Exacerbated Activation of the NLRP3 Inflammasome in the Placentas from Women Who Developed Chronic Venous Disease during Pregnancy.

Chronic venous disease (CVD) comprises a spectrum of morphofunctional disorders affecting the venous system, affecting approximately 1 in 3 women during gestation. Emerging evidence highlights diverse maternofetal implications stemming from CVD, particularly impacting the placenta. While systemic inflammation has been associated with pregnancy-related CVD, preliminary findings suggest a potential link between this condition and exacerbated inflammation in the placental tissue. Inflammasomes are major orchestrators of immune responses and inflammation in different organs and systems. Notwithstanding the relevance of inflammasomes, specifically the NLRP3 (nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3)- which has been demonstrated in the placentas of women with different obstetric complications, the precise involvement of this component in the placentas of women with CVD remains to be explored. This study employs immunohistochemistry and real-time PCR (RT-qPCR) to examine the gene and protein expression of key components in both canonical and non-canonical pathways of the NLRP3 inflammasome (NLRP3, ASC-apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain-caspase 1, caspase 5, caspase 8, and interleukin 1ß) within the placental tissue of women affected by CVD. Our findings reveal a substantial upregulation of these components in CVD-affected placentas, indicating a potential pathophysiological role of the NLRP3 inflammasome in the development of this condition. Subsequent investigations should focus on assessing translational interventions addressing this dysregulation in affected patient populations.

Segmental arterial mediolysis leading to spontaneous rupture of splenic artery and fatal hemorrhage in pregnancy.

We report an unexpected death of a 22-year-old primigravida who was admitted to the hospital with sudden abdominal pain two days before a scheduled delivery. During an emergency caesarean section due to intrauterine asphyxia, intraabdominal bleeding was observed with no apparent source of bleeding. Newly formed blood clots in the subdiaphragmatic space and arterial bleeding near the splenic hilum required a surgery on the next day. Hemorrhagic shock led to multiple organ failure on the fourth day of admission. The autopsy revealed ruptured splenic artery at the pancreatic tail and near the splenic hilum. Microscopically, different stages of segmental arterial mediolysis were observed in partially thinned and aneurysmatic artery.

Temporal patterns of pre- and post-natal target organ damage associated with hypertensive pregnancy: a systematic review.

AIMS: Hypertensive pregnancy is associated with increased risks of developing a range of vascular disorders in later life. Understanding when hypertensive target organ damage first emerges could guide optimal timing of preventive interventions. This review identifies evidence of hypertensive target organ damage across cardiac, vascular, cerebral, and renal systems at different time points from pregnancy to postpartum. METHODS AND RESULTS: Systematic review of Ovid/MEDLINE, EMBASE, and ClinicalTrials.gov up to and including February 2023 including review of reference lists. Identified articles underwent evaluation via a synthesis without meta-analysis using a vote-counting approach based on direction of effect, regardless of statistical significance. Risk of bias was assessed for each outcome domain, and only higher quality studies were used for final analysis. From 7644 articles, 76 studies, including data from 1 742 698 pregnancies, were identified of high quality that reported either blood pressure trajectories or target organ damage during or after a hypertensive pregnancy. Left ventricular hypertrophy, white matter lesions, proteinuria, and retinal microvasculature changes were first evident in women during a hypertensive pregnancy. Cardiac, cerebral, and retinal changes were also reported in studies performed during the early and late post-partum period despite reduction in blood pressure early postpartum. Cognitive dysfunction was first reported late postpartum. CONCLUSION: The majority of target organ damage reported during a hypertensive pregnancy remains evident throughout the early and late post-partum period despite variation in blood pressure. Early peri-partum strategies may be required to prevent or reverse target organ damage in women who have had a hypertensive pregnancy.

This review identifies evidence of damage to the heart, brain, and blood vessels during and after hypertensive disorders of pregnancy and compares the pattern of changes that occur to blood pressure variations. Changes in the heart, brain, and blood vessels are first found in women during a hypertensive pregnancy and are also reported early after pregnancy. The majority of target organ damage reported remains evident long after pregnancy despite variation in blood pressure levels.

Pre-pregnancy blood pressure and pregnancy outcomes: a nationwide population-based study.

