Aortic stenosis (AS) involves progressive valve obstruction and a remodeling response of the left ventriculum (LV) with systolic and diastolic dysfunction. The roles of interstitial fibrosis and myocardial steatosis in LV dysfunction in AS have not been completely characterized. We enrolled 31 patients (19 women and 12 men) with severe AS undergoing elective aortic valve replacement. The subjects were clinically evaluated, and transthoracic echocardiography was performed pre-surgery. LV septal biopsies were obtained to assess fibrosis and apoptosis and fat deposition in myocytes (perilipin 5 (PLIN5)), or in the form of adipocytes within the heart (perilipin 1 (PLIN1)), the presence of ceramides and myostatin were assessed via immunohistochemistry. After BMI adjustment, we found a positive association between fibrosis and apoptotic cardiomyocytes, as well as fibrosis and the area covered by PLIN5. Apoptosis and PLIN5 were also significantly interrelated. LV fibrosis increased with a higher medium gradient (MG) and peak gradient (PG). Ceramides and myostatin levels were higher in patients within the higher MG and PG tertiles. In the linear regression analysis, increased fibrosis correlated with increased apoptosis and myostatin, independent from confounding factors. After adjustment for age and BMI, we found a positive relationship between PLIN5 and E/A and a negative correlation between septal S’, global longitudinal strain (GLS), and fibrosis. Myostatin was inversely correlated with GLS and ejection fraction. Fibrosis and myocardial steatosis altogether contribute to ventricular dysfunction in severe AS. The association of myostatin and fibrosis with systolic dysfunction, as well as between myocardial steatosis and diastolic dysfunction, highlights potential therapeutic targets. Aortic stenosis (AS) is one of the most common valvular diseases in the Western world, with an estimated prevalence as high as 12.4% in the elderly , leadingMyocardial fibrosis is, in general, one of the hallmarks of a failing heart . Among sThe activation of profibrotic pathways, which involves a protein of the transforming growth factor-β (TGFβ) family called myostatin, is due to cardiomyocyte death with the consequent release of free fatty acids (FFAs), the recruitment of macrophages, apoptosis, and fibrosis . In LV dGlobal longitudinal strain (GLS), assessed with echocardiography, has been considered a surrogate marker for myocardial fibrosis . StudiesEctopic fat deposition in the myocardium, termed myocardial steatosis, is frequently associated with diastolic dysfunction in severe AS, ischemic heart disease, and various metabolic diseases ,18. GeneRegarding the role of myocardial steatosis in myocardial dysfunction, animal models have proved that myocardial triglyceride accumulation disrupts normal myocardial lipid metabolism and results in diastolic dysfunction . The rolAs shown thus far, both interstitial fibrosis and myocardial steatosis appear to significantly contribute to the development of myocardial dysfunction in different heart diseases and also in patients with advanced AS. However, in human studies, myocardial quality in terms of fibrosis and myosteatosis has been characterized mainly using MRI and histologically only in a few studies to validate MRI measurements ,6,15.Thus, the present study aimed to analyze the LV biopsies of patients with severe AS who had undergone surgery, fibrosis, and myocardial lipid infiltration, as well as to investigate the correlation between them and key echocardiographic parameters indicative of LV dysfunction. Furthermore, this study sought to evaluate the underlying mechanisms and pathways correlated with these histological phenomena.A total of 31 patients  diagnosed with severe AS undergoing elective cardiac surgery for aortic valve replacement were recruited as our study population. The clinical characteristics as well as the metabolic profiles and echocardiographic data of these subjects are shown in To establish the levels of fibrosis, cell apoptosis, and fat deposition, and the presence of ceramides and myostatin, in the LV samples obtained from patients with AS during surgery, we labeled and quantified these elements using different staining and detection methods, as exemplified in p = 0.007), as well as between fibrosis and the area covered by PLIN5 . Apoptosis and PLIN5 also showed a significant association . Regarding ceramides, we found only a positive trend with fibrosis (r = 0.235) and with PLIN5 (r = 0.241); however, these associations were not statistically significant.Then, we evaluated the interrelationship between the different histological characteristics of the dysfunctional LV samples obtained from AS patients, after adjustment for BMI . We intep < 0.001). A trend was also observed between PLIN5 and the MG and PG tertiles (p 0.089)   and peak gradient (PG) obtained from the echocardiography before surgery in patients with AS, dividing the patients into tertiles according to their echocardiographic parameters. As shown in tertiles . Regardip 0.089) . Finallyctively) .p = 0.025; β-coefficient = 0.464), independent from age, BMI, diabetes mellitus, statin therapy, and other histological characteristics of LV, explaining approximately 40% of its variance (R2 0.413) (data not shown in the table). Apoptosis in the model presented an association with fibrosis of borderline significance , independent from the other variables (data not shown in the table).Subsequently, we performed a multiple linear regression analysis to explore the relationship between fibrosis, which was considered as the dependent variable, and different independent variables, including age, gender, BMI, diabetes mellitus, statin therapy, apoptosis, PLIN5, ceramides, and myostatin. Fibrosis correlated with myostatin  as well as a slight negative correlation between fibrosis and GLS ; conversely, there was not any correlation between fibrosis and EF and E/A (p = 0.082) (p = 0.009), while there were no correlations between PLIN5 and GLS, EF, and DTI septal S’ , EF , GLS , the DTI septal S’ with the main histological features of the LVs of AS patients, after adjustments for age and BMI . We obse and E/A . A borde= 0.082) . Additioeptal S’ . Myostateptal S’ . FinallyIn this group of patients undergoing elective surgery for AS, myocardial fibrosis and myocardial steatosis, as evaluated histologically, collectively contributed to ventricular dysfunction. In particular, the degree of fibrosis was correlated with systolic dysfunction. and the degree of fat infiltration in the heart was related to diastolic dysfunction. In this group of patients, an increase in pressure overload, expressed as a mean or peak gradient, was related to increases in LV fibrosis and myostatin and ceramides levels. The levels of ventricular fibrosis were mainly explained by increased myostatin expression, independent from other confounding factors.AS is a disease that affects both the valve and the myocardium, as myocardial dysfunction is strictly associated with pressure overload . HoweverIn this group of patients with severe AS, myocardial fibrosis was strictly related to a reduction in systolic function. Moreover, in the regression model, the amount of fibrosis in LV biopsies was mainly explained by myostatin. Myostatin, a protein of the TGFβ family, was discovered in 1997 in skeletal muscle cells and characterized as a signal that regulates muscle growth and differentiation, as its gene deletion was responsible for the double-muscle phenotype in cattle . In addiThe role of myostatin has also been explored in humans across different types of heart diseases with cardiac remodeling and reduced LV ejection fractions, and a strong association has been found between the severity of the disease and myostatin overexpression ,13. MoreIn our study in AS patients, myostatin emerged as a significant predictor of ventricular fibrosis, independent of age, gender, BMI, diabetes mellitus, statin therapy, apoptosis, PLIN5, and ceramides, explaining approximately 40% of the variance. In a recent study using a mouse model of AS, treatment with monoclonal anti-myostatin antibodies failed to reduce cardiac hypertrophy or fibrosis . This suMyofibrosis and myosteatosis are considered two interrelated mechanisms of muscular damage associated with aging and/or obesity ,35. ThusCardiac steatosis has been linked with diastolic dysfunction in animal models and has been shown to be an independent predictor of diastolic function in diabetic and obese patients . AccordiMyocardial fibrosis and steatosis may thus contribute to LV insufficiency in AS, mainly affecting global systolic and diastolic functions, respectively. However, several studies using non-invasive imaging have shown that fibrosis could be distributed heterogeneously across ventricular walls in different cardiomyopathies ,38. A poIn our study, the histological degree of myocardial fibrosis and steatosis were significantly correlated with each other. Moreover, apoptosis resulted in being strictly related not only to myocardial fibrosis but also to myocardial steatosis. From a physiopathological point of view, it is possible to hypothesize that pressure overload causes the death of cardiomyocytes with the consequent release of free fatty acids (FFAs), the recruitment of macrophages, apoptosis, and the activation of profibrotic pathways .In the heart, as in other organs, the excess of free fatty acids starts to accumulate in the form of many different lipid metabolites such as ceramides and other sphingolipids when they cannot be stored in lipid droplets within the cells . CeramidFinally, it is known that myocardial steatosis may be due to both lipid droplets stored within cardiomyocytes and triglyceride droplets in cardiac adipocytes . We and In conclusion, our study provides data on the roles of myocardial fibrosis and steatosis in LV dysfunction, with the unique aspect of direct histological data analysis, which could be, for some aspects, more informative than non-invasive methods. However, further analyses are needed to explore