the stability and longevity of the surface. Playing surfaces containing artificial fibers have a number of benefits over natural grass surfaces, including being easier to maintain, having greater use‐tolerance, and being more resistant to broader weather changes.Rugby is a field‐based, invasion, team sport.22.1Participants were recruited as part of the ongoing Professional Rugby Injury Surveillance Project (PRISP). Clubs involved in this project were required to collect injury data as part of the competition minimum requirements. Match exposure data for this analysis were gathered from the 12 Premiership teams each season from the 2013/14 season, when the first artificial grass playing surface was introduced in elite level English men's rugby, up to and including the 2018/19 season. Across these six seasons, a total of 1053.5 eligible matches  were used to calculate exposure with 15 teams providing data due to promotion and relegation of clubs during this period.All consenting players who were members of their club's first team squad were eligible for inclusion. Players were individually consented at the start of every season regardless of whether they had consented in previous seasons. This secondary analysis was approved by the University of Bath's Research Ethics Approval Committee for Health (REACH) (EP 19.20038). Data collection for PRISP also has REACH approval (EP 16.17200). This study's methods and reporting are consistent with the Strengthening the Reporting of Observational Studies in Epidemiology ‐ Sports Injury and Illness Surveillance (STROBE‐SIIS).Analysis of combined domestic league (Premiership) and European match play data was carried out to compare injuries on artificial surfaces with injuries on natural/hybrid surfaces. Natural/hybrid was combined into one category as reliable information on whether surfaces are natural or hybrid for some teams outside the English Premiership was not always available. Only data from English teams competing in European cup competition were included in this analysis. Further analysis was carried out in a subset of domestic league (English Premiership) only data, with comparison between three categories of surface . This was deemed appropriate due to the more assured knowledge of playing surface for these venues.2.22.2.1For the purposes of this study, injury was defined as “an injury which results in at least 24 h of time loss from midnight on the night that the injury occurs,” and definitions align with the international rugby consensus statement for epidemiological studies.2.2.2Injury incidence rate was calculated as the number of injuries per 1000 player‐match‐hours. Mean severity was calculated as the total sum of days absence divided by the total number of injuries, while median severity was calculated as the midpoint of the range of injury severities within data being analyzed. Both the mean and median severity and burden were calculated to account for the potential skew in mean severity caused by a small number of long‐term injuries. Injury burden was calculated as the product of mean severity and incidence rate to give the number of days absence per 1000 player‐match hours. Burden was also calculated as the product of median severity and incidence rate and served as a sensitivity check of significant differences in mean injury burden; that is, whether such differences had been skewed by a small number of severe injury cases. Burden values that were significantly different using both mean and median severity values were considered significant. All estimates are presented with 95% Poisson confidence intervals. Significant differences were assumed if the 95% confidence intervals (CI) for the variables did not overlap and further confirmed with the use of Bonferroni‐corrected two‐tailed z‐tests. Analyses of the data in this manuscript were carried out in Microsoft Windows Excel for Windows 10 and R .33.1p = 0.09) . Injury burden was significantly greater on artificial surfaces than natural/hybrid .In the combined domestic league and European competition data, there were a total of 3351 injuries  in 42 140 h of exposure  across six seasons. Incidence rates were not significantly different on each surface  but not hybrid surfaces . Injury burden was significantly greater on artificial  compared with both hybrid  and natural surfaces . Severity category data for the domestic only data set is in Table For the domestic league‐only data, 2675 injuries were recorded during the 6 seasons  in 32 400 h of exposure . No significant differences in injury incidence rates between surfaces were observed . The mean severity of injuries on artificial surfaces  was significantly greater than on natural surfaces  (Table p = 0.002), foot/toe , and neck/cervical spine . Mean burden was significantly greater on artificial surfaces for posterior thigh , hip/groin , and foot/toe  injuries. Lower leg/achilles tendon injuries had a greater burden on natural/hybrid . There was no significant difference between artificial surface concussion incidence  and natural/hybrid surfaces . Details on all injury type data are contained in Table When analyzing the combined domestic/European dataset, incidence rates for each body location were similar on different surfaces except for lower leg/achilles tendon, which had a significantly greater incidence on natural/hybrid surfaces , and hybrid surfaces . For hip/groin, injury burden on artificial surfaces  was significantly greater than on both hybrid  and natural grass surfaces . For foot/toe, injury burden on artificial surfaces  was significantly greater than on both hybrid  and natural grass surfaces . For upper arm, injury burden was greater on artificial surfaces  than on hybrid  but not natural grass surfaces .Injury burden on artificial surfaces was also greater for some specific locations when separated in to three surfaces in the sub‐analysis. For posterior thigh, injury burden on artificial surfaces  was significantly greater than natural . Dislocation/subluxation injuries had significantly greater burden on artificial and natural grass surfaces in comparison to hybrid surfaces, but not when compared with each other .3.5There were no differences between surfaces in injury incidence rates, severity, or burden across different known match events however there were significant differences noted in both the “unknown” and “other” categories. Similar to those injuries in the domestic only data set, no pattern of characteristics was noted within “other” or “unknown” here. “Other” refers to injuries which the medical staff entering the data felt did not fit in available game event categories. “Unknown” refers to those injuries which the medical staff could not ascertain the specific event causing the injury. This is not uncommon in sports such as rugby due to the intensity of match play, multifactorial nature of many injuries and variable visibility available to medical staff when observing match play live or on video following the event.3.6p < 0.001 vs. natural 546 days/1000 h, 95% CI 476–627, p = 0.007).Calculations using mean severity values indicated greater burden from injuries sustained in tackling on artificial surfaces  compared with both other surface types . This finding is supported by research conducted in another professional cohort from the UK The overall incidence of injury was not significantly different when comparing surface types in this study  injuries have been reported to have a fourfold increase in incidence on artificial playing surfaces in comparison to natural grass. This was based on 5 injuries within the dataset, and it was noted by FullerConcussion has also been reported as having significantly greater incidence rates when matches take place on natural grass surfaces when compared to artificial surfaces4.5It is noted within the IOC epidemiological reporting consensus5This study of six seasons of domestic and European data is the largest of its kind, examining epidemiological data of injuries across playing surfaces commonly used for matches in rugby union. While injury rate between surfaces was not significantly different, overall injury severity was significantly greater when an injury was sustained on artificial surfaces in comparison with either combined natural/hybrid surface type or when natural grass was separated from hybrid. Of the above noted outcomes, significant findings were predominantly lower limb issues and regions that may be impacted by ground reaction force relationships and traction. The installation of artificial pitches undoubtedly allows for greater repeated use of the surface as well as reduced variability in hardness due to weather changes; however, these benefits must be weighed up against the potential for greater injury burden, particularly in the elite setting examined here. Injury data should be reviewed regularly in order to evaluate changes in injury patterns as pitch technology evolves.SWi and KS have received funding for this research as part of the Professional Rugby Injury Surveillance Project (PRISP), joint funded by the Rugby Football Union (RFU), and Premiership Rugby. LS is a PhD student funded as part of the PRISP group with her affiliations listed. CR is a PhD student funded jointly by the Rugby Football Union, Premiership Rugby and University of Bath. SK, KS, and MC are employed within rugby union in the United Kingdom with their institutional affiliations listed.Tables S1‐S7Click here for additional data file.