BACKGROUND: Hypertension has been known to increase the risk of obstetric complications. Recently, the American College of Cardiology endorsed lower thresholds for hypertension as systolic blood pressure of 130-139 mmHg or diastolic blood pressure 80-89 mmHg. However, there is a paucity of information regarding the impact of pre-pregnancy blood pressure on pregnancy outcomes. We aimed to evaluate the effect of pre-pregnancy blood pressure on maternal and neonatal complications. METHODS: In this nationwide, population based study, pregnant women without history of hypertension and pre-pregnancy blood pressure < 140/90 mmHg were enrolled. The primary outcome of composite morbidity was defined as any of the followings: preeclampsia, placental abruption, stillbirth, preterm birth, or low birth weight. RESULTS: A total of 375,305 pregnant women were included. After adjusting for covariates, the risk of composite morbidity was greater in those with stage I hypertension in comparison with the normotensive group (systolic blood pressure, odds ratio = 1.68, 95% CI: 1.59 - 1.78; diastolic blood pressure, odds ratio = 1.56, 95% CI: 1.42 - 1.72). There was a linear association between pre-pregnancy blood pressure and the primary outcome, with risk maximizing at newly defined stage I hypertension and with risk decreasing at lower blood pressure ranges. CONCLUSIONS: 'The lower, the better' phenomenon was still valid for both maternal and neonatal outcomes. Our results suggest that the recent changes in diagnostic thresholds for hypertension may also apply to pregnant women. Therefore, women with stage I hypertension prior to pregnancy should be carefully observed for adverse outcomes.

Teen pregnancy in the setting of familial dilated cardiomyopathy: a case report.

BACKGROUND: Women with pre-existing forms of familial cardiomyopathy are at increased risk for morbidity and mortality due to hemodynamic changes of pregnancy. There is a lack of consensus about the management and care for these patients given the rarity of this condition. This case represents possibly the youngest pregnant familial dilated cardiomyopathy patient to deliver and the youngest patient to be fitted for a wearable cardiac defibrillator in the postpartum period. CASE PRESENTATION: A 14-year-old gravida 1 with familial dilated cardiomyopathy presented late for prenatal care at 38 weeks, which precluded typical care plans including baseline and serial echocardiograms, medication management, and routine prenatal care. An echocardiogram showed severely decreased left ventricular systolic function compared to studies from one year prior. Three days later the patient presented in labor and had a spontaneous vaginal delivery complicated by postpartum hemorrhage. Her postpartum course was notable for persistence of decreased cardiac function testing and placement of a wearable cardiac defibrillator for prevention against life threatening arrhythmias. CONCLUSION: This case report adds to the literature on pregnancy complicated by familial dilated cardiomyopathy and describes management best practices and considerations during the antepartum, intrapartum, and postpartum periods.

Spontaneous Intracerebral Hemorrhage (ICH) associated with pregnancy and SARS-CoV-2 infection: a case report.

BACKGROUND: Coronavirus Disease 2019 (COVID-19) is predominately known as a respiratory disease associated with pneumonia, acute respiratory distress syndrome and multiorgan failure. However, extra-pulmonary complications of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are increasingly being recognized. In this regard, some studies implied the hemostatic and vascular involvements in patients with SARS-CoV-2 infection. CASE PRESENTATION: We describe a case of spontaneous Intracerebral Hemorrhage (ICH) in a pregnant patient with COVID-19 and history of cesarean section a week before the occurrence of ICH. The patient underwent emergent craniotomy with acceptable outcome. Hemorrhagic events, including ICH, may happen during COVID-19 infection with several possible mechanisms. CONCLUSION: COVID-19 patients, especially high-risk groups, are at a risk of intracranial hemorrhage. Therefore, close follow-up must be maintained and hemorrhagic events must be kept in mind in these cases.

Procoagulant Extracellular Vesicles Alter Trophoblast Differentiation in Mice by a Thrombo-Inflammatory Mechanism.