the molecular mechanisms involved in these relationships. It may be important to associate IHC with other complementary methods of analysis, such as, for example, real-time PCR or Western blot, which can assess the expression of target genes or evaluate the proteins involved in the principal molecular pathways. Further studies conducted in wider samples are necessary for better exploring the possible molecular mechanisms and eventual targets of therapies.Even though our results are only descriptive and require further study, especially to establish the role of cardiac adipocytes, we can speculate that intramyocardial adipocytes may become dysfunctional due to different types of stress. Besides the canonical mechanisms that contribute to adipocytes’ dysfunction, such as inflammation, ROS production, and hypoxia, a role could be also hypothesized for mechanical stress. In a 3D adipocyte culture model, Pellegrinelli et al.  showed tWe recruited a final group of 31 subjects (19 women and 12 men) undergoing elective cardiac surgery for aortic valve replacement for AS. All patients were affected by severe AS, according to the European Society of Cardiology (ESC) Guidelines of 2012 . ImportaAll subjects were clinically evaluated with measurement of their blood pressure and heart rate. Information regarding their smoking habits, the presence of diseases, and medication intake was also collected. Venous blood samples for the metabolic assessments were obtained after overnight fasting. Plasma glucose levels were measured with a glucose analyzer . Cholesterol and triglyceride levels were determined using a Techincon Auto Analyzer , and dextran–magnesium precipitation was used to derive the HDL values. Weight with an approximation of 0.1 kg  and height using a stadiometer with an approximation of 0.5 cm  were determined for all subjects. Body mass index (BMI) was computed by dividing weight in kilograms by height in square meters. Waist circumference was obtained with a measuring tape at the narrowest circumference of the abdomen.All patients underwent a preoperative echocardiogram, performed with an echocardiograph equipped with speckle-tracking analysis (Philips IEE) in the echocardiography clinics at the Cardiology Department of the University Hospital of Verona. For each subject, the following were evaluated: systolic function (the EF of the LV of the biplane Simpson method %), the degree of the AS transvalvular mean gradient (MG), and the peak trans-valve gradient (PG). Furthermore, diastolic function indices were collected using tissue Doppler imaging, such as E/A . The pathological cut-off of altered relaxation was defined as E/A < 1 ms. Finally, GLS  was measured as an index of systolic functionality, using a two-dimensional speckle-tracking method. The GLS was shown as an absolute value, and we considered normal GLS values of 17.5 ± 3.2%.In the surgical room, myocardial specimens (interventricular septum tissue) were obtained by trained surgeons after a median sternotomy, approximately 1 h after the induction of anesthesia. The biopsies were then stored for subsequent immunohistochemical evaluation.2O2) for 10 min and non-immune serum for 60 min at room temperature, respectively. The slides were then incubated sequentially with primary rabbit antibodies for 16 h at 4 °C in a humidified chamber and washed with PBS buffer three times for 5 min each. Subsequently, the sections were incubated with the secondary antibody for 30 min at 20 °C and washed again with PBS for 5 min. DAB was used as the chromogen to visualize peroxidase activity. The sections were counterstained with hematoxylin and were finally assembled with Entellan and overlaid with coverslips.Freshly isolated ventricular myocardial muscle samples were fixed via immersion in 4% paraformaldehyde in PBS (pH 7.4) overnight at 4 °C, and then dehydrated, cleared, and paraffin-embedded. Five-micrometer-thick serial sections were obtained from the embedded tissues. These sections were then stained with hematoxylin and eosin (H/E) to assess their morphologies prior to immunohistochemical processing. The following primary antibodies were used for the IHC analysis: rabbit anti-human perilipin-1 (PLIN1)  to detect adipocytes, rabbit anti-human perilipin-5 (PLIN5)  to mark lipid droplets inside cardiomyocytes, and rabbit anti-human myostatin . The secondary antibody was SignalStain Boost IHC detection reagent HRP Rabbit . A negative control was conducted by using the secondary antibody alone. A diaminobenzidine hydrochloride (DAB) substrate kit for peroxidase was used for the IHC . Briefly, the paraffin-embedded sections were dewaxed and subjected to antigen heat retrieval in sodium citrate buffer (pH 6.00) in a microwave oven for 3 cycles for 5 min each at 750 watt. Endogenous peroxidase activity and non-specific binding were blocked via incubation with 3% hydrogen peroxide  for 15 min each; and non-specific binding was blocked by incubating the sections with non-immune serum for 20 min at room temperature. The sections were then incubated with primary mouse IgM anti ceramide  for 16 h at 4 °C in a humidified chamber, washed with PBS buffer three times for 5 min each. Subsequently, the sections were incubated with the secondary antibody Biotinylated Goat anti-mouse IgM  for 30 min at 20 °C, washed with PBS for 5 min, and incubated with Vectastain ABC reagent  for 30 min at 20 °C. The sections were then washed again with PBS for 5 min. A negative control was conducted by using the secondary antibody alone.The sections were dewaxed and subjected to antigen heat retrieval in sodium citrate buffer at pH 6.00 using a microwave oven for 3 cycles for 5 min each at 750 watts. Endogenous peroxidase activity was blocked by incubating the sections with 3% HDAB was used as the chromogen to visualize peroxidase activity. The sections were counterstained with hematoxylin, assembled with Entellan, and overlaid with coverslips.Sections of the ventricles were stained with Masson’s trichrome to visualize interstitial fibrosis, according to the manufacturer’s protocol . The sections were deparaffined, rehydrated, stained with ferric hematoxylin according to Weigert for 10 min, incubated with picric acid for 4 min, quickly washed with distilled water, stained with Ponceau B solution for 4 min, quickly washed with distilled water, incubated with phosphomolybdic acid for 10 min, stained with aniline blue according to Masson for 5 min, quickly washed with distilled water, dehydrated, cleared, assembled with Entellan, and overlaid with coverslips.The detection of apoptotic cardiomyocytes was performed using the terminal-deoxynucleotidyl-transferase-mediated dUTP nick end labeling (TUNEL) method, according to the manufacturer’s protocol . To apply this method, myocardial tissues from the paraffin-embedded ventricles were cut into thin slices (5 µm thickness). In the TUNEL assay, apoptotic cardiomyocytes were identified by the presence of dark-blue-stained nuclei, while non-apoptotic cardiomyocytes displayed pink/red-stained nuclei.All ventricle sections were observed at 40×, 200× and 400× magnification using an Olympus BX51 photomicroscope microscope equipped with a KY-F58 CCD camera (JVC) and with Image-ProPlus software  or by using the EVOS FL Auto Cell Imaging System with an EVOS Onstage Incubator  photomicroscope.2 by dividing the cell count by the total area expressed in mm2.To quantify the number of PLIN1-positive adipocytes among cardiomyocytes, a manual counting method was used. The entire area of each ventricle was observed, and the number of PLIN1-positive adipocytes was manually counted. The total area of the observed section was then calculated using ImageJ software (ImageJ1.8.3) on the acquired images and the number of adipocytes was expressed as cells/mm2 area; range: 3.21–28.32 LDs/mm2 area). Myostatin was detected in all LV samples . All biopsies were also positive for ceramides inside the cardiomyocytes .The optical density (OD) analysis of PLIN5, myostatin, and ceramides was performed on the whole ventricle sections. Images acquired at 200× magnification were analyzed using the Color Threshold function of ImageJ software and manual threshold correction when necessary. All LV biopsies were positive for PLIN5, with a very variable range within the group  in the study population.2 and as the average number of cardiomyocytes undergoing apoptosis/10,000 cardiomyocytes [The degree of apoptosis was calculated by counting the number of dark-blue-stained nuclei in cardiomyocytes using ImageJ software on five images acquired at 200× magnification. The degree of apoptosis was then expressed as the number of dark-blue-stained nuclei/mmmyocytes . The scoThe results were reported as means ± standard deviation (SD). Nonparametric tests were used for non-normally distributed variables. Tau-b di Kendall correlations were used to test the level of correlation between the variables. Linear multiple regression was performed to evaluate the effects of the independent variables on the fibrosis-dependent variable. A significance level of 5% was always adopted. All analyses were performed using SPSS .In patients with severe aortic stenosis, myocardial fibrosis and myocardial steatosis, which were histologically evaluated, collectively contributed to ventricular dysfunction, correlating with systolic and diastolic dysfunction, respectively. Our study suggests synergistic roles of myofibrosis and myosteatosis in determining ventricular damage in patients with AS and pressure overload. Pressure overload is related to an increase in both myostatin and fibrosis in the myocardium, as well as an increase in myocardial steatosis and ceramide deposition in the ventriculum. Apoptosis is linked to both the degree of fibrosis and steatosis in the LVs of patients with AS.These associations may highlight potential therapeutic targets to be explored in other experimental models. Furthermore, cardiac adipocytes are also present in the ventricles of patients with AS, close to damaged areas, with a role that is yet to be completely explored.