The study of eco‐evolutionary dynamics, that is of the intertwinning between ecological and evolutionary processes when they occur at comparable time scales, is of growing interest in the current context of global change. However, many eco‐evolutionary studies overlook the role of interindividual interactions, which are hard to predict and yet central to selective values. Here, we aimed at putting forward models that simulate interindividual interactions in an eco‐evolutionary framework: the demo‐genetic agent‐based models (DG‐ABMs). Being demo‐genetic, DG‐ABMs consider the feedback loop between ecological and evolutionary processes. Being agent‐based, DG‐ABMs follow populations of interacting individuals with sets of traits that vary among the individuals. We argue that the ability of DG‐ABMs to take into account the genetic heterogeneity—that affects individual decisions/traits related to local and instantaneous conditions—differentiates them from analytical models, another type of model largely used by evolutionary biologists to investigate eco‐evolutionary feedback loops. Based on the review of studies employing DG‐ABMs and explicitly or implicitly accounting for competitive, cooperative or reproductive interactions, we illustrate that DG‐ABMs are particularly relevant for the exploration of fundamental, yet pressing, questions in evolutionary ecology across various levels of organization. By jointly modelling the effects of management practices and other eco‐evolutionary processes on interindividual interactions and population dynamics, DG‐ABMs are also effective prospective and decision support tools to evaluate the short‐ and long‐term evolutionary costs and benefits of management strategies and to assess potential trade‐offs. Finally, we provide a list of the recent practical advances of the ABM community that should facilitate the development of DG‐ABMs. This is largely motivated by the increasing realization that ecological and evolutionary responses of populations can occur on similar temporal scales, with potential consequences on dynamics from gene to ecosystem  affecting the demographic dynamics  and ultimately individual fitness or even inclusive fitness . After defining these models, we survey the literature to illustrate how DG‐ABMs can be used to investigate fundamental issues in evolutionary ecology, as well as to assist the management of natural populations facing environmental changes.Our objectives here are to put forward models that explicitly 2At the very core of the eco‐evolutionary models is the need of specifying the genetically variable and heritable traits, their impact on the focal organism's life history and the ecological embedding that determines how life‐history traits affect and are affected by environmental conditions and the demographic context  were used to investigate more complex scenarios and explore unexpected eco‐evolutionary feedback loops, with approaches spreading on a spectrum of complexity well‐described by DeAngelis and Mooij . On the On the other side of the spectrum, some ABMs employ a specific bottom‐up approach to fully integrate individual interactions and their outcome over time and space within a population, the result of which will dictate the strength and direction of evolutionary processes at the population level  population dynamics models with heritable trait variation and phenotype‐dependent interactions between individuals Box . A key f3In their recent review of individual‐based modelling of eco‐evolutionary dynamics, Romero‐Mujalli et al.  illustraTo that aim, we searched the Web of Science Core Collection between 1955 and 2022 for various combinations of keywords Figure . A first4In the selected 89 studies, competition was by far the most considered interaction (79 studies), followed by reproductive interactions (38 studies) and cooperative interactions (four studies only). We found 32 studies accounting for two types of interaction simultaneously.On average, 1.9 traits (between 1 and 19 traits) per study were considered as evolvable. The nature of evolvable trait(s) depended on the interaction type, the species/kingdom considered and the level of generality/realism/precision of the model  used a Mendelian inheritance process either in a population genetic framework  or combined with a quantitative genetic framework . Besides, 22 studies (24.7%) used an infinitesimal quantitative genetic framework , and two studies (2.2%) tested for population versus quantitative genetic framework. Note that our definition of DG‐ABM is larger than the one suggested by some authors  to represent Most of the reviewed multispecies DG‐ABMs focussed on competitive interactions, in an explicit prey–predators' or community context. For instance, Kang and Thibert‐Plante  illustraOverall, it appears that DG‐ABMs have a large potential to address fundamental eco‐evolutionary questions accounting for multiple drivers of fitness, and are increasingly used in an integrative way, allowing effects to flow up and down between organization levels.7demographic control of populations, in particular through individual phenotype‐based choices, it can deeply impact all demographic processes and population genetic composition, and therefore the intensity and direction of the evolutionary processes  and genetic performances  between gene pools  while preserving its genetic value and diversity, or to determine how to minimize the risks of demo‐genetic collapses of populations facing climate change. Furthermore, by controlling the social context of populations, management drives the overall ecological processes and thus affects biotic and abiotic stressors, the susceptibility of populations to these stressors, and selection intensity . All these recommendations should benefit the development of DG‐ABMs.The above‐listed examples from our literature review illustrate the diversity of interindividual interactions, adaptive traits and ecological processes that can be investigated using DG‐ABMs. This diversity is a strength but requires active strategies to better identify possible links between similar models developed to answer different questions, and to structure the community of developers and users of these models. Identified as ABMs, DG‐ABMs can benefit from multiple advances in the ABM community. The flexibility of the approach ranges from very simple and generic models to very complex and specific models, depending on model assumptions and objectives population dynamics models with heritable trait variation and phenotype‐dependent interactions between individuals. Our literature review illustrates how the bottom‐up construction of fitness in these DG‐ABMs allows them to provide new insights into various fundamental and applied questions in ecology and evolution.Previous reviews of the literature have indicated that ABMs in general are not used to address general questions in ecology and evolution, but have a more ‘narrow’ or ‘pragmatic’ scope (DeAngelis & Grimm, The authors declare that they have no competing interests.Figure S1Click here for additional data file.Table S1Click here for additional data file.Table S2Click here for additional data file.Table S3Click here for additional data file.


Current theory predicts that the intensity of biotic interactions, particularly herbivory, decreases with increasing latitude and elevation. However, recent studies have revealed substantial variation in both the latitudinal and elevational patterns of herbivory. This variation is often attributed to differences in study design and the type of data collected by different researchers. Here, we used a similar sampling protocol along elevational gradients in six mountain ranges, located at different latitudes within temperate Eurasia, to uncover the sources of variation in elevational patterns in insect herbivory on woody plant leaves. We discovered a considerable variation in elevational patterns among different mountain ranges; nevertheless, herbivory generally decreased with increasing elevation at both the community‐wide and individual plant species levels. This decrease was mostly due to openly living defoliators, whereas no significant association was detected between herbivory and elevation among insects living within plant tissues . The elevational decrease in herbivory was significant for deciduous plants but not for evergreen plants, and for tall plants but not for low‐stature plants. The community‐wide herbivory increased with increases in both specific leaf area and leaf size. The strength of the negative correlation between herbivory and elevation increased from lower to higher latitudes. We conclude that despite the predicted overall decrease with elevation, elevational gradients in herbivory demonstrate considerable variation, and this variation is mostly associated with herbivore feeding habits, some plant traits, and latitude of the mountain range. We used a standardized sampling protocol along elevational gradients in six mountain ranges, located at different latitudes within temperate Eurasia, to uncover the sources of variation in elevational patterns in insect herbivory on woody plant leaves at both community and species levels. We found that an overall decrease in herbivory with increasing elevation was mostly due to openly living defoliators, whereas no significant association was detected between herbivory and elevation among insects living within plant tissues . The strength of the negative correlation between herbivory and elevation increased from lower to higher latitudes. We estimated the desired elevations for data collection before visiting the study region, and we then selected  the study site with the least disturbed plant community among several accessible sites located at the chosen elevation. We were unsuccessful in collecting the planned number of samples in the Caucasus because of the virtual absence of woody plants in the alpine meadows and the scarcity of natural vegetation at low elevations.2.2The sampling was conducted in the second half of the growth season, when the majority of insect herbivores had completed their feeding but well before the start of leaf fall at any of the study sites. Naturally, the growth period decreases with an increase in elevation; and this decrease could contribute to elevational changes in leaf damage. However, keeping in mind that the greatest part of the damage is imposed on young leaves  from common woody plant species. We selected branches for sampling while standing at a distance of 5–10 m away  to avoid unconscious selection bias. We disregarded a few branches that were grazed by vertebrate herbivores, which usually remove the entire shoots or greater parts of adjacent leaves; this ‘coarse’ damage is easily distinguished from a ‘fine’ and relatively minor damage imposed on individual leaves by invertebrate herbivores. All samples were collected and processed by the same persons (MVK and VZ) who had no a priori knowledge of the herbivory levels in the visited regions and/or the collected plant species.In the Alps and in the Cairngorms, we first selected up to five woody plant species that dominated the community , and we then haphazardly collected one branch (or group of branches) from each of the five mature individuals of each selected species . In the other mountain ranges, we did not select