Sex differences in left-ventricular strain in a murine model of coxsackievirus B3 myocarditis.

Myocarditis is typically caused by viral infections, but most cases are thought to be subclinical. Echocardiography is often used for initial assessment of myocarditis patients but is poor at detecting subtle changes in cardiac dysfunction. Cardiac strain, such as global longitudinal strain (GLS) and global circumferential strain (GCS), represents an increasingly used set of measurements which can detect these subtle changes. Using a murine model of coxsackievirus B3 myocarditis, we characterized functional changes in the heart using echocardiography during myocarditis and by sex. We found that 2D GLS, 4D mode, and 4D strains detected a significant reduction in ejection fraction and GLS during myocarditis compared to baseline and in males compared to females. Furthermore, worse GLS correlated to increased levels of CD45+, CD11b+, and CD3+ immune cells. Our findings closely resemble published reports of GLS in patients with myocarditis indicating the usefulness of this animal model for translational studies of myocarditis.

Screening for peripartum cardiomyopathies using artificial intelligence in Nigeria (SPEC-AI Nigeria): Clinical trial rationale and design.

BACKGROUND: Artificial intelligence (AI), and more specifically deep learning, models have demonstrated the potential to augment physician diagnostic capabilities and improve cardiovascular health if incorporated into routine clinical practice. However, many of these tools are yet to be evaluated prospectively in the setting of a rigorous clinical trial-a critical step prior to implementing broadly in routine clinical practice. OBJECTIVES: To describe the rationale and design of a proposed clinical trial aimed at evaluating an AI-enabled electrocardiogram (AI-ECG) for cardiomyopathy detection in an obstetric population in Nigeria. DESIGN: The protocol will enroll 1,000 pregnant and postpartum women who reside in Nigeria in a prospective randomized clinical trial. Nigeria has the highest reported incidence of peripartum cardiomyopathy worldwide. Women aged 18 and older, seen for routine obstetric care at 6 sites (2 Northern and 4 Southern) in Nigeria will be included. Participants will be randomized to the study intervention or control arm in a 1:1 fashion. This study aims to enroll participants representative of the general obstetric population at each site. The primary outcome is a new diagnosis of cardiomyopathy, defined as left ventricular ejection fraction (LVEF) < 50% during pregnancy or within 12 months postpartum. Secondary outcomes will include the detection of impaired left ventricular function (at different LVEF cut-offs), and exploratory outcomes will include the effectiveness of AI-ECG tools for cardiomyopathy detection, new diagnosis of cardiovascular disease, and the development of composite adverse maternal cardiovascular outcomes. SUMMARY: This clinical trial focuses on the emerging field of cardio-obstetrics and will serve as foundational data for the use of AI-ECG tools in an obstetric population in Nigeria. This study will gather essential data regarding the utility of the AI-ECG for cardiomyopathy detection in a predominantly Black population of women and pave the way for clinical implementation of these models in routine practice. TRIAL REGISTRATION: Clinicaltrials.gov: NCT05438576.

Characteristics, Treatment Patterns, and Clinical Outcomes After Heart Failure Hospitalizations During the COVID-19 Pandemic, March to October 2020.

OBJECTIVE: To compare clinical characteristics, treatment patterns, and 30-day all-cause readmission and mortality between patients hospitalized for heart failure (HF) before and during the coronavirus disease 2019 (COVID-19) pandemic. PATIENTS AND METHODS: The study was conducted at 16 hospitals across 3 geographically dispersed US states. The study included 6769 adults (mean age, 74 years; 56% [5033 of 8989] men) with cumulative 8989 HF hospitalizations: 2341 hospitalizations during the COVID-19 pandemic (March 1 through October 30, 2020) and 6648 in the pre-COVID-19 (October 1, 2018, through February 28, 2020) comparator group. We used Poisson regression, Kaplan-Meier estimates, multivariable logistic, and Cox regression analysis to determine whether prespecified study outcomes varied by time frames. RESULTS: The adjusted 30-day readmission rate decreased from 13.1% (872 of 6648) in the pre-COVID-19 period to 10.0% (234 of 2341) in the COVID-19 pandemic period (relative risk reduction, 23%; hazard ratio, 0.77; 95% CI, 0.66 to 0.89). Conversely, all-cause mortality increased from 9.7% (645 of 6648) in the pre-COVID-19 period to 11.3% (264 of 2341) in the COVID-19 pandemic period (relative risk increase, 16%; number of admissions needed for one additional death, 62.5; hazard ratio, 1.19; 95% CI, 1.02 to 1.39). Despite significant differences in rates of index hospitalization, readmission, and mortality across the study time frames, the disease severity, HF subtypes, and treatment patterns remained unchanged (P>0.05). CONCLUSION: The findings of this large tristate multicenter cohort study of HF hospitalizations suggest lower rates of index hospitalizations and 30-day readmissions but higher incidence of 30-day mortality with broadly similar use of HF medication, surgical interventions, and devices during the COVID-19 pandemic compared with the pre-COVID-19 time frame.