Hypertension is the most common chronic disease and the leading risk factor for disability and premature deaths worldwide. Approximately 10–20% of all patients with hypertension and 15–18% of the general population who are treated for hypertension have resistant hypertension (RH). Patients with RH have a higher risk of end-organ damage, such as carotid intima–media thickening, retinopathy, left ventricular hypertrophy and heart failure, myocardial infarction, stroke, impaired renal function, and death than those with controlled blood pressure. In the present study, we applied echocardiography to patients with RH to evaluate myocardial work (MW) and determine whether it is predictive for the occurrence of adverse events within 3 years.We included 283 outpatients and inpatients aged ≥ 18 years who met the clinical criteria for RH, without arrhythmia and severe aortic valve stenosis, between July 2018 and June 2019. The patients were followed up for 3 years from starting enrollment, and any adverse event that occurred during the period was used as the observation end point. Each enrolled patient underwent a complete transthoracic echocardiogram examination, blood pressure was measured and recorded, and MW was then analyzed.Eighty-two (28.98%) patients with RH had adverse events, such as myocardial infarction , heart failure , renal insufficiency , renal failure , cerebral infarction , and cerebral hemorrhage , and no death events occurred. In patients with RH and adverse events, global longitudinal strain (GLS) (− 16% vs. − 18%), the global work index (2079 mmHg% vs. 2327 mmHg%), global constructive work (2321 mmHg% vs. 2610 mmHg%), and global work efficiency (93% vs. 94%) were lower than those in patients without adverse events. However, global wasted work (GWW) was higher in patients with RH and adverse events than in those without adverse events (161 mmHg% vs. 127 mmHg%). GLS and GWW were the most significant in predicting adverse events.MW, especially GLS and GWW, is a good method to predict 3-year adverse events in patients with RH. Hypertension affects approximately one billion adults. Hypertension accounts for approximately 9% of global disability-adjusted life years and is associated with more than nine million deaths annually , 2. On tResistant hypertension (RH) is defined as the failure to achieve recommended clinic (office) blood pressure (BP) goals, despite the concurrent use of three antihypertensive medications of different classes at optimal dosages These medications commonly include a long-acting calcium channel blocker, a blocker of the renin–angiotensin system (an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker), and a diuretic, or achieving BP goals with four or more drugs after causes of pseudoresistance are ruled out . The preAdverse events associated with hypertension comprise all fatal and nonfatal cardiovascular events. These events include fatal and nonfatal acute myocardial infarction, sudden cardiac death, new-onset heart failure, death from progressive heart failure, any myocardial revascularization procedure, fatal and nonfatal stroke, any aortic or lower limb revascularization procedure, any amputation above the ankle, death from aortic or peripheral arterial disease, the beginning of dialysis, and death due to renal failure .This study aimed to investigate a method and related indicators that can be used to predict the occurrence of adverse events in patients with RH. Increased cardiac afterload affects the myocardium owing to chronic hypertension. Therefore, we decided to apply myocardial work (MW) and related indicators evaluating by echocardiography in patients with RH to determine which indicators could be used to predict the occurrence of adverse events. This method was first proposed by Russell and his colleagues, and is a non-invasive echocardiographic method based upon an estimated left ventricular (LV) pressure curve in combination with strain by speckle-tracking echocardiography (STE) . They foThis was a single-center, prospective, observational study that included 283 outpatients and inpatients aged ≥ 18 years who met the clinical criteria for RH without arrhythmia and severe aortic valve stenosis. These patients had regular therapy at Zhongshan Hospital (Xiamen), Fudan University between July 2018 and June 2019 and were followed up for 3 years. At the same time, we selected the same number of non-hypertensive outpatients or inpatients with a similar sex and age composition as controls. Patients with RH who had adverse events during the follow-up were included in the independent group, while patients with RH who did not have adverse events were included as controls. The indices related to global MW in patients with RH at the time of enrollment were retrospectively analyzed. The differences in correlation parameters of MW between the two groups were compared to obtain some useful indices for predicting adverse events in patients with RH. Exclusion criteria were as follows: patients < 18 years old, those with pseudo-RH, arrhythmia, severe aortic valve stenosis, or poor image quality, patients who have been diagnosed with obstructive sleep apnea (OSA), those who refused to participate in the study, and those who could not sign a written consent form.−1). We used the LV short axis view to measure LV wall thickness, and used the apical two-, three-, and four- chamber views to analyze LV global MW according to the suggestions by Russel et al. [Comprehensive transthoracic echocardiography (TTE) was performed by an experienced sonographer using a Vivid E95 ultrasound system equipped with an M5S 3.5-MHz transducer  with analysis software . All patients underwent a complete TTE examination. Patients were scanned in the left lateral decubitus position and connected to an electrocardiogram. All two-dimensional (2D) and Doppler recordings and measurements were performed according to American Society of Echocardiography guidelines . Two-diml et al. .Myocardial work (MW) classically has been calculated as the area of pressure–volume loop of the left ventricle (LV), following the brilliant pioneering ideas of Otto Frank at the end of the nineteenth century and later of Hiruyuki Suga and Kiichi Sugawara, who modeled work done by the LV as an extension of Hooke’s law of the elasticity of a spring and introduced the concept of time-varying elastance . An expeMW is composed of the following parameters: (1) Global MW index (GWI): total work within the area of the LV pressure–strain loop and is calculated from mitral valve closure to mitral valve opening. (2) Constructive MW: work performed by the LV contributing to LV ejection during systole. Constructive MW is defined as shortening of myocytes during systole and lengthening of myocytes during isovolumic relaxation. (3) Wasted MW: work performed by the LV that does not contribute to LV ejection. Wasted MW is defined as myocardial work during lengthening in systole {adding shortening during isovolumic relaxation (IVR)}. (4) MW efficiency: constructive MW/(constructive MW+wasted MW) .The analysis of MW was performed mainly through the analysis software of the instrument or was performed offline with the same software. GLS analysis was the main step in the analysis of MW because GLS represents the displacement of LV myocardial deformation. We used 2D speckle-tracking to acquire the GLS. In this process, event timing was the first important step. Most speckle-tracking software packages use an electrocardiogram (R-wave trigger for defining the zero reference of the strain curve). However, this method is only applicable when QRS is normal, and if conduction delay occurs, the zero reference of the strain curve will be incorrectly defined . The besAll subjects were followed up with telephone conduction each 3 moth and interview conduction each 6 moths. The observation period for each subject was the number of months from the baseline evaluation to the date of the last clinical visit or the first end point, whichever came first. Any fatal or nonfatal adverse events happened was regarded as the end point. End points were adjudicated from medical records, and interviews with the attending physicians and patients’ families, using a standard questionnaire reviewed by an independent observer.t-test. Differences between the two types of continuous data that were not normally distributed were compared by the rank sum test, and differences between the two types of categorical data were compared by the chi-square test. All reported P values were two-sided, and a value of P < 0.05 was considered statistically significant. The cut-off points with diagnostic value are shown by the receiver operating characteristic (ROC) curve. A logistic regression analysis was used to analyze multiple factors that could produce the same outcome. In order to understand which factors contribute to the occurrence of adverse events, we use logistic regression and Cox regression analysis was used to analyze the events over time during the 3-years followed up.Statistical analysis was performed using IBM SPSS software . Continuous data are expressed as the mean and standard deviation or median with the 25th–75th interquartile range (IQR), and categorical data are expressed as the percentage and frequency. Differences between the two types of continuous data consistent with a normal distribution were compared by the P<0.05). In the RH group, the median office SBP, office DBP, GLS, GWI, GCW, GWW, and GWE were significantly higher than those in the control group .The patients’ baseline characteristics are shown in Table According to the definition of adverse events mentioned above, adverse events included myocardial infarction, heart failure, renal insufficiency, renal failure, cerebral infarction, and cerebral hemorrhage. No death events occurred Table .Table 2TP = 0.008) in the adverse events group than in the non-adverse events group (43.9% vs. 31.9%), while only 47.1% of patients in the non-adverse events group had a family history of hypertension and 33.8% had LV wall remodeling. Laboratory indicators, such as blood glucose concentrations, were higher in the adverse events group than in the non-adverse events group . The mean low-density lipoprotein concentration was lower in the adverse events group than in the non-adverse events group , but high-density lipoprotein, total cholesterol, and triglyceride concentrations were not significantly different between the two groups. Furthermore, BMI, BSA, office SBP, office DBP, 24-h ambulatory BP  and all MW-related indicators  in the adverse events group were significantly lower than those in the non-adverse events group. However, GWW was significantly higher in the adverse events group than in the non-adverse event group (P < 0.05).Table According to the ROC curve analysis of GLS Fig. A and GWWP = 0.01). GLS with an absolute value of 16% as the cut-off value had a significant effect on adverse events . GWW with 127 mmHg% as the cut-off value had a significant effect on adverse events . Other factors, such as alcohol consumption  and blood glucose concentrations , also had a significant effect on adverse events . Meanwhile, SBP also was a factor causing adverse events, SBP .  Echocardiography is still a safe and effective method to evaluate myocardial damage and cardiac contractile function, and can also be used to predict adverse events in patients with RH. (ii) Related indicators of MW were significantly different between patients with RH and adverse events and those without adverse events. Among these indicators, GLS, GWI, GCW, GWE in patients with adverse events were significantly reduced, and GWW was increased. (iii) Patients with a family history of hypertension developed high blood pressure (HBP) earlier, and LV remodeling occurred earlier and was more significant. If patients consumed alcohol, and had high blood glucose and high-density lipoprotein concentrations, adverse events were more likely to occur. The effect of hypertension on the heart is mainly achieved through the following three factors. (i) At the early stage of hypertension, the main damage is cardiac diastolic dysfunction, which increases LV filling pressure and heart cavity preload. High afterload caused by high BP then leads to LV eccentric or centripetal hypertrophy, and oxygen consumption to the subendocardial myocardium increases. Regardless of eccentric hypertrophy or centripetal hypertrophy, the myocardial alignment changes to some extent, and the interaction between cardiomyocytes also changes. This in turn affects effective myocardial contraction, and wasted work is increased. In addition, because of the heart resisting the high BP, myocardial contraction force is enhanced, and the lumen of the coronary arteries in the subendocardial myocardium is compressed and narrowed, eventually leading to myocardial ischemia. (ii) An increase in arterial BP leads to an increase in cardiac afterload to resist the increased BP and ensure cardiac output. Cardiomyocytes then increase in thickness, the coronary lumen collapses, and extravascular resistance increases, further leading to an increase in myocardial oxygen consumption. In addition, the thickened myocardium decreases the coronary blood flow reserve, leading to myocardial ischemia and hypoxia. (iii) Hypertension itself can lead to coronary artery stiffness, thereby causing myocardial ischemia and hypoxia. The result of the combination of myocardial ischemia and hypoxia causes myocardial fibrosis, myocardial uncoordinated contraction, and increased myocardial inactivity, which in turn acts on the heart, leading to cardiac hypertrophy and then heart failure.Myocardial strain has been used to identify subclinical myocardial dysfunction in patients with hypertension for more than a decade. Among the different deformation (strain) components, longitudinal strain is important for predicting adverse events in patients with RH. Longitudinal strain corresponds to the function of the subendocardial layer of the myocardium in which longitudinal fibers are subjected to the negative effect of early development of fibrosis in hypertensive heart disease . A histoFrom the results of our study, GWW is another useful predictive index, it was higher in adverse events’ group. This finding may be related to long-term hypertension, leading to myocardial ischemia, especially the subendocardial myocardium, plays the main contractile role during the contraction process, leading to the wasted work increased. Slimani et al. assessed intraoperative myocardial histology and the stress–strain relationship in 101 patients with aortic stenosis (AS) who underwent aortic valve replacement , they foDiabetes mellitus is an independent risk factor for coronary heart disease, and the proportion of patients with coronary heart disease can be as high as that in the diabetic population (55%) . CoronarIn conclusion, a family history of hypertension, hyperglycemia, hypertension itself, and LV hypertrophy eventually lead to abnormal coronary blood perfusion, and myocardial coronary artery perfusion is reduced. These series of events result in myocardial damage, decreased GLS, and increased GWW, which play an important role in adverse events in patients with RH.This was a single-center study, and the enrolled subjects were limited to those who visited our hospital. Additionally, the number of RH patients included was not large and not sufficiently representative. Therefore, the results may only represent the population in the region where our hospital is located. There was also no group comparison by sex, and this remains to be further studied. The observation time was only 3 years, the data may be more meaningful if the follow-up period is extended. In addition, our criteria for the diagnosis of hypertension were SBP ≥140 mmHg and/or DBP ≥90 mmHg according to the American College of Cardiology/American Heart Association Guideline for the Prevention, Detection, Evaluation and Management of High Blood Pressure in Adults . This guAdverse events in patients with RH are the result of a combination of multiple factors. Patients with a family history of hypertension, combined with hyperglycemia, LV wall remodeling, and alcohol consumption, are more likely to have adverse events within 3 years. GLS and GWW are not only factors affecting the occurrence of adverse events but also reliable indicators for predicting the occurrence of adverse events, such as the absolute value of GLS < 16% and GWW > 127 mmHg%.