the species to be collected. Instead, we collected one branch from each of 15–25 individuals of woody plants irrespective of their identity using the following procedure. Each of the two collectors walked along a straight line, making stops at approximately 10 m intervals and collecting a branch from a species, which had the greatest foliar biomass  within a 2 × 10 m plot behind the collector. This change was introduced to better reflect herbivory in species‐rich plant communities and to avoid possible subjectivity in the selection of plant species to be collected. All other details of the protocol were the same across all regions, and we assumed that under both these protocols the numbers of sampled individuals of each species were roughly proportional to the contributions of these species to the community‐wide foliar biomass. Importantly, the sampling protocol was always identical within each gradient, and thus a minor difference outlined above is unlikely to influence the results of meta‐analysis based on correlations between herbivory and elevation within individual gradients.2.3In the laboratory, each leaf was carefully examined for the presence of damage imposed by chewing, galling, and mining invertebrates. In conifers, we  to one of the damage classes according to the percentage of the leaf area that was consumed or otherwise damaged by insects, as follows: 0 (intact leaves), 0.01%–1%, 1%–5%, 5%–25%, 25%–50%, 50%–75%, and 75%–100%. The last class included the petioles of fully consumed leaves and missing needles. We calculated the proportion of foliage area lost to insects  by multiplying the number of leaves in each damage class by the respective median values of the damaged leaf area ; the obtained values were then summed for all damage classes and divided by the total number of leaves (including undamaged ones) in a sample  and weighed them to the nearest 1 mg. We then punched out 5–12 disks  from those leaves, dried the disks and the remaining parts of leaves for 24 h at 105°C, and then weighed them to the nearest 0.1 mg.2) divided by their dry weight (mg). Leaf area (mm2) was calculated by multiplying dry leaf weight (mg) by SLA (mm2 mg−1).When the leaves were too small to allow punching of leaf disks, we press‐dried the leaves and measured their total area from their photographs using Adobe Photoshop 2020. This measured area was then divided by 0.902 to correct for leaf shrinkage during drying. This correction factor was obtained by averaging the ratio between dry and fresh areas of 60 leaf disks collected from the leaves of 20 plant species from our study regions. We did not measure SLA in needle‐bearing plants. The dry weight of an individual leaf was calculated by dividing the weight of the punched leaves plus disks by the number of leaves. The water content in leaf tissues was calculated by dividing the difference between the wet and dry weight of a leaf by its wet weight. The SLA was calculated as the total area of the disks or leaves (mm2.510(x + 0.01) transformation to normalize the distribution of the residuals, and we averaged the herbivory data  for either site‐specific values  or by plant species by site combinations . The latter analysis was restricted to measurements of herbivory on the same plant species conducted at least in four study sites within the same mountain range. We classified the collected plant species (i) as low stature  or tall (above 70 cm) and (ii) as evergreen or deciduous.Our attempt to explore the proportion of insect damage in leaves using a generalized linear mixed model with a beta error distribution and a logit link function failed: the model based on 1289 sample‐specific values did not converge. Therefore, we used a logχ2 distribution . We compared zr between regions, herbivore feeding guilds, groups of plants that differ in leaf longevity and stature or between community‐wide and species‐specific effects by calculating the between‐group heterogeneity (QB) using a random effects meta‐analytical model, and we tested QB against the χ2 distribution with the number of groups minus one degree of freedom. We then calculated an average value of zr and its 95% confidence interval (CI95). The effects were considered significant when this confidence interval did not include zero. The association between the strength of the elevational gradients and the latitude of a study region was explored using meta‐regression .Across the 69 study sites, plants lost (mean ± SE) 2.24 ± 0.23% of their leaf area to externally feeding defoliators, 0.036 ± 0.012% to gallers, and 0.111 ± 0.018% to miners; the total losses to insects amounted 2.38 ± 0.24%. The total herbivory at the lowest elevation site of each gradient did not correlate with the latitude of the study site . The total herbivory significantly decreased with an increase in elevation in Altai and Avachinskij, but neither the decrease observed in Cairngorms and Troodos nor the increase observed in the Alps and the Caucasus was statistically significant . By contrast, a meta‐analysis of gradient‐specific data .The elevational patterns in total community‐wide herbivory differed among the six mountain ranges . Herbivory on deciduous plants decreased with elevation, while herbivory on evergreen plants did not show any elevational changes . Plant losses to defoliators significantly decreased with increasing elevation, while the association between herbivory and elevation for gallers and miners was not significant  significantly decreased with an increase in elevation, whereas the elevational changes in herbivory were not significant for the low shrubs ; rather, it became weaker with a decrease in latitudes of the study region  did not depend on the difference in elevation between the highest and the lowest sites . By contrast, leaf area of leaf‐bearing plants decreased with increasing elevation across six regions . The elevational changes in community‐wide herbivory were not associated with leaf water content  but increased with an increase in both SLA  and leaf area .Neither the community‐wide SLA nor water content changed with elevation . The similar difference between tall and low woody plants observed in polar mountains , are in line with meta‐analysis, which found that plant life‐history traits are better predictors of plant susceptibility to chewing herbivores than are primary and secondary chemistry or physical leaf traits  analyzing data from study sites located at different altitudes and latitudes but not forming continuous elevational gradients ; data curation ; formal analysis ; investigation ; methodology ; writing – original draft ; writing – review and editing . Vitali Zverev: Investigation ; methodology ; visualization ; writing – review and editing . Elena L. Zvereva: Conceptualization ; writing – original draft ; writing – review and editing .The authors do not have any conflict of interest.Appendix S1Click here for additional data file.


Congenital complete atrioventricular block (CCAVB) is usually due to failure of atrioventricular nodal conduction with preservation of the His‐Purkinje system. Most patients with CCAVB ultimately require pacemaker therapy to restore physiologic heart rates, dealing with the detrimental effects of chronic right ventricular (RV) pacing on cardiac structure and function. The ideal stimulation pattern aims to mimic the normal conduction to restore electromechanical coupling, preventing the harmful effects of lack of atrioventricular and inter‐intraventricular synchrony. This can be done through conduction system pacing. Using His bundle pacing (HBP) for cardiac resynchronization therapy in two complete congenital atrioventricular block patients, we have reported better exercise tolerance and echocardiographic improvements related to reversible left ventricular dysfunction that can be corrected by restoration of the normal activation pathway via the His‐Purkinje network. The 12‐lead ECG showed sinus rhythm with complete atrioventricular block and a ventricular‐paced QRS  associated with evident septal dyskinesia .In this perspective, key questions in CCAVB are yet unanswered owing to the impossibility to run methodologically correct studies in this pediatric population. The timing to consider pacing is individually based. The choice of the pacing site and mode has been mostly debated in literature (Cabrera Ortega et al., A first pacemaker implant or replacement after early childhood or in adolescence is a different setting, because key decisions are taken for long‐term cardiac pacing in a view to restore—possibly—all the 3 electrophysiologic determinants of cardiac function. A mild LV systolic dysfunction, especially when associated with functional mitral or tricuspid regurgitation and initial left atrial enlargement, is a clinical hint of the RV pacing detrimental effect and may promote upgrading the system to restore cardiac synchronicity. CRT is well known to improve cardiac function in RV pacing‐induced heart failure/LV dysfunction (Höijer et al., A single case of cardiac resynchronization via direct HBP in a CCAVB patient with RV pacing‐associated cardiomyopathy has been reported to date (Rehwinkel et al., The ongoing development of dedicated tools and the improved skillfulness in HBP implantation have now set the ground for the expansion of this pacing modality to CCAVB patients.3.1The observations about these two patients need to be confirmed in a large series of CCAVB patients. Moreover, some caveats are to be considered, such as persistence of conduction in the His‐Purkinje network at long term; minimization of intravascular leads that dwell lifelong in young patients; device longevity when a moderate‐to‐high HBP threshold dictates a high current drain; and lead revision in the event of loss of capture, as the number of pocket surgeries is a main predisposing factor to infection. Technical aspects like the amount of lead slack need to accommodate for patients’ growth are better addressed in late rather than in early childhood.4Taken these points as a habit at innovation, we believe that HBP should be explored as the first‐choice strategy in CCAVB undergoing pacemaker implantation in childhood, and in CCAVB candidates to upgrading because of RV pacing–associated LV dysfunction. A challenge may be represented by the possible increase in chronic pacing threshold, as also reported by Dandamudi et al. (Dandamudi et al., Mauro Biffi has held educational activity and received honoraria as speaker's bureau for Biotronik, Boston Scientific, and Medtronic. Matteo Ziacchi has held educational activity and received honoraria as speaker's bureau for Biotronik, Boston Scientific Abbott and Medtronic. All other authors declare that they have no conflict of interests.5This study was conducted in accordance with Helsinki Declaration as revised in 2013. Statements of written informed consent from legally authorized representatives/parents are available. All figures and tables are sourced from authors’ clinical cases at IRCCS Azienda Ospedaliero‐Universitaria Sant’Orsola‐Malpighi di Bologna.6Dr Biffi and Dr Ziacchi performed devices implantation. Dr Piemontese, Dr Biffi, Dr Ziacchi wrote the manuscript. All the authors equally contributed to the data collection and analysis at the implant and during the patients' follow‐up. Dr Massaro was the language reviewer.