Procoagulant extracellular vesicles (EV) and platelet activation have been associated with gestational vascular complications. EV-induced platelet-mediated placental inflammasome activation has been shown to cause preeclampsia-like symptoms in mice. However, the effect of EV-mediated placental thrombo-inflammation on trophoblast differentiation remains unknown. Here, we identify that the EV-induced thrombo-inflammatory pathway modulates trophoblast morphology and differentiation. EVs and platelets reduce syncytiotrophoblast differentiation while increasing giant trophoblast and spongiotrophoblast including the glycogen-rich cells. These effects are platelet-dependent and mediated by the NLRP3 inflammasome. In humans, inflammasome activation was negatively correlated with trophoblast differentiation marker GCM1 and positively correlated with blood pressure. These data identify a crucial role of EV-induced placental thrombo-inflammation on altering trophoblast differentiation and suggest platelet activation or inflammasome activation as a therapeutic target in order to achieve successful placentation.

Peripartum Cardiomyopathy.

IMPORTANCE: Peripartum cardiomyopathy is a rare form of heart failure due to left ventricular systolic dysfunction that affects women late in pregnancy and the postpartum period. A diagnosis of exclusion, peripartum cardiomyopathy can be difficult to diagnose in the context of the normal physiologic changes of pregnancy and requires a high index of suspicion. EVIDENCE ACQUISITION: Original research articles, review articles, and guidelines on peripartum cardiomyopathy were reviewed. RESULTS: The etiology of peripartum cardiomyopathy remains poorly defined, but theories include genetic predisposition, as well as myocardial inflammation and angiogenic dysregulation. Risk factors for this condition include hypertensive disorders of pregnancy, Black race, and maternal age older than 30 years. Patients with peripartum cardiomyopathy are at increased risk of acute clinical decompensation, cardiac arrhythmias, thromboembolic complications, and death. Primary treatment modalities include initiation of a medication regimen aimed at the optimization of preload and reduction of afterload. Maternal clinical status is the primary determinant for timing of delivery. CONCLUSIONS: Prompt diagnosis and medical management by an interdisciplinary care team are vital for improving outcomes in patients with peripartum cardiomyopathy.

Abnormal proinflammatory and stressor environmental with increased the regulatory cellular IGF-1/PAPP-A/STC and Wnt-1/ß-Catenin canonical pathway in placenta of women with Chronic venous Disease during Pregnancy.

Lower limbs venous insufficiency refers to a wide variety of venous disorders grouped by the term of chronic venous disease (CVD). Hemodynamic and hormonal changes related to pregnancy period, may promote the development of CVD affecting approximately 1 in 3 women. It has been shown that the presence of this condition is associated with damage and placental suffering. Thus, taking IGF-1/PAPP-A/STC-2, inflammatory cytokines production, PI3K/Akt and Wnt/ ß-catenin pathways as a part of the alterations that occurs in the placenta due to CVD, the aim of this study will be to examine the main components of these pathways. Genic and protein expression of PAPP-A, STC-2, IGF-1, IRS-4 Wnt-1, ß-catenin, c-myc, Cyclin D1, IL-4/IL-6 and PI3K/Akt/mTOR pathway will be analysed through RT-qPCR and immunohistochemical techniques in women with CVD (n=62) and pregnant women without this condition (HC) (n=52). PAPP-A, IGF-1, IL-4, IL-6, IRS-4, PI3K, Akt, mTOR, Wnt-1, ß-catenin, c-myc and Cyclin D1 expression were found to be increased in women with CVD, whereas STC-2 were decreased in this group, compared to non-affected women. Our study has demonstrated that IGF-1/PAPP-A/STC-2 axis, PI3K/Akt and Wnt/ß-catenin pathways, along with c-myc, Cyclin D1 and inflammatory cytokines are altered in placenta women with CVD. These results extent the knowledge that CVD is associated to a placenta damage with abnormal tissue environment and cellular regulation.

Molecular Insights into the Thrombotic and Microvascular Injury in Placental Endothelium of Women with Mild or Severe COVID-19.

Clinical manifestations of coronavirus disease 2019 (COVID-19) in pregnant women are diverse, and little is known of the impact of the disease on placental physiology. Severe acute respiratory syndrome coronavirus (SARS-CoV-2) has been detected in the human placenta, and its binding receptor ACE2 is present in a variety of placental cells, including endothelium. Here, we analyze the impact of COVID-19 in placental endothelium, studying by immunofluorescence the expression of von Willebrand factor (vWf), claudin-5, and vascular endothelial (VE) cadherin in the decidua and chorionic villi of placentas from women with mild and severe COVID-19 in comparison to healthy controls. Our results indicate that: (1) vWf expression increases in the endothelium of decidua and chorionic villi of placentas derived from women with COVID-19, being higher in severe cases; (2) Claudin-5 and VE-cadherin expression decrease in the decidua and chorionic villus of placentas from women with severe COVID-19 but not in those with mild disease. Placental histological analysis reveals thrombosis, infarcts, and vascular wall remodeling, confirming the deleterious effect of COVID-19 on placental vessels. Together, these results suggest that placentas from women with COVID-19 have a condition of leaky endothelium and thrombosis, which is sensitive to disease severity.