Although not completely devoid of risk, pregnancy can be managed in virtually all patients affected by even the most complex forms of congenital heart disease. It is not however advisable in patients with any form of pulmonary arterial hypertension. Pregnancy is even manageable in patients with univentricular heart converted to Fontan circulation. A personalised risk stratification should be performed, and patients affected by advanced NYHA functional class appropriately warned of the potential risks. In this setting, metabolomics might represent a novel tool for use in conducting personalised risk stratification. All pregnancies, particularly those at higher risk, should be managed in a tertiary care centre capable of providing the necessary assistance to both the mother and infant. With a few rare exceptions, vaginal delivery is to be preferred over caesarean section due to the lower degree of maternal and foetal complications. The desire for motherhood, at times extreme in women with congenital heart disease, may often be accomplished, thus providing a ray of hope in the lives of these patients. A significantly higher number of cases of congenital heart disease (CHD) is observed in the adult population  when compared to the number of live paediatric subjects affected by the same condition. Indeed, early diagnosis and progresses made in the field of interventional and surgical treatment have enabled more than 90% of CHD patients to reach adulthood . A largeThe aim of this narrative review is to assess the risk and the management of pregnancy in moderate or great complexity ACHD patients.The prevalence of CHD worldwide is approximately 9/1000 neonates, with some geographical variations . A slighTo investigate why pregnancy is so poorly tolerated in this population, a series of physiological changes that occur during pregnancy should be taken into account ,7.As early as the sixth week of gestation, the primordial heart starts to beat. Likewise, the increase in blood volume manifested throughout pregnancy is first detected in the early weeks of pregnancy and increases rapidly up until the fourth/fifth month of gestation, subsequently progressing at a slower rate ,7.Concomitantly, systemic vascular resistance decreases by approximately 30% compared to baseline, due to both the effect of pregnancy hormones and subsequent development of the placenta. This in turn determines reduced vascular tone with consequent decrease in systemic blood pressure (BP) ,7.This vasodilation is compensated for by an approx. 30–50% increased cardiac output (CO) compared to baseline. This increased output is the result of an increase in both stroke volume and heart rate, with the latter occurring largely during the third trimester. These hemodynamic changes place an additional burden on the heart with increased end-systolic and end-diastolic ventricular volumes. At the end of pregnancy, labour and delivery are both seen as critical events due to the presence of an additional rise in cardiac output and increased oxygen demand. Uterine contractions each produce an approx. 500 cc increase in circulating blood volume. During delivery, a sudden increase in systemic vascular resistance elicited by placental expulsion determines an increment in ventricular filling pressure. Baseline conditions are normally restored within 2–6 weeks of vaginal delivery, or longer in the case of caesarean section. The heart then continues to be subjected to a higher burden following delivery as, paradoxically, although uterine compression on the inferior vena cava lessens, an increased systemic venous return to the heart is manifested .Pregnancy is intrinsically associated with a state of hypercoagulability, a factor to not underestimate in the presence of a series of conditions  .It is evident therefore that the cardiovascular system of a patient affected by depressed cardiac function, increased pulmonary pressure or single ventricle circulation will be faced with a series of major challenges as pregnancy commences.Nevertheless, as a general rule, vaginal delivery is the preferred option, with elective caesarean section limited to women affected by ventricular dysfunction and advanced NYHA functional status . This isMajor cardiac complications during pregnancy include onset of arrhythmias, in particular ventricular arrhythmia, heart failure, fainting episodes, chest pain and thromboembolic events   Figure .Patients with Fontan circulation and cyanotic heart disease have been found to be at higher risk of spontaneous or elective miscarriage .A mortality rate of up to 4% has been reported for infants born to mothers affected by congenital heart disease ,12.The ROPAC registry is the main source of information for issues relating to pregnancy and heart disease. Published for the first time in 2007, the registry is kept continuously updated with data deriving from numerous hospitals worldwide (the majority of which European), and currently includes data from approx. 6000 pregnant women affected mainly by congenital (57%) and valvular heart disease (29%) .The ROPAC registry highlighted the highest mortality rate in patients with pulmonary hypertension . Heart failure was diagnosed in 11% of the population, whilst arrhythmias were present in 2% of cases. The main risk factors for onset of maternal complications during pregnancy comprised pre-existing heart failure, NYHA functional class > II, systemic ejection fraction < 40%, mWHO functional class 4 and use of anticoagulants .Accordingly, risk stratification represents an important tool aimed at limiting potential maternal and foetal complications.The risk of onset of pregnancy-related cardiac complications may be predicted using a series of scoring systems such as CARPREG (CARdiac disease in PREGnancy) and ZAHARA. To date, however, higher-risk populations  have been under-represented in both systems; therefore, the currently recommended and most widely used scoring system is the World Health Organisation (mWHO) risk scale ,14, whicPatients are thus classified as: very low risk (class I), low to moderate risk (class II), high risk (class III), in which pregnancy is not advised, and lastly, extremely high risk (class IV), in which pregnancy is contraindicated .The first group (mWHO I) comprises minor corrected heart defects , mild pulmonary stenosis, minor valve defects and isolated atrial and ventricular extra-systoles.The second group (mWHO II) includes patients with minor uncorrected defects (ASD e VSD) and corrected tetralogy of Fallot, the majority of supraventricular and ventricular arrhythmias and Turner’s syndrome without aortic dilation.The intermediate group (mWHO II–III) comprises patients with mild ventricular dysfunction (EF > 45%), hypertrophic cardiomyopathy, mild mitral valve stenosis, moderate aortic stenosis, Marfan syndrome without aortic dilatation, aorta < 45 mm , repaired coarctation and repaired atrioventricular canal.2; patients with tetralogy of Fallot and aortic diameter < 50 mm.The third group (mWHO III) is made up of patients affected by moderate ventricular dysfunction, EF 30–45%, previous peripartum cardiomyopathy with no residual impairment of systolic function, patients with a mechanical valve, patients with Fontan circulation, systemic right ventricle with conserved or slightly reduced systolic function, cyanotic heart disease (unrepaired), moderate stenosis of the mitral valve, severe asymptomatic aortic stenosis, moderate aortic dilatation 40–45 mm in patients with Marfan syndrome, aortic dilatation 45–50 mm in patients with bicuspid aortic valve, patients with Turner’s syndrome and ASI (aortic size index) of 20–25 mm/m2; patients with tetralogy of Fallot and ascending aorta diameter > 50 mm, severe aortic coarctation, patients with complex Fontan circulation [The last group (mWHO IV) includes patients with any form of pulmonary arterial hypertension, severe systemic ventricular dysfunction , previous peripartum cardiomyopathy with residual ventricular dysfunction, severe stenosis of the mitral valve, severe symptomatic aortic stenosis, patients with moderate or severe systemic right ventricle dysfunction, Marfan syndrome with aortic dilatation > 45 mm, aortic dilatation > 50 mm in the context of aortic disease associated with bicuspid aortic valve, patients with Turner’s syndrome and ASI > 25 mm/mculation .Maternal mortality risk increases gradually between the first and last group patient groups, with a frequency of maternal cardiac events ranging from 2.5 to 5% amongst patients in the first group to 40–100% in patients from the 4th group .Pre-conception counselling should be provided to all women intending to initiate pregnancy, in particular patients affected by complex congenital heart disease. Counselling should be administered by either a cardiologist with expertise in the field of congenital adult heart disease or a gynaecologist with expertise in the specific field (multidisciplinary team) .Pregnant women with NYHA functional class I may not need to be managed in a tertiary care hospital, whilst patients with NYHA functional class II or higher should always receive care in this type of setting. Delivery should take place in a hospital setting equipped to provide adequate support to both mothers and infants .A pathophysiological classification of CHD  with relBelow, the authors evaluate pregnancy management in the presence of a series of major highly or moderately complex heart diseases.Tetralogy of Fallot (TOF) is a common cyanotic congenital heart disease accounting for approx. 5–6% of all congenital heart diseases. The American Heart Association classifies TOF as a moderately complex heart disease ,18.In the presence of TOF, gestational risks are associated with potential surgical repair, presence of residual defects and patient’s overall clinical status. Healthcare staff involved in patient care should be fully trained to recognise the different scenarios that may be presented. In the absence of significant residual defects or post-repair complications and presence of normal ventricular function pregnancy is considered low risk .Patients subjected to transannular patch repair tend to develop severe pulmonary insufficiency. Consequently, the right ventricle adapts to this continual volume overload by dilating (Frank-Starling law). Significantly dilated and malfunctioning right ventricles do not tolerate pregnancy well, and whilst pulmonary valve failure per se is not a serious problem, it does however add an additional volumetric burden beyond the physiological increase present in pregnancy. Prior to programming a pregnancy, pulmonary insufficiency should be corrected, preferably by means of percutaneous biological valve implantation, where possible, or alternatively, surgery. Although the indication for correction is clear in symptomatic patients, in asymptomatic patients, the case should be discussed regularly taking into account other parameters as illustrated in the European Society of Cardiology guidelines on congenital heart disease in adulthood . The preResidual stenosis is even worse tolerated than pulmonary insufficiency, whilst mild stenosis is generally well tolerated; it should however be taken into account that the condition will tend to worsen during pregnancy due to the higher volume of circulating blood .Complications of maternal heart disease have been described in 7–10% of cases, largely represented by supraventricular arrhythmias, symptomatic right heart failure, pulmonary embolism and progressive right ventricle enlargement .Frequency of check-ups should be based on the patient’s clinical and echocardiographic status.Patients receiving treatment with ace inhibitors should suspend treatment