N = 462) composed of 142 psychiatric patients and 320 community‐dwelling individuals completed the Childhood Trauma Questionnaire (CTQ), the Personality Inventory for DSM‐5 (PID‐5), and the Symptom Checklist (SCL‐27) for internalizing psychopathology. The effect of childhood traumas explained 34% of the variance in internalizing symptoms while controlling for the influence of age and gender. The traits accounted for 78% of this effect, which was predominantly exerted through the domains of Negative Affectivity, Detachment, and Psychoticism, and specifically through the facets of Depressivity, Suspiciousness, Anxiousness, Perceptual Dysregulation, and Distractibility. This finding provides preliminary support for the proposed model indicating that the aforementioned maladaptive trait domains potentially function as mediating links by which childhood traumas are translated into internalizing symptoms in adulthood. However, these findings must be interpreted with caution due to the cross‐sectional and retrospective mono‐method design of this study. Clinical implications are discussed in relation to transdiagnostic treatment and the potential value of specifying trait domain specifiers in ICD‐11 and DSM‐5 models of personality disorders.Research supports a strong relationship between childhood maltreatment and internalizing psychopathology , and features of personality are assumed to explain some of this relationship. In this study, we proposed a model in which maladaptive traits mediate the effect of childhood trauma history on internalizing symptoms in adult individuals. A mixed sample ( Diagnostic and statistical manual (DSM‐5), childhood trauma is highlighted as a putative etiological contributor to a range of mental disorders, in particular internalized mental health symptoms characterized by internal suffering such as anxiety and depression , mediate the relationship between childhood trauma history and adult internalizing symptoms. This was approached by analyzing the cross‐sectional meditational effects of five PID‐5 trait domains , simultaneously, while also comparing the effects of these trait domains against one another.et al., Because most previous research has highlighted features of Neuroticism and low Extraversion as primary mediators of the relationship in question  comprising 142 clinical and 320 community‐dwelling participants was included . A total of 351 citizens agreed to participate and were subsequently e‐mailed a secure link to the online assessment procedure, which eventually was completed by 320 participants.et al., All data were collected via a secure online questionnaire platform (SurveyXact), which prevented missing data. All 462 participants provided informed consent. As a part of their treatment program all clinical participants were given individual feedback on their personality trait profiles. As incentive for participation, the community‐dwelling participants were offered feedback on their personality trait profiles per e‐mail. The study protocol was notified to the Danish Data Protection Agency (SJ‐PSY‐01) and pre‐approved by the Regional Ethics Committee of Zealand. Some of the data and procedures used in the present study were also employed in other already published studies  as an indicator of internalizing symptomatology. On the 27 five‐point Likert‐scale items  participants rated the intensity of symptoms within the past 7 days reflecting state features. In the present study, the Cronbach's alpha value for the GSI was 0.96, and the mean corrected item‐total correlation was 0.67 .Symptom Check List 27 (SCL‐27) is a 27‐item self‐report inventory capturing current internalizing symptomatology (within the last 7 days) including depressive symptoms, dysthymic symptoms, vegetative symptoms, agoraphobic symptoms, symptoms of social phobia, and symptoms of mistrust  on a dependent variable (DV) is composed of the direct effect of the IV on the DV and the indirect effect through a proposed mediator variable. In the case of multiple parallel mediation, the total indirect effect of all proposed mediators and the specific indirect effect of each single mediator can be estimated. In the current study, we examined the direct and indirect effects of the CTQ score on the SCL‐27 score through the five PID‐5 domain scores, simultaneously. This procedure allows us to calculate the indirect effect of the individual mediator while controlling for the influence of other potential mediators. Based on recommendations by Hayes  and MacKTable Childhood trauma explained 34% of the variance in internalizing symptom distress  when adjusting for the influence of age and gender. Results of multiple parallel mediation analysis for the PID‐5 traits are presented in Fig. As shown in Fig. As shown in Fig. In the present study, we set out to test a proposed model in which PID‐5 traits mediate the effect of childhood traumas on internalizing symptom distress in adulthood. Overall, we found that childhood traumas explained 34% of the variance in symptom distress. The total indirect effect of PID‐5 trait domains accounted for 78% of the total effect of childhood traumas on internalizing symptoms. Although, these findings are based on statistical inferences from a cross‐sectional sample along with a single measurement method, it underscores the significant role of PID‐5 maladaptive personality traits  as potential mediators in the path between childhood adversities and current internalizing symptoms. Accordingly, the proposed mediational model may be a reasonable basis for more comprehensive investigation in future studies. Moreover, these preliminary results may support the value of systematically assessing psychological liabilities such as PID‐5 traits in traumatized patients with internalizing psychopathology.Consistent with our primary hypothesis, the most substantial mediating effects applied to the PID‐5 trait domains of Detachment, Negative Affectivity, and Psychoticism. The PID‐5 trait domain of Disinhibition showed a significant but very modest indirect effect, whereas the effect of Antagonism was non‐significant. The substantial indirect effects of Negative Affectivity, Detachment, and Psychoticism suggest that features of these domains may be particularly related to both traumas and internalizing disorders.et al.  had been accessible. Moreover, the retrospectively recollected reporting may have been influenced by recall bias and state‐dependent memory reflecting both personality and current mental condition. However, research suggests that retrospective self‐reports and prospective records of childhood maltreatment are highly comparable, which support the utility of self‐reported childhood adversities (Scott, McLaughlin, Smith & Ellis, Third, both PID‐5 traits and internalizing symptoms were almost concurrently self‐reported involving a risk for artificially high correlations among measures (Campbell & Fiske, et al., Finally, we recommend future studies in developmental psychopathology to focus on the DSM‐5 and ICD‐11 component of global personality dysfunction (Bach, Brown, Mulder, Newton‐Howes, Simonsen & Sellbom,


Cardiovascular diseases (CVDs) are the result of complex pathophysiological processes in the tissues comprising the heart and blood vessels. Inflammation is the main culprit for the development of cardiovascular dysfunction, and it may be traced to cellular stress events including apoptosis, oxidative and shear stress, and cellular and humoral immune responses, all of which impair the system's structure and function. An intracellular chaperone, heat shock protein 60 (HSP60) is an intriguing example of a protein that may both be an ally and a foe for cardiovascular homeostasis; on one hand providing protection against cellular injury, and on the other triggering damaging responses through innate and adaptive immunity. In this review we will discuss the functions of HSP60 and its effects on cells and the immune system regulation, only to later address its implications in the development and progression of CVD. Lastly, we summarize the outcome of various studies targeting HSP60 as a potential therapeutic strategy for cardiovascular and other diseases. ADPadenosine diphosphateAMIacute myocardial infarctionAPCantigen presenting cellApoB‐100apolipoprotein B‐100ATPadenosine triphosphateBakBcl‐2 homologous antagonist/killerBaxBcl‐2 homologous X proteinBCRB cell receptorBNPbrain natriuretic peptideCADcoronary artery calcification score, coronary artery diseaseCAFchronic atrial fibrillationCCR2C‐C chemokine receptorCOX‐2cyclooxygenase‐2DAMPdamage associated molecular patternDCdendritic cellDCMdilated cardiomyopathyeGFPenhanced green fluorescent proteinERKextracellular signal regulated kinaseHFheart failureHFpEFheart failure with preserved ejection fractionHMGB1high mobility group box 1HSAhuman serum albuminHSF‐1heat shock transcription factor 1HSPheat shock proteinHSP10heat shock protein 10HSP27heat shock protein 27HSP60heat shock protein 60HSP70heat shock protein 70ICAM‐1intercellular adhesion molecule 1IFN‐γinterferon γIGF‐1insulin like growth factor‐1ILinterleukiniNOSinducible nitric oxide synthaseIRAK‐1IL‐1R associated kinaseJNKJun N‐terminal kinasesLDLlow density lipoproteinLDLRlow density lipoprotein receptorLPSlipopolysaccharideMAPKMAP kinaseMDAmalondialdehydeMHC‐Imajor histocompatibility complex‐IMHC‐IImajor histocompatibility complex‐IImiR‐1microRNA‐1mRNAmitochondrial RNAmtHSP60mitochondrial HSP60MyD88TLR‐4 myeloid differentiation protein 88NF‐κBnuclear factor κBNKnatural killerNOnitric oxideNOS‐2nitric oxide synthase 2NSTEMInon ST‐elevation myocardial infarctionoxLDLoxidized LDLPAHpulmonary arterial hypertensionPAMPpathogen associated molecular patternPCNAproliferating cell nuclear antigenPRRpattern‐recognition receptorROSreactive oxygen speciesRT‐PCRreverse transcriptase polymerase chain reactionsiRNAsmall interfering RNASTEMIST‐elevation myocardial infarctionTCRT cell receptorTGF‐βtransforming growth factor βTh1type 1 T helper cellTh17type 17 T helper cellTh2type 2 T helper cellTIRToll/IL‐1 receptorTLRtoll‐like receptorTNF‐αtumor necrosis factor αTRAF6TNF receptor associated factor 6Tregregulatory T cellsTRIFTIR‐domain‐containing adapter inducing interferon bT cellT lymphocyteVCAM‐1vascular cell adhesion molecule‐1VSMCvascular