Clinical Characteristics of Patients with Myocarditis following COVID-19 mRNA Vaccination: A Systematic Review and Meta-Analysis.

COVID-19 mRNA vaccinations have recently been implicated in causing myocarditis. Therefore, the primary aim of this systematic review and meta-analysis was to investigate the clinical characteristics of patients with myocarditis following mRNA vaccination. The secondary aims were to report common imaging and laboratory findings, as well as treatment regimes, in these patients. A literature search was performed from December 2019 to June 2022. Eligible studies reported patients older than 18 years vaccinated with mRNA, a diagnosis of myocarditis, and subsequent outcomes. Pooled mean or proportion were analyzed using a random-effects model. Seventy-five unique studies (patient n = 188, 89.4% male, mean age 18-67 years) were included. Eighty-six patients had Moderna vaccines while one hundred and two patients had Pfizer-BioNTech vaccines. The most common presenting symptoms were chest pain (34.5%), fever (17.1%), myalgia (12.4%), and chills (12.1%). The most common radiologic findings were ST-related changes on an electrocardiogram (58.7%) and hypokinesia on cardiac magnetic resonance imaging or echocardiography (50.7%). Laboratory findings included elevated Troponin I levels (81.7%) and elevated C-reactive protein (71.5%). Seven patients were admitted to the intensive care unit. The most common treatment modality was non-steroid anti-inflammatory drugs (36.6%) followed by colchicine (28.5%). This meta-analysis presents novel evidence to suggest possible myocarditis post mRNA vaccination in certain individuals, especially young male patients. Clinical practice must therefore take appropriate pre-cautionary measures when administrating COVID-19 mRNA vaccinations.

Upregulation of Endothelin-1 May Predict Chemotherapy-Induced Cardiotoxicity in Women with Breast Cancer.

As survival in breast cancer patients from newer therapies increases, concerns for chemotherapy-induced cardiotoxicity (CIC) have offset some of these benefits, manifesting as a decline in left ventricular ejection fraction (LVEF). Patients receiving anthracycline-based chemotherapy followed by trastuzumab are at risk for CIC. Previous research evaluating whether clinical biomarkers predict cardiotoxicity has been inconsistent. Recently, angiotensin II type 1 receptor (ATR1) and endothelin 1 (ET1) have been shown to play a role in breast tumor growth. We evaluated ATR1 and ET1 expression in breast cancer tissue and its association with CIC. A total of 33 paraffin-embedded breast tissue specimens from women with breast cancer treated with anthracycline-based chemotherapy and trastuzumab were analyzed by immunohistochemistry (IHC) and qRT-PCR. We found that ET1 expression was increased in patients with an LVEF ≤ 50% (p = 0.032) with a lower LVEF correlating with higher ET1 expression (r = 0.377, p = 0.031). In patients with a change in LVEF of greater than 10%, greater ET1 expression was noted compared to those without a change in LVEF (p = 0.017). Increased ET1 expression in breast tumor tissue is associated with reduced LVEF. Future studies need to examine whether ET1 may be a tissue biomarker that helps predict the risk of developing CIC in women with breast cancer.

Detecting cardiomyopathies in pregnancy and the postpartum period with an electrocardiogram-based deep learning model.