due to the risk of teratogenic effects on the foetus, whilst diuretics (furosemide) may continue to be used .Obstetric complications may arise in up to 30% of cases . VaginalEbstein anomaly, a moderately complex congenital heart disorder, accounts for less than 1% of all congenital heart diseases . Due to The main problems related to Ebstein anomaly include tricuspid valve insufficiency, heart failure, onset of arrhythmias and cyanosis which are variably manifested due to persistent presence of atrial septal defect or patent foramen ovale with consequent right-left shunt of desaturated blood. Patients displaying saturation levels of <85% and/or heart failure should be advised not to embark on pregnancy (Class IIa Level C) .Patients with valvular insufficiency and/or mild ventricular dysfunction should tolerate pregnancy well. Conversely, patients with significant pre-existing right or left cardiac dysfunction will tolerate pregnancy poorly due to inability of the heart to meet the required increase in cardiac output. Patients with severe symptomatic valvular insufficiency should undergo surgical correction prior to initiating pregnancy .The onset of prevalently supraventricular arrhythmias (including accessory pathway tachycardias such as Wolff–Parkinson–White syndrome) represents the most frequent complication linked to this condition and may result in less positive outcomes . To thisElectrical cardioversion is recommended in hemodynamically unstable patients, whilst those who are hemodynamically stable may be treated by means of vagal manoeuvres or use of adenosine. In patients with broad complex tachycardia, accessory pathway tachycardia cannot be excluded, thus indicating use of flecainide as a substitute for AV nodal blocking drugs .Major risk factors for the foetus are represented by maternal heart failure and degree of cyanosis, resulting in potential premature birth and small for gestational age infants. One study observed lower birth weight in infants delivered to mothers with cyanotic Ebstein anomaly compared to those born to non-cyanotic mothers (2.5 Kg vs. 3.1 Kg) . A perinFrequency of follow-up during pregnancy is guided by the clinical conditions of the mother. Women who are cyanotic women or present with ventricular dysfunction should be seen every one or two months. Vaginal delivery is recommended .Patients affected by systemic right ventricle were born with a transposition of the great arteries which was either congenitally corrected (cc-TGA) or underwent correction by means of palliative surgery. The latter is the case of a dextro-transposition of the great arteries (d-TGA) corrected by means of atrial switch using the Mustard or Senning procedure  . AlthougPatients with cc-TGA manifest complications associated with dysfunction of the right atrioventricular valve, dysfunction of the systemic right ventricle and electrical conduction disorders leading to complete AV block in 30% of cases .Conversely, the most frequently observed complications in d-TGV patients following atrial switch include arrhythmias , progressive subaortic left ventricular dysfunction, tricuspid valve insufficiency and intra-atrial baffle obstruction or leaks .Accordingly, following a Mustard/Senning procedure, patients with cc-TGA or d-TGA are advised to actively prevent pregnancy, particularly in the presence of an NYHA functional class III–IV, moderate-severe ventricular dysfunction with EF < 40% or severe tricuspid insufficiency (Class IIa Level c) . LikewisLiterature data relating to post-atrial switch patients are lacking and frequently contrasting. A study published several years ago compared a group of female patients who had undergone palliative atrial switch and later initiated a pregnancy with others who had never been pregnant. Mean duration of follow-up was 100 months. Worsening of systemic tricuspid valve regurgitation was observed amongst the group of pregnant women (52%), whilst no such findings were reported in patients from the other group. However, no significant differences were found with regard to worsening of systolic function, onset of arrhythmias or thromboembolic events. Infants were characterised by lower birth weight and intrauterine growth delay. In more than one third of women, tricuspid insufficiency did not decrease over the post-partum follow-up period . ConversThe onset of arrhythmias is generally treated with beta-blockers; however, particular caution should be exercised in patients with cc-TGA in view of the tendency to develop bradycardia caused by sinus node dysfunction during atrial switch or atrioventricular block .There is a paucity of data in literature focused on pregnancy in women with cc-TGA, the majority of which based on small retrospective samples. A study conducted by Kowalik et al. of 20 pregnant women with cc-TGA demonstrated that full-term pregnancy can be achieved. The most common cardiovascular complications observed were supraventricular arrhythmias. Long-term follow-up revealed no significant effect of pregnancy on systemic left ventricular function . PresencMoreover, in pregnant cc-TGA patients, progressive systemic tricuspid valve regurgitation is more severe than that observed following atrial switch in d-TGV .All studies highlighted how patients with systemic right ventricle, either congenital or manifested consequent to palliative surgery, tended to give birth to low birth weight infants . These pPulmonary hypertension (PH) is a disorder manifested secondary to numerous pathological conditions, including congenital heart disease. PH is defined as an increase in mean pulmonary pressure > 20 mmHg, increased pulmonary vascular resistance ≥ 3 Woods units and a wedge pressure ≤ 15 mmHg ,39.An additional sub-classification is present in the context of pulmonary hypertension manifested as a consequence of congenital defects .The first group is comprised of patients with Eisenmenger syndrome. Specifically, this includes all intracardiac and extracardiac defects initially manifested as systemic pulmonary shunt and progressing over time to determine severe elevation of pulmonary vascular resistance, thus resulting in systemic-pulmonary or bidirectional shunt.The second group includes patients affected by arterial pulmonary hypertension associated with prevalently systemic-pulmonary shunt, irrespective of correctability. These defects are of moderate-large entity; vascular resistance is only slightly or moderately increased, although systemic-pulmonary shunt is ongoing and cyanosis is present only on exertion.The third group is comprised of patients with marked increase in pulmonary vascular resistance in the presence of minor defects (VSD < 1 cm and ASD < 2 cm), or defects detected incidentally which alone would not determine an increase in pulmonary vascular resistance. Closure of these defects is contraindicated.Lastly, the fourth group includes patients prone to developing pulmonary arterial hypertension either immediately following correction of congenital heart defects or months or even years after correction .In view of the significantly higher risk of maternal mortality both during and after pregnancy in women with pulmonary arterial hypertension, pregnancy is strongly contraindicated (Class III Level B) . The leaNeonatal outcome is likewise poor. Foetal and/or neonatal mortality is in the range of approx. 7%, with premature birth occurring in approximately 86% of cases, and failure to thrive in 24% .Taking into account the pulmonary barrage manifested in patients with pulmonary arterial hypertension, it is clearly evident that this condition fails to adapt to the increased blood volume typically observed in pregnancy. Pulmonary circulation is unable to cope with the increased output that impinges on the right ventricle, thus resulting in heart failure. Moreover, these patients already present with an underlying prothrombotic status which is inevitably exacerbated during pregnancy; therefore, patients with Eisenmenger syndrome are characterised by an increased risk of paradoxical embolism. The efficacy of standard pharmacological treatment for PDE during pregnancy remains to be clarified. Advanced pharmacological treatment should be established as early as possible to prevent onset of cardiopulmonary failure. Animal studies have demonstrated the teratogenicity of endothelin receptor antagonists ; therefore, other classes of drugs such as phosphodiesterase inhibitors (sildenafil) and/or prostacyclin analogues should be used on a personalised basis. Nifedipine appears however to be safe for use in the treatment of reactive pulmonary arterial hypertension ,42.Once the patient has been warned that pregnancy is strongly contraindicated, if she still wishes to face the challenge involved, she should be immediately referred to a tertiary care centre for frequent clinical check-ups (even weekly) and taught how to recognise the early clinical signs and symptoms of heart failure .Delivery will be performed by scheduled caesarean section between 32 and 34 weeks gestation ,44. As sThis condition is classified as a highly complex heart disease  and is aThis type of circulation is characterised by a higher incidence of arrhythmias, increased risk of thrombosis and high systemic venous pressure. Furthermore, these patients are increasingly prone to developing long-term complications such as protein-losing enteropathy, plastic bronchitis, and systolic and diastolic dysfunction of the single ventricle . As mentThere is a relatively low risk (approximately 6%) of the foetus being born with congenital heart disease, although this percentage is higher than that observed in the general population. It is crucial therefore that the mother is given the opportunity to undergo a complete foetal echocardiogram during pregnancy .The increased blood volume typically observed during pregnancy represents a major challenge for a univentricular heart, particularly when dysfunctional or accompanied by insufficiency of the sole atrioventricular valve . To dateIndeed, in view of the increased risk of thromboembolism, if not already established, all patients should be prescribed anticoagulant treatment (class IIa) ,24.Monthly check-ups should be scheduled both throughout pregnancy and following delivery. Vaginal delivery is preferred due to the lower risk of associated infection, lower blood loss and lower risk of thromboembolism. Women affected by severe heart failure should however be delivered by caesarean section to minimise the effects of continual Valsalva manoeuvres that may be required during vaginal delivery .In women with mechanical valves, pregnancy is linked with a very high -risk of maternal, obstetric, and offspring complications (mWHO class III). In the ROPAC registry, the chances of an event-free pregnancy with a live birth were just 58% for women with a mechanical valve .Regarding maternal risk, the chance of mechanical valve thrombosis is significantly during pregnancy. It decreases with adequate dosing of anticoagulant therapy, varies on the basis of type and position of the mechanical valve, and on the basis of additional patient-related risk factors . CurrentAs regards obstetric and offspring risk, all anticoagulant therapies carry an increased risk of miscarriage and bleeding . In the Oral vitamin k antagonists are the most efficient anticoagulant therapy against these complications in ACHD pregnant ladies. However, they can trigger foetal complications. In fact, since warfarin has a low molecular weight, it crosses the placenta and harms the foetus. It is the so-called foetal warfarin syndrome or warfarin embriopathy, a well-recognised complication of first trimester warfarin use in pregnancy. The disease is