smooth muscle cell1The cardiovascular system, comprising the heart and blood vessels, has a central role in human physiology, with its main contribution being the continuous supply of nutrients and blood to the remaining tissues to support their metabolic activities. Often regarded as a pump, the heart is a highly specialized muscle that contracts in a sustained and rhythmic fashion to keep blood flowing throughout an entire circuitry of arteries and veins that branch out to reach peripheral tissues and allow for nutrient and oxygen diffusion. A constant heartbeat is indispensable to maintain the body alive, and thus the pump is ever active. This nonstop agenda demands that the heart is also provided with an effective nutrient supply of its own. The net result of the process hitherto described is metabolically favorable because of the pump's high efficiency, requiring ~4% of the cardiac output at rest to comply with its duties.The heart is an organ that runs preferentially on oxidative phosphorylation to satisfy its energy demands, so that it is highly dependable on continuous blood flow and even a minor shortage due to obstruction may greatly impair its contractility and lead to death. To avert the potential threat of substrate deprivation, cardiac tissues rely on protective mechanisms including a collateral circulation, an antioxidant system and other intracellular stress responses that safeguard their integrity. Among these defense schemes, the heat shock protein (HSP) response is a remarkably preserved evolutionary feature that is present both in prokaryotic and eukaryotic organisms. The great heterogeneity of responses elicited by this system is also the result of the sizable number of members this protein family has. HSPs were originally identified due to their prompt activation after abrupt increases in temperature and they were theorized to assist cells in adapting and surviving under these circumstances.Heat shock protein 60 (HSP60), a prominent protein of the HSP family, has been exhaustively studied because of its cardioprotective properties, which include processing misfolded proteins, antiapoptotic activity, and dynamization of key transcription factors for mitochondrial biogenesis and calcium handling. Paradoxically, this very same protein may also be a source of inflammation not only for the tissues it stems from, but also for peripheral ones. It has been demonstrated that it stimulates both innate and adaptive immunity behaving as a damage associated molecular pattern (DAMP) eliciting robust immune responses triggering some mechanisms of inflammation, an integral part of cardiovascular disease (CVD) pathophysiology.2HSPs are a large family of intracellular proteins that received their name after the discovery that their upregulation responds to heat shock, and their overall purpose is to grant protection against this otherwise menacing condition Table . They arApart from being a very well phylogenetically preserved protein, HSP60 is present in a wide array of organisms, including fungi, plants, bacteria, and mammals.Escherichia coli GroEL, Chlamydia trachomatis HSP60 GroEL‐like, Mycobacterium tuberculosis HSP65 and HSP60 of fungi such as Aspergillus spp., Candida spp., and Histoplasma spp.These structural similarities became greatly helpful when studying the function of HSP60 in cell biology. Most of the knowledge we have about human HSP60 came from previous observations of several prototypes that have since been used; these include bacterial homologues such as Recently, it has been suggested that in the extracellular space HSP60 can be released via the exosomal pathway and during necrosis via passive leakage, implying that both processes may play a role in death signaling.3HSP60 is encoded within the nuclear genome and is expressed in the cytosol as a precursor termed naive HSP60, which differs from mitochondrial HSP60 (mtHSP60). The former carries a 26 amino acid (aa) sequence which serves as a mitochondrial import segment necessary for its transport into the organelle.In its minimal functional unit, HSP60 exists as a single ring structure forming a heptameric toroid, although it is mostly present as two‐stacked heptameric rings which form a central enclosure where proteins are folded in an ATPase‐dependent activity.In speaking about HSP60's quintessential role as a chaperonin, it should be stated that it is known to occur as a cooperative effort that requires another HSP. HSP10 co‐chaperonin, a related mitochondrial chaperone, is necessary for said purpose, whereby it functions as a cover for the developing toroidal canal. In a similar fashion, HSP10 also assembles into heptameric structures.4A relevant characteristic of mammalian HSP60 that sets it apart from its chloroplast and bacterial homologues is its cochaperonin specificity. According to Levy‐Rimler et al., not only does mammalian HSP60 associate into tetradecamers or monomers depending on whether protein concentrations are high or low, respectively, but it also functions exclusively with its own specific mitochondrial 10 kDa cofactor HSP10, while other HSP60 homologues can work with any cognate of HSPE1 (HSP10).2+ handling and regulation of reactive oxygen species (ROS) production.As HSP60 interacts with HSP70 to form an HSP60–HSP70 complex, it allows the transportation of proteins across the cell. A major client for this chaperoning complex is mitochondrial transcription factor A, a protein with a pivotal role in the homeostasis of the organelle from which its name derives, primarily by fine‐tuning the expression of genes associated with mitochondrial biogenesis, CaIn apoptosis, HSP60 interacts with a number of proteins related to proapoptotic as well as antiapoptotic events such as procaspase‐3,5The following segment describes some of the roles that have been suggested HSP60 plays within nonimmune somatic cells. The following are activities different to the classically described for the chaperonin, and thus further evidence from other research groups will be needed to solidify these findings and state them as canon functions of the protein.Chlamydia pneumoniae has mitogenic effects on VSMCs through regulation of HSP60 levels by increasing endogenous intracellular HSP60 expression levels.Apart from its chaperoning and protein folding roles and immune response stimulating capacity, that will be described, HSP60 acts as a mediator for many other functions. For example, in vascular smooth muscle cells (VSMCs), it has been demonstrated that human and bacterial HSP60 induce proliferation.2 and NOS‐2 for nitric oxide (NO) production.Porphyromonas gingivalis was able to downregulate expression levels of VE‐cadherin and eNOS in human endothelial cells after coincubation.In endothelial cells, ATP synthase is yet another of the many polypeptide clients of HSP60 and Alard et al.In cardiomyocyte cells, it is well established that toll‐like receptors (TLRs) are expressed on the cell membrane, specifically TLR4 and TLR2.Among the possible neurological pathways mediating the expression of HSPs, it has been determined that cholinergic activation via muscarinic acetylcholine receptors in hippocampal neurons leads to an increase in heat shock transcription factor 1 (HSF1)‐Ser326 modification which leads to the activation of this transcription factor, with a dose and time‐dependent increase in HSPs including HSP70, HSP90, and HSP60.In various types of cancer, HSP60 appears to have a role in diagnosis, prognosis and prevention.In addition to the already numerous roles so far described in which HSP60 is involved, recent reports suggest that its apoptotic‐related activities may be important for embryonic development. By using Cre‐LoxP HSP60 transgenic models, it has been observed that mouse embryos expressing HSP60 were born with congenital atrial septal defects, severe hemorrhage and evidence of increased myocyte apoptosis, which may account for the inborn structural damages aforementioned.The proteomic profiles of the cardiac chambers have proven to be heterogenous from one another, an interesting feature about HSP60. It has been reported that basoapical proteomic differences exist within the left and right ventricles.Thus, HSP60 has various relevant roles apart from the well analyzed and studied task as a chaperone and interacts with a number of proteins, which are key for proper cellular functioning. However, as the synthesis of HSP60 is upregulated and liberated by stress stimuli in different types of cells, it is also one of the main culprits in the pathophysiology of some CVDs given the downstream effects of HSP60. In the cardiovascular system, the release of HSP60 into the bloodstream is a process undertaken directly by cardiomyocytes via exosomes rather than the classic Golgi apparatus pathway under stress conditions where the chaperone protein remains tightly attached to the exosome membrane to eventually be released into the extracellular space.6Previous studies have demonstrated that HSP60 has proinflammatory properties when interacting with innate immunity cells, for example, macrophages and dendritic cells (DCs). DCs possess membranous extensions that inspect the area covered and are very phagocytic. They participate both in the innate and adaptive immunity when activated which allow them to rapidly intake the antigen and secrete cytokines Figure . The molc from mitochondria, caspase‐3 activation, and DNA cleavage. To further investigate the role of HSP60 in apoptosis, participation of IL‐1β and TNF‐α, inflammatory cytokines produced by HSP60 and TLR4 engagement were analyzed and the results showed that DNA fragmentation occurred by TNF‐α and not by IL‐1β.When found in the extracellular space, HSP60 may play both proinflammatory and anti‐inflammatory roles depending on its interactions with cell‐surface receptors including TLRs, while it may also bind to other proteins during an immune response to assist in their presentation to lymphocytes.Microglia, members of the mononuclear phagocytic system, are the only cells in the central nervous system that express TLR4 on their surface and are thus responsive to the release of HSP60 in the extracellular matrix of neuronal tissues after cellular injury. A study performed by Lehnardt et al.,Streptococcus pneumoniae is poorly immunogenic as other polysaccharides in certain age groups, a study was done to test the ability of p458, a peptide from the sequence of HSP60, to evoke a robust immune response.Lastly, peptides of HSP60 can also elicit an innate immune response. Peptide fragments of HSP60 have been documented to trigger the innate immune system. To address the fact that As such, HSP60 exhibits some considerable signaling properties and acts as a potent activator of a wide range of intracellular and extracellular responses in nonimmune as well as innate immune cells as previously mentioned. However, the role of HSP60 in the immune system is much more complex and participates in conjunction with the adaptive immunity system acting as a dynamic link. In the following section, some of the regulatory roles of this protein in the adaptive immunity will be further explained by illustrating the dual role HSP60 possesses as a proinflammatory and anti‐inflammatory molecule.7Innate receptors recognize predictable ligands or antigens and mount an inflammatory response. However, T cell receptors (TCRs) of the adaptive immune response function differently. TCRs collectively recognize various antigens and are clonally distributed, promoting proliferation, and activation of antigen‐specific cells, generating T cells or memory B cells+RO− subset.