Human-induced pluripotent stem cells for modelling metabolic perturbations and impaired bioenergetics underlying cardiomyopathies.

Normal cardiac contractile and relaxation functions are critically dependent on a continuous energy supply. Accordingly, metabolic perturbations and impaired mitochondrial bioenergetics with subsequent disruption of ATP production underpin a wide variety of cardiac diseases, including diabetic cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, anthracycline cardiomyopathy, peripartum cardiomyopathy, and mitochondrial cardiomyopathies. Crucially, there are no specific treatments for preventing the onset or progression of these cardiomyopathies to heart failure, one of the leading causes of death and disability worldwide. Therefore, new treatments are needed to target the metabolic disturbances and impaired mitochondrial bioenergetics underlying these cardiomyopathies in order to improve health outcomes in these patients. However, investigation of the underlying mechanisms and the identification of novel therapeutic targets have been hampered by the lack of appropriate animal disease models. Furthermore, interspecies variation precludes the use of animal models for studying certain disorders, whereas patient-derived primary cell lines have limited lifespan and availability. Fortunately, the discovery of human-induced pluripotent stem cells has provided a promising tool for modelling cardiomyopathies via human heart tissue in a dish. In this review article, we highlight the use of patient-derived iPSCs for studying the pathogenesis underlying cardiomyopathies associated with metabolic perturbations and impaired mitochondrial bioenergetics, as the ability of iPSCs for self-renewal and differentiation makes them an ideal platform for investigating disease pathogenesis in a controlled in vitro environment. Continuing progress will help elucidate novel mechanistic pathways, and discover novel therapies for preventing the onset and progression of heart failure, thereby advancing a new era of personalized therapeutics for improving health outcomes in patients with cardiomyopathy.

Lipidomic profiling of chorionic villi in the placentas of women with chronic venous disease.

Background: Chronic venous disease (CVD) is a prevalent lower limb venous pathology that especially affects women, who also show an increased risk of this disease during pregnancy. Studies have shown significant structural changes in the placentas of women with CVD and several markers of tissue damage have been also described. Patients and Methods: To try to understand the different placental pathologies, research efforts have focused on examining metabolomic profiles as indicators of the repercussions of these vascular disorders. This study examines changes produced in the metabolomic profiles of chorionic villi in the placentas of women with CVD. In a study population of 12 pregnant women, 6 with and 6 without CVD, we compared through mass spectroscopy coupled to ultra-high performance liquid chromatography (UHPLC-MS), 240 metabolites in chorionic villus samples. Results: This study is the first to detect in the placental villi of pregnant women with CVD, modifications in lysophosphatidylcholines and amino acids along with diminished levels of other lipids such as triglycerides, sphingomyelins, and non-esterified omega 9 fatty acids, suggesting a role of these abnormalities in the pathogenesis of CVD. Conclusions: Our findings are a starting point for future studies designed to examine the impacts of CVD on maternal and fetal well-being.

How I treat thrombotic thrombocytopenic purpura in pregnancy.

Thrombotic thrombocytopenic purpura (TTP) is an acute, life-threatening thrombotic microangiopathy (TMA) caused by acquired or congenital severe deficiency of ADAMTS13. Pregnancy is a recognized risk factor for precipitating acute (first or recurrent) episodes of TTP. Differential diagnosis with other TMAs is particularly difficult when the first TTP event occurs during pregnancy; a high index of suspicion and prompt recognition of TTP are essential for achieving a good maternal and fetal outcome. An accurate distinction between congenital and acquired cases of pregnancy-related TTP is mandatory for safe subsequent pregnancy planning. In this article, we summarize the current knowledge on pregnancy-associated TTP and describe how we manage TTP during pregnancy in our clinical practice.

How I treat venous thromboembolism in pregnancy.