characterised by nasal hypoplasia and skeletal abnormalities, including short limbs and digits, and stippled epiphyses. Even when taken in the second or third trimester, warfarin can cause optic nerve atrophy, developmental delay, and microcephaly. ESC guidelines suggest administering warfarin just in the second and third trimester . MaternaWith oral vitamin k antagonists therapy, haemorragic risk during vaginal delivery is not increased. On the contrary, it is augmented in case of caesarian section . WarfariMany cardiac medicines appear safe for use amid and after pregnancy. However, evidence is lacking for some of them. Many of them carry risk of adverse events. Shared decision making, considering risks and benefits of drugs, is crucial to help women weigh up potential risks to themselves and their unborn babies.Regarding beta blockers, they are commonly used by pregnant women. However, foetal bradycardia, hypotension, and hypoglycaemia are often reported along with low birth weight .Concerning antiarrhythmic agents, amiodarone might be used in special circumstances, although it is linked with a risk of hypothyroidism, goitre, bradycardia, foetal growth restriction, and prematurity at birth . The eviDiuretics such as furosemide, bumetanide, and hydrochlorothiazide can cause oligohydroamnios and electrolyte imbalance in the foetus.As regards anticoagulants, warfarin carries a risk of foetal abnormalities if used in the first trimester of pregnancy. It can cause intracranial foetal bleeding in the second trimester. Low-molecular-weight heparin can seldom trigger osteoporosis and markedly less throbocytopenia than unfractionated heparin .The drugs which are contraindicated in pregnancy are angiotensin converting enzyme inhibitors and angiotensin receptor blockers  and spironolactone  .The risk of CHD recurring in the offspring of women affected by congenital heart defects however is not trivial. As a general rule, foetal echocardiography is routinely used to check the developing heart to rule out this risk, although the presence of CHD may at times be missed at ultrasound scan. In this setting, metabolomics might represent a novel technique for use in detecting CHD in utero with a higher sensitivity and specificity than foetal echocardiography. As an example, several studies have succeeded in identifying different metabolic fingerprints when analysing maternal fluids  during the first, second, and third trimester of pregnancy. The findings obtained indicated an apparent link with risk of developing CHD in the offspring ,59,60,61Although not completely devoid of risk, pregnancy can be managed in virtually all patients affected by even the most complex forms of congenital heart disease. It is not however advisable in patients with any form of pulmonary arterial hypertension. Pregnancy is even manageable in patients with Fontan circulation. A personalised risk stratification should be performed, and patients affected by advanced NYHA functional class appropriately warned of the potential risks.All pregnancies, particularly those at higher risk, should be managed in a tertiary care centre capable of providing the necessary assistance to both the mother and infant.With a few rare exceptions, vaginal delivery is to be preferred over caesarean section due to the lower degree of maternal and foetal complications .The desire for motherhood, at times extreme in women with congenital heart disease, may often be accomplished, thus providing a ray of hope in the lives of these patients.


Long-term mechanical circulatory support by a left ventricular assist device (LVAD), with or without an additional temporary or long-term right ventricular (RV) support, is a life-saving therapy for advanced heart failure (HF) refractory to pharmacological treatment, as well as for both device and surgical optimization therapies. In patients with chronic non-ischemic cardiomyopathy (NICM), timely prediction of HF’s transition into its end stage, necessitating life-saving heart transplantation or long-term VAD support (as a bridge-to-transplantation or destination therapy), remains particularly challenging, given the wide range of possible etiologies, pathophysiological features, and clinical presentations of NICM. Decision-making between the necessity of an LVAD or a biventricular assist device (BVAD) is crucial because both unnecessary use of a BVAD and irreversible right ventricular (RV) failure after LVAD implantation can seriously impair patient outcomes. The pre-operative or, at the latest, intraoperative prediction of RV function after LVAD implantation is reliably possible, but necessitates integrative evaluations of many different echocardiographic, hemodynamic, clinical, and laboratory parameters. VADs create favorable conditions for the reversal of structural and functional cardiac alterations not only in acute forms of HF, but also in chronic HF. Although full cardiac recovery is rather unusual in VAD recipients with pre-implant chronic HF, the search for myocardial reverse remodelling and functional improvement is worthwhile because, for sufficiently recovered patients, weaning from VADs has proved to be feasible and capable of providing survival benefits and better quality of life even if recovery remains incomplete. This review article aimed to provide an updated theoretical and practical background for those engaged in this highly demanding and still current topic due to the continuous technical progress in the optimization of long-term VADs, as well as due to the new challenges which have emerged in conjunction with the proof of a possible myocardial recovery during long-term ventricular support up to levels which allow successful device explantation. For patients with advanced (stage D) chronic heart failure (HF) refractory to guideline-directed pharmacological treatment as well as to both device and surgical optimization therapies , long-term mechanical circulatory support (MCS) by a left ventricular assist device (LVAD), with or without an additional temporary or long-term right ventricular (RV) support, is a well-established life-saving therapeutic option . ImplantThe survival benefit for durable LVAD support has progressively improved. Recent trials with newer generation LVADs revealed two-year survival rates above 80%, which were similar to those reported for the early survival after HTx ,2. The lIt is important to note that the BTT and DT designations are not unchangeable. Patients may cross over from one group to the other as their clinical state improves or deteriorates, or if a formerly transplant-eligible patient must remain on indefinite VAD support because of newly arisen risks related to different co-morbidites .This review article aimed to provide an updated theoretical and practical basis for those engaged in this highly demanding and still current topic due to the continuous technical progress in the optimization of MCS devices, as well as due to the new challenges which have emerged in conjunction with the increasing evidence of a possible myocardial recovery during long-term VAD support up to levels which allow successful device explantation. Cardiomyopathies are a heterogeneous group of myocardial diseases that cause structural and functional damages which induce mechanical and/or electrical cardiac dysfunction, which, in turn, result in dilated, hypertrophic, or restrictive pathophysiology ,10. The Chronic inflammatory cardiomyopathy, a progressive disorder most often either directly induced or associated with different virus infections, is the most common cause of advanced HF in patients with NICM ,12,13. I1-AABs, α-myosin-AABs, and cardiac troponin I AABs) revealed a particularly relevant pathologic potential .,15.14,15otential ,23. It hotential .1-adreno-receptors (β1-AABs) proved to have a particularly high pathophysiological relevance in both the development and the progression of the disease , respectively) appeared not to be predictive for cardiac stability without LVAD support, the positive PV of LVEF ≥45% in combination with either LVEDD ≤ 55 mm or RWTED ≥0.38 can reach up to 86% and 87%, respectively /LVEDD] are indispensable for the reliable prediction of long-term post-weaning cardiac stability. Conversely, LVEF values ≥45% in patients without normalization of LV size (LVEDD >55 mm) and geometry (RWTED < 0.38) revealed a PV of 89% for HF recurrence during the first three years after LVAD explantation which was slightly higher than the 88% PV for early post-explant HF recurrence revealed by LVEF values of 35–45% in patients with complete reversal of LV size and geometry alterations . . 117]. Because the most optimal duration of VAD support for the achievement of the maximum possible improvement in cardiac function varies widely among the VAD recipients, even if all of them had a NICM-induced HF before devise implantation, the VAD should be removed in recovered patients only after the follow-up off-pump tests show no further cardiac improvement ,144. AltBased on the experience gained to date, elective LVAD explantation can be considered in patients with sinus rhythm, normal and stable CI, PCWP, and mean RA pressure during the final off-pump trial, normal and stable off-pump LV size and geometry, stable LVEF ≥45% after maximum functional cardiac improvement between the pre-explant follow-up off-pump trials and during the final pre-explant off-pump trial, absence of or no relevant MR, AR, TR, or PR, as well as absence of RV dilation and/or relevant pulmonary hypertension during the final off-pump trial ,123,146.Given the multitude of factors involved in the maintenance of cardiac stability after VAD explantation, their different impact on cardiac anatomy and function, the high complexity of their possible interactions, as well as the usually incomplete functional recovery of the supported ventricle, weaning decision-making remains a difficult and challenging task. This also explains the lack of generally accepted guidelines for decision-making in favor of or against the elective removal of a durable mechanical ventricular support. The major steps for the evaluation of cardiac recovery and weaning decision-making in durable LVAD and BVAD recipients, based on ECHO and RHC off-pump examinations obtained in resting conditions, were recently described in a more detailed manner . In patients with NICM-related chronic HF, timely prediction of HF transition into its end stage, necessitating HTx or long-term VAD support as a BTT or DT, remains difficult and particularly challenging given the broad spectrum of possible etiologies, pathophysiological particularities, and clinical presentations of NICM. It is important to note that in patients with DCM, LVEF and LVEDD have not been proven to be useful for the prediction of HF’s transition to its end stage, whereas aggravation of MR and diastolic dysfunction, as well as increases in the TPR can provide useful prognostic information. Evaluation of MF by CMR imaging can also provide valuable information for the prognostic assessment of DCM-related HF. Decision-making between the possibilities of implanting only a long-term LVAD or the necessity of using a long-term BVAD for a patient is crucial because both unnecessary use of a BVAD and irreversible RVF after LVAD implantation will significantly impair patient outcomes. Pre-operative or, at the latest, intraoperative prediction of RV function after LVAD implantation is reliably possible, but necessitates integrative evaluations of many different hemodynamic, ECHO, clinical, and laboratory parameters. Based on the convincing weaning successes obtained in carefully selected VAD recipients with NICM as the underlying cause for the pre-implant