+CD25− effector T cell suppression, thus inhibiting cytokine production and proliferation.In vitro, purified human HSP60 stimulates T cell proliferation in an autoreactive manner, the basis of many autoimmunity and inflammatory diseases, specifically the CD45RAEarlier studies on autoimmune diseases have explored in depth the anti‐inflammatory properties of HSP60 and its function as an ergotope. T cells recognize HSP60 produced endogenously by cells undergoing stress at the site of inflammation, captured by MHC‐II molecules of APCs.On the other hand, stimulation of B cell activation and proliferation by HSP60 in mice have been observed in a dose‐dependent manner, also demonstrating additional changes including induction of the synthesis and expression of costimulatory molecules in B cells including CD86, CD40, and CD69. Furthermore, along with the secretion of IL‐10 and IL‐6, immunoglobulin (Ig) G3 was secreted by Ig switch machinery.P. gingivalis, Aggregatibacter actinomycetemcomitans, and Bacteroides forsythus express HSP60 homologous with E. coli, GroEL, and periodontitis patients tend to have serum antibodies to the bacterial HSP60.P. gingivalis (PgHSP60) showing a “epitope spreading” pattern, the unfurling of an autoimmune response specific to an antigen to different epitopes, in both groups.Antigen mimicry, a phenomenon that occurs secondary to high sequence homology between bacterial and mammalian HSPs also elicits strong autoimmune responses, creating a correlation between bacterial infection and an ensuing autoimmune response. It has been observed in periodontitis that bacteria representative of this disease such as From this preamble, we get a good grasp of the repertoire of functions HSP60 features in the immune and nonimmune realm as well as the robust capacity it has to elicit an inflammatory response, or even mitigate it, as observed in some of the studies previously mentioned. All of these tasks combined give rise to the potential capacity of HSP60 or its peptides to participate at different stages of CVD progression, which can be at early atherogenesis or in the final stages of a failing heart. In the following section, we will review some of the recent investigations done on HSP60 in the spectrum of CVDs, highlighting the relevant findings and its implications for therapeutic purposes.8CVDs are the consequence of a plethora of stress‐inducing stimuli that may act upon cardiac tissues, mainly the myocardium, disabling the heart's structure and function. Coronary artery plaques are major contributors of progressive decline in delivery of oxygen and nutrients to the myocardium. In situ inflammation is also an important feature of ongoing injurious events, and can manifest as cytokine secretion from resident cells, triggering proinflammatory programs and recruiting cells of the immune system to affected areas. Failure to clear the initiating stressor results in repeated injury to the tissues involved and induction of programmed cell death, a common finding leading to organ dysfunction in these pathologies.8.1High blood pressure remains as one of the leading causes of mortality worldwide, estimates going as high as 10.4 millions of deaths per year. The global burden remains elevated and its impact in cardiovascular morbidity and mortality still remains as an important contributor and risk factor despite efforts by different committees to tackle and treat patients before falling in the category of hypertension.It has long been reported that patients with hypertension manifest clinical improvement after taking dry sauna baths, although the exact factors related to this observed amelioration remain partially unknown.A comparative study was done to determine the differences in serum concentrations of anti‐HSP60, HSP60 and antimycobacterial 65‐kDa protein antibodies between normotensive and borderline hypertensive individuals.8.2Atherosclerosis is a serious disease with a slow but steady progression that occurs due to a number of chronic inflammatory processes in the arterial intima, a layer of the arterial wall just below the endothelium, which when amplified by different factors, can cause partial or complete obstruction of the vessel leading to a life threatening insult to the heart. Now considered an autoimmune disease, the chronic inflammation generally culminates in the formation of a plaque which menacingly narrows the vessel's diameter, depriving the heart muscle of adequate blood flow and sufficient oxygen causing cardiac ischemia. However, if a sudden rupture of the plaque occurs, coronary artery occlusion can occur, causing a myocardial infarction.M. tuberculosis (mHSP65). Rabbits under a cholesterol‐rich diet who were immunized with HSP65 as well developed a more serious degree of atherosclerosis than those only immunized or fed with a cholesterol‐rich diet alone.A study reported by Xu et al.C. trachomatis HSP60, and the E. coli homologue GroEL] cross‐reactivity occurs due to a 95% sequence homology between bacterial HSPs and a 50%–55% sequence homology between bacterial and human HSP60.As an immunogenic antigen, after infection or vaccination the subject develops immunity against bacterial HSP60.Regarding the presence of endogenous HSP60 in the circulation, some studies have linked possible mechanisms of disease progression in atherosclerosis to this phenomenon, including cell death due to stress, inflammation or infectious agents as previously described, and soluble HSP60 (sHSP60) locally released from atheromas.Other mechanisms attributed as possible contributors to atherosuceptibility include vascular shear stress and heterogeneity in endothelial phenotypes.vasa vasorum and carotid artery endothelial cells using immunohistochemistry.C. pneumoniae and cytomegalovirus were increased, although no markers related to infection to these last two pathogens were found.A recent study compared the activating effect that oxLDL and HSP60 have on T cells via DCs and whether these two antigens depend on each other for activation.As HSP60's implicated pathway in atherosclerosis includes activation of T cells, monocytes, and DCs, it facilitates the attachment to endothelial cells and transmigration into the intima as demonstrated in a study that reported T cell activation by HSP60 through DCs in a MHC‐II dependent‐fashion, when DCs were cocultured with HSP60 and T cells.−/−) and lymphocyte‐deficient (RAG1−/−) mice, atherosclerotic lesions development was reduced by 54% in comparison with only atherosclerosis‐prone (LDLR−/−) mice.+ are the first to extravasate.+ and CD8+ T cells as well as DCs and macrophages.+ memory effector cells.+CD25+CD45RO+ T cells, which engage with endothelial cells that express HSP60, forming adhesion molecules (VCAM‐1 and E‐selectin) at sites with predisposition for progressive development of atherosclerotic lesions after exposure.Activated T cells in atherosclerosis are an essential component in atherosclerosis. In atherosclerosis‐prone , and A. actinomycetemcomitans HSP60 (AaHSP60) in comparison to non‐CAD patients reinforcing the importance of the role of bacterial HSP60, specifically oral pathogens, as risk factors for the progression of CVD.In the human heart, the role that HSP60 plays in the setting of CAD has been long proposed by Knowlton and Strivatsa,+ T cells and proinflammatory Th1 cells. On the other hand, HSP60 serum protein levels correlate with its serum antibodies.High levels of HSP60 in serum have been identified in multiple settings in CAD. In C57BL/6J mice that underwent coronary artery ligation a rapid rise of phosphorylated IRAK‐1  and HSP60 intracellular depletion were seen owing to increased secretion into the extracellular space, with HSP60 ability to activate extrinsic apoptotic pathways in cardiomyocytes, via caspase‐8, perpetuating deleterious effects in myocardial ischemia.