One to 2 pregnant women in 1000 will experience venous thromboembolism (VTE) during pregnancy or postpartum. Pulmonary embolism (PE) is a leading cause of maternal mortality, and deep vein thrombosis leads to maternal morbidity, with postthrombotic syndrome potentially diminishing quality of life for a woman's lifetime. However, the evidence base for pregnancy-related VTE management remains weak. Evidence-based guideline recommendations are often extrapolated from nonpregnant women and thus weak or conditional, resulting in wide variation of practice. In women with suspected PE, the pregnancy-adapted YEARS algorithm is safe and efficient, rendering computed tomographic pulmonary angiography to rule out PE unnecessary in 39%. Low molecular weight heparin (LMWH) in therapeutic doses is the treatment of choice during pregnancy, and anticoagulation (LMWH or vitamin K antagonists [VKAs]) should be continued until 6 weeks after delivery, with a 3-month minimum total duration. LMWH or VKA use does not preclude breastfeeding. Postpartum, direct oral anticoagulants are an option if a woman does not breastfeed and long-term use is intended. Management of delivery, including type of analgesia, requires a multidisciplinary approach and depends on local preferences and patient-specific conditions. Several options are possible, including waiting for spontaneous delivery with temporary LMWH interruption. Prophylaxis for recurrent VTE prevention in subsequent pregnancies is indicated in most women with a history of VTE.

Relevance of the assessment of natriuretic peptide plasma concentrations in hypertensive pregnant women.

Assessment of the plasma concentrations of natriuretic peptides (NPs) is widely used to diagnose and evaluate the progression of cardiac failure, and their potential as markers of preeclampsia (PE) has been examined in recent years. It has been established that plasma concentrations of NPs do not change in the course of normal pregnancy. However, elevated levels of these peptides may have a prognostic value in patients with PE. This study presents information about the relevance of NPs assessment in the evaluation of physiological pregnancy, as well as in pregnancy complicated with arterial hypertension. The most commonly examined NPs is the N-terminal fragment of the brain natriuretic peptide (NT-proBNP), and it may be prognostic marker of PE and other complications of pregnancy.

Successful pregnancy in women with inferior vena cava stenosis - case report and discussion.

OBJECTIVES: Inferior vena cava syndrome (IVCS) is a heterogenous group of symptoms resulting in obstruction of the main vein inflow . Common reasons are thrombotic changes and tumors. Incidence of inferior vena cava (IVC) anomalies is 0.3% in general population. Iatrogenic IVC lesions caused by catheter insertion play increasing role. Treatment varies depending on the condition. MATERIAL AND METHODS: 32-year old patient was diagnosed with IVC stenosis during infertility related preconception evaluation and informed about increased risk in planned pregnancy. Throughout the well progressing pregnancy patient received low molecular weight heparin. RESULTS: The diagnosis was confirmed intraoperatively during the planned cesarean section. Early postpartum period was normal and patient was discharged with antithrombotic prophylaxis. CONCLUSIONS: Isolated IVC stenosis in pregnancy has not been yet reported in medical literature. Even though IVC anomalies may be associated with other congenital changes, in this case the central venous line treatment in infancy seems to be the most likely cause. Malformations are often accidentally diagnosed because patients are usually asymptomatic. CT and MRI are recommended diagnostic tools. Conservative treatment is recommended for asymptomatic patients, as opposed to surgical treatment for symptomatic. However, due to condition's rarity, there is no evidence based approach management.

ß1 adrenoceptor antibodies induce myocardial apoptosis via inhibiting PGC-1α-related pathway.