end-stage HF, weaning from VADs can be considered as a validated and feasible clinical option, even if cardiac recovery remains incomplete. Although ventricular reverse remodeling and improvement of myocardial function during long-term VAD support enabling successful explantation of the device in patients with pre-implant HF caused by chronic NICM is relatively rare, the weaning results  can be equal or even greater than those after HTx, and the explanted patients are spared from the side effects of the immunosuppression therapy necessary after HTx. Therefore, ECHO-screenings for the detection of potential weaning candidates should be performed not only in LVAD recipients throughout the whole post-implant time, but also in BVAD recipients, although successful device explantations in the latter patients occur even more rarely. The most attractive potential indication for VADs could be their elective implantation as a therapeutic strategy for recovery in earlier stages of HF, when the reversibility of myocardial alterations is higher. This, however, necessitates a reliable prediction of VAD-promoted recovery before implantation, because VAD therapy is not a risk-free option. Unfortunately, although recovery the rates are higher in younger persons with shorter durations of HF, less ventricular dilation, and less fibrosis, neither the pre-implant LV size and EF nor the HF duration, patient age, or the absence of relevant fibrosis can predict the success of an elective VAD implantation as a BTR. Can future research on molecular and cellular levels provide a platform for new adjunctive therapies  aimed to optimize recovery and increase the number of weaning candidates?Can future research on cellular, molecular, and genomic levels provide data which might allow the detection of patients with the potential for recovery before VAD implantation?There are two essential open questions for the future:


The course of diseases such as hypertension, systolic heart failure and heart failure with a preserved ejection fraction is affected by interactions between the left ventricle (LV) and the vasculature. To study these interactions, a computationally efficient, biophysically based mathematical model for the circulatory system is presented. In a four-chamber model of the heart, the LV is represented by a previously described low-order, wall volume-preserving model that includes torsion and base-to-apex and circumferential wall shortening and lengthening, and the other chambers are represented using spherical geometries. Active and passive myocardial mechanics of all four chambers are included. The cardiac model is coupled with a wave propagation model for the aorta and a closed lumped-parameter circulation model. Parameters for the normal heart and aorta are determined by fitting to experimental data. Changes in the timing and magnitude of pulse wave reflections by the aorta are demonstrated with changes in compliance and taper of the aorta as seen in aging , and resulting effects on LV pressure–volume loops and LV fiber stress and sarcomere shortening are predicted. Effects of aging of the aorta combined with reduced LV contractile force (failing heart) are examined. In the failing heart, changes in aortic properties with aging affect stroke volume and sarcomere shortening without appreciable augmentation of aortic pressure, and the reflected pressure wave contributes an increased proportion of aortic pressure.The online version contains supplementary material available at 10.1007/s10237-023-01690-w. The aging aorta is marked by changes in stiffness, diameter, length, taper and impedance  partial differential Euler equations for propagation of flow and pressure waves can predict the timing and magnitude of pulse wave reflections . The equation for the mapping from initial to deformed shapes is derived from the condition The model for left ventricular dynamics has been described previously  or part of a sphere (RV), whose radius changes with time described by a parameter The four cardiac valves are represented by a 0-D Bernoulli-type model  to 550 cm/s (middle-aged) and 781 cm/s (old), resulting in the earlier arrival of the peak in the reflected wave. Furthermore, the increasing impedance of the aorta results in increased amplitude of the reflected wave. In simulations of the cardiac cycle, the function In Fig. Figure With aging, the flow pulse at the aortic inlet shown in Fig. Figure normal (impaired (125 kPa) and failing (50 kPa). In each case, normal), 2.0 (impaired) and 0.88 (failing) in units of mmHg/cm3 and correlate with the assumed levels of contractility, as expected.To examine effects of reduced LV contractility, three levels of maximal force generation are considered: impaired contractility, the loss of contractile force is somewhat compensated by a shift to higher sarcomere lengths, i.e., up the length-tension curve, as a result of increased LV volume  if contractility is failing. In the latter case, the LV has reached the limit of expansion in response to increased preload and cannot compensate for the reduction in ejection resulting from increased afterload. Maximum aortic pressure increases with aging aorta with normal and impaired LV contractility, but this effect is blunted when contractility is failing. This prediction is consistent with results from a clinical study of patients with systolic dysfunction (LVSD) Below is the link to the electronic supplementary material.


Children with Down syndrome showed a stronger correlation between systemic cellularity and pulmonary vascular resistance index . Endothelial progenitor cells were reduced along their transit through the lung, whereas circulating endothelial cells did not suffer any modification across the pulmonary circulation. In children with yet to be repaired left-to-right shunts, endothelial progenitor cells and circulating endothelial cell counts are increased compared to healthy subjects.Endothelial progenitor cells and circulating endothelial cells have been proposed as useful markers of severity and disease progression in certain vascular diseases, including pulmonary arterial hypertension. Our study focused on evaluating the levels of circulating endothelial progenitor cells and circulating endothelial cells in patients with congenital left-to-right shunts and pulmonary hypertension undergoing definitive repair. Endothelial progenitor cells  and circulating endothelial cells  were prospectively measured in seventy-four children (including children with Down syndrome), median age six years (2.75–10), with clinically significant left-to-right shunts undergoing transcatheter or surgical repair and compared to thirty healthy controls. Endothelial progenitor cells and, particularly, circulating endothelial cells were significantly higher in children with heart disease and pulmonary arterial hypertension when compared to controls. Endothelial progenitor cells showed significant correlation with pulmonary vascular resistance index when measured both systemically ( Peripheral vein blood samples were drawn from controls to determine EPC and CEC count. This prospective study was supported by the National Council of Science and Technology (CONACYT); under the Sectorial Fund for Health Research and Social Security (FOSSIS No. 234296). Our study was approved by the Internal Review Board  in compliance of all the appropriate steps taken to protect the rights and welfare of participating subjects in the research. Parental informed consent (and patient assent when appropriate) where provided in accordance with the principles outlined in the Declaration of Helsinki.We included children aged 2 to 18 years with clinically significant left-to-right shunts with varying degrees of hemodynamic impact. Clinical and demographic characteristics, along with a complete physical and echocardiographic assessment were recorded. All patients underwent a diagnostic right and left heart study (cardiac catheterization) for complete baseline hemodynamic evaluation and operability assessment –12. Acut2.2.Immunostaining flow cytometry was used for cellular characterization and quantification –18. EPC Detailed analysis was performed comparing the number of EPC and CEC according to type of shunt and site of sampling, with particular focus on correlation between the type and number of cells and hemodynamic impact. Furthermore, we compared groups according to the presence (or absence) of PAH as per its most recent definition of a mean pulmonary artery pressure ≥20 mmHg and pulmonary vascular disease (defined by a pulmonary vascular resistance index (PVRi) ≥than 3 Wood units). Lastly, comparison between patients with DS and non-syndromic children was thoroughly analysed.2.3.U tests, as appropriate, for continuous variables. The strengths of correlation between cellularity and pulmonary hemodynamic were assessed using Spearman's rank correlations. Results were reported using two-tailed significance; statistical significance was set at P ≤ 0.05. All analyses were performed using SPSS version 17.0 statistical software .All categorical data were summarized as frequencies and percentages. All continuous variables were tested and confirmed to have a non-normal distribution as determined by the Shapiro-Wilks test. Continuous variables were reported as medians and 25th and 75th percentiles . Statistical differences across groups were assessed, either using the chi-square or Fisher's exact tests in the case of categorical variables or the Kruskal–Wallis or Mann–Whitney 3.n = 39); ventricular septal defect (n = 13); atrial septal defect (n = 18), atrioventricular septal defect (n = 2), aortopulmonary window and truncus arteriosus (n = 1 each). Eleven (15%) patients were children with Down syndrome. Demographic and clinical characteristics along with total EPC and CEC determination of patients vs. healthy controls (n = 30) are shown in Seventy-four children [median age 6 years (2.75–10)] with clinically significant left-to-right shunts were prospectively studied between December 2016 and December 2018. Defects included patent ductus arteriosus  and BSA  correlated with EPC when measured in the systemic circulation. Also, EPC were shown to have a significant correlation with PVRi when measured both systemically  . No significant correlation was found between EPC and pulmonary artery pressures (either systolic or median) or the pulmonary to systemic flow ratio (Qp:Qs). In children with DS, correlations between cellularity and hemodynamic variables behaved differently. There was a strong correlation between EPC at systemic level and PVRi  . In similar fashion to the total cohort, no significant correlations were found between children with DS regarding EPC or CEC and pulmonary artery pressure.In the whole group, age (= 0.026)  and in t= 0.002)  and CEC 3.2.Obtaining blood samples at the pulmonary artery and either the femoral artery or the pulmonary vein  allowed us to explore the potential role of the pulmonary circulation to determine the final cellularity by performing simple subtraction of systemic—pulmonary artery cell counts. The results of this analysis are shown in 4.It has been established that measurement of systemic EPC and CEC may provide an estimate of individual vascular competence that results from the delicate balance between injury and repair and may, in turn, yield valuable prognostic clues in certain vascular diseases including several forms of pulmonary hypertension , 16. It 4.1.Previous studies have emphasized the role of EPC and CEC in the setting of idiopathic pulmonary arterial hypertension and PAH-CHD. 1–9 Smajda et al. 4, 5 and Levy et al. 8 (within the same group of investigators) demonstrated that CEC counts are increased and may well be defined as exclusive markers of irreversible PAH in patients with PAH-CHD (as defined by the persistence of pulmonary hypertension at least six months after repair) or patients with definitive idiopathic PAH. In contrast, they found CEC counts in patients with reversible PAH  were low and not any different from controls. Furthermore, they highlighted relevant implications regarding PAH therapy, particularly reduction of CEC in patients with irreversible forms of PAH when started on PAH-specific medications and thus useful to monitor response to treatment. 