++CD16+ subset of intermediate monocytes stimulated by HSP60 demonstrated higher levels of chemokine expression, such as C‐C chemokine receptor type 2 (CCR2), CCR5, and CX3CR1.A study aimed toward the patterns of expression of monocytes in patients with unstable angina, a disease that is part of spectrum of CAD, reported that HSP60 is expressed under stress conditions where correct blood flow is hindered to the myocardial tissue, and induces IL‐12p70 secretion by intermediate monocytes, a subset involved in antigen presentation.Apart from Th1 polarization that occurs in the active phase of CAD, it is crucial to emphasize the fact that Th1, Th2, Th17, and Tregs subsets have already been identified in atherosclerotic plaquesIn this regard, the innate and adaptive immune response to locally released endogenous cellular molecules such as HSPs, fibrinogen and soluble heparan sulfate, which occurs after ischemia, has a primordial role in aiding tissue inflammation and damage through cytokine secretion and leukocyte recruitment. Thus, these components together carry heavy weight as important contributors to the overall inflammatory processes that occur.8.4Arrhythmia is one of a kind in terms of pathophysiology understanding and curative methods. During recent years many new therapeutic options to control, prevent or cure arrhythmogenic hearts have been developed. Novel focuses are currently on therapeutic options; some in the form of pills, others in interventional methods, but it is remarkable that a complete understanding of arrhythmogenesis is still missing. Currently it can be named only some of the risk factors for developing sudden  or chronic arrhythmias, such as hypertension, atherosclerosis, obesity, some metabolic states, certain drugs or increasing age; but it would be great to recognize arrhythmia‐prone hearts with molecular markers.Chronic atrial fibrillation (CAF), the most common arrhythmia in adult patients, is the most studied rhythm. Recent lines of investigation regarding molecular expression patterns, including some DAMPS such as HSPs, have focused on myocardial adaptation responses to chronic or acute insults while having CAF. In a study performed by Schäfler et al.,HSPs have been studied in patients with permanent CAF after mitral valve surgery, and its capacity in stabilizing spontaneously restored sinus rhythm. A group of 135 patients who were previously diagnosed to have permanent CAF  were more over separated into two groups, a sinus rhythm group and an atrial fibrillation group, on the basis of recurrence of atrial fibrillation or persistence of sinus rhythm after the next 7 days following surgical intervention.l‐type calcium channels; it inhibits TNF‐α pathways and increase IL‐10, an anti‐inflammatory cytokine.Recently, the effects of inflammatory biomarkers for predicting recurrent atrial fibrillation following ablation therapy have been studied.To establish the participation of HSPs on the progression and different stages of atrial fibrillation, the presence of some HSPs, including HSP73, HSP72, HSP27, and HSP60 in sinus rhythm controls and in patients with persistent atrial fibrillation or paroxysmal, were studied.8.5HF accounts for great morbidity and mortality worldwide and due to its variable etiologies and association with multiple chronic diseases it has become one of the most studied cardiac conditions. The advent of better prognosis from treatment of acute HF events and an ageing population has ultimately led to an exponential increase in prevalence; justifying a need for better understanding of pathophysiology and therapeutic options. In regard to HSPs several studies have been performed in the last few years, generally showing correlation between HF and rising HSP levels.It has been well established that increased levels of HSP60 are found in failing hearts. Knowlton et al.Most studies report a similar trend on HSP60 levels during the development of HF. For instance, De Souza et al.Interestingly in HF, HSP60 follows an abnormal distribution. In a study, 66% of the total HSP60 was found in the mitochondria, 25% in the cytosol, and the remaining 9% was located in the plasma membrane.The potential predictive role of HSP60 in assessing HF severity and outcome has also been studied.−) toxicity is yet another known event related to acute HF, where cardiovascular impairment is manifested by electrolyte imbalances leading to ventricular arrhythmias, a strong oxidative response with concomitant decrease in its antioxidative counterpart, induction of myocardial apoptosis and necrosis, ATP depletion and cytoskeletal dysfunction. Since HSP expression responds to all of the aforementioned stress‐inducing stimuli, Panneerselvam et al.− toxicity. A dose‐dependent increase in both myocardial transcript and protein levels for HSPs and HSF‐1 including HSP70, HSP60, HSP32, and HSP27 was reported, while an inverse pattern was observed for HSP40 and HSP90.− toxicity.Acute fluoride  III and IV HF patients. Moreover, based on literature reports suggesting that vagus nerve stimulation leads to an increase in HSP70, they also sought for a causal role of HSP60 and HSP70 as cellular resistance factors induced by the therapeutic intervention.Chronic hypersympathetic activity is a frequent finding in HF as indicated by high resting heart rate (HR). In an organ with an already compromised contractility, persistent stimulation by the sympathetic nervous system (SNS) implies increasing the workload the heart is subjected to, and the resulting stress this system is endowed with activates endogenous defense mechanisms, including the HSPs response. In this context, Afanasiev et al.,And finally, supporting the well‐established phenomenon that HSP60 binds to TLR4 as described earlier,8.6Among HF patients, there is a particular subset who display some of the hallmark features of the disease, including increased LV end diastolic diameter and reduced LV ejection fraction, but do not otherwise stem from CAD. Nevertheless, it has been observed that these patients show evidence of coronary microvascular impairment, which is believed to be a result of nonconventional risk factors. Because of their association with CVD and endothelial dysfunction, Giannessi et al.8.7Cardiomyopathy comprises a heterogeneous group of diseases with mechanical or electrical disturbances of myocardium. Etiologies are multiple and the end result is ventricular dysfunction and progressive HF. Association with some types of cardiomyopathies and inflammatory mechanisms has been vastly described in the last few decades.In relation to DCM a research study demonstrated that the myocardium from DCM patients expresses significantly more HSP60 compared to that from heart donors without CVD.+ enriched population) and secreted HSP60, suggesting that chronic inflammation induced by T cells and their secretion of IL‐6 compromises mitochondrial integrity and activity as observed by the induction of the apoptotic intrinsic pathway and the release of HSP60.The onset of some forms of DCM are believed to be related to an autoimmune component that induces cardiac tissue remodeling through chronic inflammation. The increased expression of cell adhesion molecules observed in cells under stress make it possible for leukocytes to infiltrate into tissues following a chemokine gradient established by cells undergoing inflammation. A subtype of DCM, inflammatory DCM shows features similar to myocarditis and to the tissue remodeling and mechanical dysfunction of DCM. Immunohistochemistry of iDCM biopsies positive for CD3, CD45Ro, and CD68 are essential for diagnosis. To determine the mechanisms associated with the progression of iDCM, Bironaite et al.HSP60 has been proven to be a cornerstone for mitochondrial metabolism regulation during induced insults in vitro but recent information has confirmed its paramount role in preventing DCM. Fan et al.Finally, viral myocarditis, often linked to Coxsackievirus B3 (CVB3) infection, is known to be a predisposing factor for DCM, since the inflammatory response elicited during infection leads to a polyclonal expansion of immune cells even after the pathogen has been cleared, which may lead to autoimmunity. A chronic exposure to CVB3 has led to DCM through antibody‐mediated immunity, as IgM to antigens such as ɑ cardiac actin and HSP60 were found in sera of mice.8.8Hypertension is a common risk factor present in around 40%–60% of heart failure with preserved ejection fraction (HFpEF) patients which was historically referred to as diastolic HF in literature; however, recent pathophysiological understanding of the disease suggests other components for its development. Currently HFpEF attributes to nearly 50% of HF patients and its rising prevalence due to increasing comorbidities and lack of therapeutic options make it the perfect target for interesting new methods of investigation.Left ventricle stress induced by hypertensive states has been studied as a potent inflammatory inducer. Mechanosensitive adhesion proteins such as adhesins and integrins have demonstrated to induce cellular inflammatory responses. IL‐18, TNF‐α, and IL‐6, and ANP can be induced in stretched myocytes and cyclic overload states have shown TLR4 upregulation.In recent years emerging pathophysiological models are evidencing the systemic microvascular endothelial inflammation as a key factor for development of the condition. With these models all known causes of microvascular endothelial inflammation are recently recognized as independent risk factors; with obesity, diabetes mellitus, metabolic syndrome, lung diseases, smoking, and even iron deficiency being observed now as primary or secondary contributors. Inflammatory states seem to be initiated by multiple stressors with endothelial dysregulation being a paramount starting point. From here the increase in endothelial adhesion molecules and cytokines promotes monocyte migration. The consequences of macrophages inside the vessels and myocardium are an increase in ILs and other inflammatory mediators. Effects of multiple cytokines have been described and their effects on cardiomyocyte dysregulation are starting to emerge. IL‐1β and TNF‐α are notorious to cause dysregulation of calcium handling by the sarcoplasmic reticulum; leading to a negative inotropic effect. IL‐6 has been shown to reduce titin phosphorylation with increased cardiomyocyte stiffness. IL‐1β and TNF‐α also perform on cardiac fibroblasts upregulating angiotensin II type 1 receptors with fibrosis enhancement. Lastly, TNF‐α levels correlate with TGF‐β levels and its well‐known extracellular matrix effects. The endpoint of all these disturbances is increased stress to cardiomyocytes by inflammation and fibrosis, increased oxidative stress and alterations in cardiomyocyte signaling pathways. Ultimately slow LV relaxation and elevated diastolic left ventricle stiffness begin to appear.In diabetic cardiomyopathy, it is well established that HSP60 molecules contribute as an important defense mechanism against hyperglycemic state‐induced apoptosis to cardiomyocytes. Although some of its benefits remain unknown, Chen et al.8.9Pulmonary arterial hypertension (PAH) as a pathological entity involves a varied list of etiologies and its complete pathophysiological mechanisms are not fully understood. From chronic pulmonary insults to idiopathic or even venous system pathologies, PAH involves a continuous elevation