BACKGROUND: Peripartum cardiomyopathy (PPCM) is life-threatening heart disease. However, the causes and pathogenesis of PPCM remain unclear. Previous studies found that ß1 adrenoceptor antibodies (ß1AA) had possible involvement in the development of PPCM. In the present study, we determined the potential relationship between PPCM and ß1AA, including the mechanism of ß1AA leading to PPCM. METHODS: We extracted the ß1AA from the postpartum Wistar rats that were injected by the antigen peptide segment of the ß1 adrenoceptor to produce PPCM. We tested the effects of ß1AA on H9C2 cell line by CCK-8, LDH, TUNEL, SA-ELISA, qRT-PCR, and western blot methods. Furthermore, PGC-1α was overexpressed to rescue the effect of ß1AA on H9C2 cells. RESULTS: We found that the extracted ß1AA induced apoptosis of cardiac myocytes of H9C2 cell line. Moreover, the expression of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), which is a master regulator of mitochondrial metabolism, and its downstream transcript vascular endothelial growth factor (VEGF) got decreased in H9C2 cells after ß1AA treatment. In addition, the effect of ß1AA could be inhibited by atenolol, the antagonist of ß1 adrenoceptors (ß1AR) and imitated by isoprenaline, the agonist of ß1AR. Furthermore, overexpression of PGC-1α in the H9C2 cells rescued the apoptosis of cells and inhibitory expression of VEGF induced by ß1AA. CONCLUSIONS: Our results suggest that the symptoms of PPCM due to myocardial cell apoptosis induced by ß1AA inhibiting the PGC-1α-related pathway impairs mitochondrial energy metabolism. Therefore, our results uncover a previously unknown role of the ß1AA pathway in the etiology of PPCM and provide a novel potential target for the treatment of PPCM.

Pregnancy-induced Cardiovascular Pathologies: Importance of Structural Components and Lipids.

Pregnancy leads to adaptations for maternal and fetal energy needs. The cardiovascular system bears the brunt of the adaptations as the heart and vessels enable nutrient supply to maternal organs facilitated by the placenta to the fetus. The components of the cardiovascular system are critical in the balance between maternal homeostatic and fetus driven homeorhetic regulation. Since lipids intersect maternal cardiovascular function and fetal needs with growth and in stress, factors affecting lipid deposition and mobilization impact risk outcomes. Here, the cardiovascular components and functional derangements associated with cardiovascular pathology in pregnancy, vis-à-vis lipid deposition, mobilization and maternal and/or cardiac and fetal energy needs are detailed. Most reports on the components and associated pathology in pregnancy, are on derangements affecting the extracellular matrix and epicardial fat, followed by the endothelium, vascular smooth muscle, pericytes and myocytes. Targeted studies on all cardiovascular components and pathological outcomes in pregnancy will enhance targeted interventions.

Body Mass Index in Young Women and Risk of Cardiomyopathy: A Long-Term Follow-Up Study in Sweden.

BACKGROUND: Incidence rates of cardiomyopathies, which are a common cause of heart failure in young people, have increased during the last decades. An association between body weight in adolescence and future cardiomyopathy among men was recently identified. Whether or not this holds true also for women is unknown. The aim was therefore to determine whether for young women being overweight or obese is associated with a higher risk of developing cardiomyopathy. METHODS: This was a registry-based national prospective cohort study with data collected from the Swedish Medical Birth Register, 1982 to 2014, with up to 33 years of follow-up. Included women were of childbearing age (18-45 years) during the initial antenatal visit in their first or second pregnancy (n=1 393 346). We obtained baseline data on body mass index (BMI), smoking, education, and previous disorders. After exclusions, mainly because of previous disorders, the final sample was composed of 1 388 571 women. Cardiomyopathy cases were identified by linking the Medical Birth Register to the National Patient and Cause of Death registers. RESULTS: In total, we identified 1699 cases of cardiomyopathy (mean age at diagnosis, 46.2 [SD 9.1] years) during the follow-up with an incidence rate of 5.9 per 100 000 observation years. Of these, 481 were diagnosed with dilated cardiomyopathy, 246 had hypertrophic cardiomyopathy, 61 had alcohol/drug-induced cardiomyopathy, and 509 had other forms. The lowest risk for being diagnosed with a cardiomyopathy was detected at a BMI of 21 kg/m2, with a gradual increase in risk with higher BMI, particularly for dilated cardiomyopathy, where a hazard ratio of 4.71 (95% CI, 2.81-7.89) was found for severely obese subjects (BMI ≥35 kg/m2), as compared with BMI 20 to <22.5. CONCLUSIONS: Elevated BMI among young women was associated with an increased risk of being diagnosed with a subsequent cardiomyopathy, especially dilated cardiomyopathy, starting already at mildly elevated body weight, whereas severe obesity entailed an almost 5-fold increase in risk. With the increasing numbers of persons who are overweight or obese, higher rates of cardiomyopathy can be expected in the future, along with an altered disease burden related to adiposity.