7, 8 Also, a recent case-control study by Xiaofel- Li et al, 9 found a direct and significant correlation between the mean pulmonary artery pressure and the pulmonary to systemic flow ratio (Qp:Qs) and CEC levels in patients with PAH-CHD. Similarly, the role of EPC in the setting of idiopathic PAH and PAH-CHD (including Eisenmenger syndrome) has also been explored. Diller et al. 3 have shown that EPC counts are reduced in these patients when compared to healthy controls. Altogether, these studies strongly suggest that in the setting of advanced stages of pulmonary vascular disease, EPC are reduced impairing the intrinsic reparative capability of the pulmonary endothelium, whereas increased CEC are proper reflection of established vascular damage. Interestingly and unlike Xiaofel Li et al, 9 we did not find any significant correlation between CEC and important hemodynamic variables . We believe the latter, can be partially explained because irreversible vascular damage in our patients has not yet been established. If anything, there was a weak but statistically significant correlation between EPC counts and PVRi in the whole group suggesting an elevated number of EPC in patients (in need of repair) with higher PVRi. However, it is important to stress out that EPC and CEC counts were not different when we analyzed them separately in groups with and without pulmonary arterial hypertension or in groups with and without pulmonary vascular disease. Our findings regarding elevated counts of both EPC and CEC rather suggest that the delicate process of injury and repair is ongoing , 16, 17.4.2.Prevalence of congenital heart defects in children with DS vary from 44% to 58%, with a preponderance of persistent left-to-right shunts (single or in combination) that represent approximately 85% of all cardiac anomalies found in this population . It has 5.In children with yet to be repaired left-to-right shunts, EPC and CEC counts are increased when compared to healthy subjects albeit cellular counts at this stage cannot clearly establish the degree of severity of elevated pulmonary artery pressure and/or pulmonary vascular resistance, except perhaps for children with DS. The nature of our findings regarding elevated counts of EPC and CEC in children with PAH-CHD rather suggests that the delicate process of endothelial injury and repair is continuous and intricately related. To this end, ongoing pulmonary vascular damage might be eventually suppressed once the shunt is repaired and the stimuli arising from shear stress imposed by increased pulmonary blood flow and consequently pressure is no longer present.One of the limitations of our study is that the control group is older than the group of patients studied (median age 13 vs. 6 years old), one variable that can confound comparisons between groups, but this can be explained by the early onset of symptoms in patients with congenital heart diseases with left to right shunt compared with the control group which consisted in healthy children that were sent to our institution based on suspected heart disease that was ruled out after proper evaluation.The strength of this study and the aim of it is that there is a group of patients in which we don't know the evolution after the congenital defect has been repaired despite all the evaluation before the procedure that supports clinical decision. That is why we suggest that determination of endothelial progenitor cells and circulating endothelial cells can be an additional tool in decision-making that can help predict the long-term results of patients with congenital heart disease and left-to-right shunt.


Stress cardiomyopathy (Takotsubo syndrome) is a rare and transient cardiac dysfunction that has been reported in pregnant women with multiple triggering conditions. In general, those cases recovered from the acute cardiac insult within a few weeks.We report a 33-year-old 22 weeks pregnant woman, who presented with an episode of status epilepticus and subsequently developed acute heart failure. She had full recovery within three weeks and continued her pregnancy till term. She became pregnant again two years after this initial insult, remained asymptomatic with stable cardiac function and had normal vaginal delivery at term. Takotsubo syndrome was first reported in 1990 by the Japanese. The name is descriptive of the echocardiogram appearance of the left ventricle at the end of the systolic phase that appears like the Japanese octopus trap  . In a syVarious case reports of Takotsubo syndrome have been published following status epilepticus in the general population . In a seThe underlying pathology of Takotsubo syndrome is not fully understood. Various proposed mechanisms include excessive catecholamines, coronary artery spasms, and microvascular dysfunction. It was found to be associated more with psychiatric and neurological disorders ,2.Patients usually present with substernal chest pain, dyspnea, or syncope. In addition, they present with changes in the ST segment in the chest leads, significant rise of troponin levels, mild elevation of creatine kinase, and marked elevation of brain natriuretic peptide. Transient apical systolic left ventricular dysfunction is often found .Supportive care and recovery from the physical or emotional insult often result in recovery of cardiac function; few patients develop complications such as shock and acute heart failure which may need ICU care ,2.We report a case of a 33-year-old, gravida three, 22 weeks pregnant woman brought by ambulance to our emergency department in an unconscious state with an ongoing generalized tonic-clonic seizure for the last one hour before the presentation.Upon arrival, she had a temperature of 37 °C, heart rate of 145 beats per minute, blood pressure of 113/76 mmHg, respiratory rate of 30 cycles per minute and arterial oxygen saturation (SaO2) of 100%. She received initial emergency management, including oxygen support, IV diazepam and magnesium sulfate.She was intubated and transferred to the intensive care unit. She was administered IV levetiracetam 1000 mg followed by levetiracetam 2000 mg IV along with oxcarbazepine 900 mg twice daily through the Ryles tube. She was kept intubated and ventilated for the low threshold for recurrent seizures. The patient's past medical history revealed an established diagnosis of focal epilepsy  since the age of 21 years; she was compliant with medications and neuro-medical follow-up. She had remained seizure-free for nine months before the presentation. The bedside obstetric sonogram showed a single active fetus in cephalic presentation, with parameters corresponding to 22 weeks of gestation and an estimated fetal weight of 500 grams. There were no signs of placental abruption or subchorionic hematoma, and the amount of amniotic fluid was within the normal range.Thirty minutes after arriving at the ICU, she had a sudden drop in blood pressure to 66/30 mm Hg, with heart rate reaching 150 beats/minute. She was managed with fluid challenge and required inotropes support with norepinephrine. Her ECG displayed sinus tachycardia with global non-specific ST-T changes  and left atrium (LA), left ventricular ejection fraction (LVEF) 20-30%, moderate to severe mitral regurgitation (MR), Type 3 diastolic dysfunction, moderate tricuspid regurgitation (TR), and right ventricular systolic pressure (RVSP) 38 mm hg. Parenteral dobutamine, furosemide, and low molecular weight heparin were added to the management protocol.CT scan brain was reported as normal; serial electroencephalograms (EEGs) showed bilateral slow waves, more on the right side, with some irritative discharges on the right frontocentral area.The patient’s preliminary diagnosis was stress cardiomyopathy secondary to status epilepticus, and a multidisciplinary approach to management was carried out involving the concerned subspecialties of neurology, cardiology and obstetrics.On the fifth day, inotropic medications were discontinued, and she was extubated. On the sixth day, she was transferred out of the ICU and continued on anti-failure medications including furosemide and bisoprolol. Angiotensin converting enzyme (ACE) inhibitors were not started as they are contraindicated in pregnancy.On the ninth day, she was in well condition, asymptomatic, vitally stable and discharged home.The follow-up echocardiogram at two and four weeks after discharge showed recovery of the left ventricular systolic function with an estimated EF of 50-55%, normal LV mass indexed with normal LV diastolic function, normal LA, thickened mitral leaflets with mild to moderate MR, trivial TR and normal PA systolic pressure 20 mmHg.She had an uneventful normal vaginal delivery at 38 weeks with an infant weighing 2310 grams and an APGAR score of 8 and 9. She remained in a stable medical condition at three- and six-month follow-ups after delivery.Two years later she presented again to our facility pregnant in her third trimester; she remained seizure-free and compliant to the antiepileptic medications at higher doses than the previous pregnancy, cardiac wise she remained asymptomatic with normal echocardiogram. She completed her pregnancy till term and had an uneventful normal vaginal delivery.Our case is a 22 weeks pregnant epileptic patient who developed acute heart failure following an attack of status epilepticus. Our initial differential diagnosis included coronary artery disease, pulmonary embolism, and worsening preexisting cardiomyopathy or stress cardiomyopathy. Since our patient had completely recovered from the cardiac function within two weeks and remained well and asymptomatic, our final diagnosis was stress cardiomyopathy.Generally, stress cardiomyopathy-induced heart failure is managed like heart failure due to other etiologies, including diuretics and beta blockers. ACE inhibitors or angiotensin receptor blockers (ARBs) were deferred for her due to pregnancy. The duration of anti-failure therapy is not yet well established; in our patient, we carried on for six weeks after the improvement of the cardiac function .Takotsubo syndrome can occur at different intervals from the onset of acute insult . In our Takotsubo syndrome is a rare condition during pregnancy, with most of the reported cases occurring during the late third trimester or in the postpartum period, but our patient had an early presentation at 22 weeks of gestation with acute stress cardiomyopathy-induced heart failure triggered by an attack of status epilepticus, she was intensively managed and carried on with her pregnancy till term; two years later she became pregnant, remained asymptomatic with uneventful antenatal and post-natal period.Stress cardiomyopathy can have lethal sequelae, especially during the postictal period. Pregnant women following a seizure episode may not present the classic symptoms of acute cardiac injury; hence, seizure-induced stress cardiomyopathy can be missed or underdiagnosed. We recommend that the monitoring of the pregnant woman following a seizure episode may include close hemodynamics observation, serial ECG and cardiac enzymes with echocardiogram as indicated.