of pulmonary vascular resistance. The end result of such insult is right ventricular remodeling and ultimately right HF.The relationship between PAH pathogenesis and HSPs has been demonstrated by recording elevated levels of some HSPs in PAH patients. Several authors have correlated the appearance of some HSPs as a safeguarding mechanism against stress which promotes resistance to apoptosis and proliferation of VSMCs.Furthermore, the inhibition and downregulation of HSP90 and HSP70 respectively has proven to be effective in some experimental models of PAH.As a brief summary of interpretation and for better understanding we developed the following model of interaction between HSP60 and the above‐mentioned insults Figure . Establi9Since the emergence of interesting findings regarding HSP60 as a mitochondrial chaperone, studies have consistently shown that its localization can also extend to outside the mitochondria performing both non‐chaperoning and chaperoning roles. As aforementioned, accumulating data has evidenced that HSP60 is present in different stages of CVD, which exhibit impaired concentration levels of HSP60. Gathering evidence of HSP60 as a signaling molecule and an inflammation elicitor and reviewing all the previous findings in different CVDs, a clear pathway to elaborate potential therapies is demarcated by targeting this chaperonin and other proteins related to the various downstream effects it triggers Figure .In this regard, studies have shed light to some small molecule modulators for this protein. Some are natural molecules and others are synthetic entities with uncommon pharmacophores or structural motifs with the capacity to modulate its function Table . In the 9.1Eupenicillium brefeldianumPenicillium spp. Both of them exert their effects by binding to a Cys442 residue on HSP60, but only epolactaene tert‐butyl ester interferes with its ATPase through what appears to be an allosteric modulationCoscinoderma sp. sponge from the micronesian islands that modifies the chaperonin's structure by targeting its cysteine residues for sulfationAspergillus ochraceus, WC76466 and CNC358 respectively. These molecules also induce posttranslational modifications by alkylating thiol groups on the chaperonin, although more research is needed to support their overall effect on the protein's activityAs described throughout this review, the HSP60‐related cardiovascular burden encompasses several pathophysiological mechanisms and targets while it also plays a crucial part in different diseases. Developing modulators targeting HSP60 are potentially useful as therapeutics as blockage of HSP60 halts posterior inflammatory cascades to flare up in the myocardium.Terminalia arjunaMolecules that modulate HSP60 at protein expression levels have also been reported and mainly include compounds from plants such as the aqueous extract of the tree Lastly, the reduction of serum levels of anti‐HSP60 and anti‐HSP65 Igs is another attractive therapeutic ally, since these also cause systemic damage by activating the complement cascade and specific receptors immune cells. In this regard, some lipid lowering drugs from the family of statins, such as simvastatin and fluvastatin, have been reported to lower HSP60‐specific Ig seric levels although this observation is likely independent from their hypolipidemic and anti‐inflammatory effects. Aerobic exercise is interesting in that it is a nonpharmacological strategy that has also shown to reduce seric anti‐HSP60 Ig levels, suggesting another mechanism by which physical activity may be beneficial for various diseases.9.2An alternative to the use of anti‐HSP60 for therapeutic purposes is inhibiting TLRs, since these play a predominant role in the pathway for HSP60‐induced inflammatory response. Specifically, TLR4 genetic deletion has proven to attenuate inflammation in the myocardium during ischemia/reperfusion.9.3The immune system clears pathogens by responding to antigen stimulation under normal circumstances, this is referred to as the positive immune response. In contrast, the immune system may develop “unresponsiveness” specific to certain antigens after antigen stimulation, which is referred to as immunological tolerance (immune tolerance) according to Sun et al.,−/− or LDLr−/− mice.+CD25+Foxp3+ and CD11b+ as their commonly associated phenotypic markers, respectively.Vaccination strategies that have proven to be successful in inducing a tolerogenic state usually follow oral or nasal administration routes Table . In thesImmunization using HSP60 as an antigen can be carried by administering the whole protein or selected disease‐inducing peptides to which tolerization is desired; this last approach accounts for more tailored vaccines inducing tolerance to sequences of interest while sparing immunogenicity for the rest. Oral immunization using peptides from HSP60 together with some from other atherosclerosis‐related antigens such as oxLDL and ApoB‐100 have also been tested demonstrating effective induction of tolerance featuring the cellular and molecular hallmarks aforementioned; moreover multi‐antigenic vaccines using more than two antigenic sources are yet another take on tolerization that is being explored in the search for higher specificity responses.9.42+/Mn2+–dependent 1L (PPM1L) in post‐AMI inflammation and LV remodeling was studied in vivo.Innate immunity originally evolved as an immediate protective response to foreign antigens, as induction of antibodies takes 4–5 days. However, this important part of the immune system has a dark side, as it also responds to the release of common endogenous proteins into the extracellular space. As previously mentioned, a rising number of evidence points toward the damaging role played by DAMPs released into the extracellular space after MI, where they may activate PRRs and promote inflammation in the surrounding affected tissues, which may serve as a bona fide mechanism for macrophage recruitment and clearance of necrotic and apoptotic cell debris, as well as activation of myofibroblasts to produce granulation tissue that allows for local repair. Nevertheless, failure to contain the inflammatory response leads to continuous remodeling of the affected tissues, which explains the progressive changes in the left ventricle following damage by MI. Thus, inflammation is a hidden contributor to the development of HF. In this regard, some studies have discovered other potential therapeutic strategies that influence the inflammation agenda. In a study that shed light on the mechanisms behind cardiac dysfunction post‐AMI, the role of the protein phosphatase MgKO mice, which was associated with an increased release of cytokines such as TNF‐α, IL‐6, and IL‐1β by cardiac CD11b+ macrophages.KO mice.Another group studied Kelch repeat and BTB domain‐containing protein 7 (KBTBD7) and miR‐21 as novel markers associated to inflammation and development of innate immune responses to DAMPs, using HSP60 as a prototype, in an in vivo mouse model of CAL‐induced AMI.10According to the World Health Organization, CVDs occupy first place in morbidity and mortality worldwide. It is estimated that by the year 2020, deaths from CVD will increase by 15%–20% and about 23.6 million people will expire from these disorders by 2030, mainly from stroke and heart disease. The beginning and development of these pathologies are intimately related to proinflammatory mechanisms occurring at different structural levels leading to the development and progression of cardiovascular damage accompanied by acute or sustained production of proinflammatory cytokines. Indirectly and acutely, these proinflammatory cytokines can depress the contractility of cardiomyocytes, by affecting the response to β‐adrenergic stimuli thereof, by modulating NO activation mechanisms. As we discussed in this study, some of the molecules that have aroused great interest for its participation in autocrine or paracrine effects and in the modulation of the immune system and its possible capacity to act as a marker of cardiovascular cellular damage are the HSPs. In particular, HSP60 plays an important role by its function as a modulator of the innate and adaptive immune response. It has been shown that in patients with several CVDs, HSP60 presents an abnormal cellular distribution, localized in the cell membrane, which has been correlated with an increase in cell death by apoptosis. On the other hand, it has been shown that the presence of extracellular HSP60 activates the immune response facilitating a systemic proinflammatory state, with a rise in TNF‐α production and other proinflammatory mediators that perpetuate the progression of HF.This dual role of HSP60 as an immunomodulator and biomarker of damage allow us to explore the potential therapeutic options in a short and medium term. Until now, it has been evident that the modulation of the immune system by means of antigenic molecules could be established as a powerful curative strategy. Novel treatments may target the inhibition or stimulation of inflammatory mediators to induce a specific response on various inflammatory biomarkers and the inactivation of modulators of cell damage and death. This specialized area targeting specifically HSP60 in CVD seems to be still fresh and yet to be looked into deeply. Therefore we believe further interest will be garnered in this field as various studies mentioned earlier describe promising results exploiting the capacity to trigger or mitigate inflammation, as well as the regulation of expression levels of HSP60, while taking into account the functions and effects it elicits, all of which could be used at different stages of disease progression in CVDs where studies reveal different patterns of expression levels of HSP60 as well as the participation of various inflammatory components and other HSPs members, all of which are well established direct and indirect targets of HSP60. As promising as it looks, much more is yet to be understood and a long path lies ahead with unexplored terrain to be covered.The authors declare that there are no conflict of interests.IKS and IAMR searched literature; IKS, IAMR, RAVL, and CEGB conceptualized and drafted the manuscript; IKS, GTA, AAK, and CEGB revised the manuscript; IKS, AAK, and CEGB discussed the manuscript.