AIMS: Cardiovascular disease is a major threat to maternal health, with cardiomyopathy being among the most common acquired cardiovascular diseases during pregnancy and the postpartum period. The aim of our study was to evaluate the effectiveness of an electrocardiogram (ECG)-based deep learning model in identifying cardiomyopathy during pregnancy and the postpartum period. METHODS AND RESULTS: We used an ECG-based deep learning model to detect cardiomyopathy in a cohort of women who were pregnant or in the postpartum period seen at Mayo Clinic. Model performance was evaluated using the area under the receiver operating characteristic curve (AUC), accuracy, sensitivity, and specificity. We compared the diagnostic probabilities of the deep learning model with natriuretic peptides and a multivariable model consisting of demographic and clinical parameters. The study cohort included 1807 women; 7%, 10%, and 13% had left ventricular ejection fraction (LVEF) of 35% or less, <45%, and <50%, respectively. The ECG-based deep learning model identified cardiomyopathy with AUCs of 0.92 (LVEF ≤ 35%), 0.89 (LVEF < 45%), and 0.87 (LVEF < 50%). For LVEF of 35% or less, AUC was higher in Black (0.95) and Hispanic (0.98) women compared to White (0.91). Natriuretic peptides and the multivariable model had AUCs of 0.85 to 0.86 and 0.72, respectively. CONCLUSIONS: An ECG-based deep learning model effectively identifies cardiomyopathy during pregnancy and the postpartum period and outperforms natriuretic peptides and traditional clinical parameters with the potential to become a powerful initial screening tool for cardiomyopathy in the obstetric care setting.

Relation of brain natriuretic peptide level to extent of left ventricular scarring in patients with chronic heart failure secondary to ischemic cardiomyopathy.

Multiple factors influence brain natriuretic peptide (BNP) release in patients with heart failure. We hypothesized that extensive myocardial scarring could result in an attenuated BNP response. A total of 115 patients with New York Heart Association class III chronic heart failure and ischemic cardiomyopathy were evaluated for ischemia, hibernation, and myocardial scarring by dipyridamole-rubidium-positron emission tomographic scanning with fluorine-18, 2-fluoro-2-deoxyyglucose. Plasma BNP levels were determined within 2 weeks of the study. Left ventricular dimension and function were evaluated by echocardiography. Patients were categorized as having <33% myocardial scar (n=67) or>or=33% myocardial scar (n=48). BNP measurements were correlated with amount of myocardial scarring. Compared with patients with less scar, those with >or=33% scar had lower BNP levels (mean 317+/-364 vs 635+/-852 pg/ml, median 212 vs 357, p=0.016). Using multiple regression analysis, presence of scarring was associated with decreased BNP response (p=0.022). Further, patients with <33% scar in whom a higher BNP level was noted had more ischemia (51% vs 27%, p=0.01) and greater myocardial hibernation (22+/-14% vs 12+/-7%, p=0.02) compared with patients with >or=33% scar. In conclusion, in patients with chronic heart failure, a decreased BNP response indicated extensive myocardial scarring.

Hypogammaglobulinemia and infection risk in solid organ transplant recipients.

PURPOSE OF REVIEW: Hypogammaglobulinemia may develop as a result of a number of immune deficiency syndromes that can be devastating. This review article explores the risk of infection associated with hypogammaglobulinemia in solid organ transplantation and discusses therapeutic strategies to alleviate such a risk. RECENT FINDINGS: Hypogammaglobulinemia is associated with increased risk of opportunistic infections, particularly during the 6-month posttransplant period when viral infections are most prevalent. The preemptive use of immunoglobulin replacement results in a significant reduction of opportunistic infections in patients with moderate and severe hypogammaglobulinemia. SUMMARY: Monitoring immunoglobulin G levels may aid in clinical management of solid organ transplant recipients. The preemptive use of immunoglobulin replacement may serve as a new strategy for managing solid organ transplant recipients with hypogammaglobulinemia.

Myocardial degradation and left bundle branch block predict conversion to low ejection fraction in heart failure with preserved systolic function.

The authors prospectively investigated whether left bundle branch block (LBBB) and myocardial degradation as indicated by elevated troponin T (tnT) predict the phenomenon of systolic conversion to low ejection fraction (EF 40%). Thirty consecutive patients with HFPSF were included and followed over a 4-year interval. A follow-up EF assessment was performed in 25 patients. Six of 15 patients with tnT >or=0.01 ng/mL demonstrated systolic conversion to low EF on follow-up, while none of the 10 patients with tnT <0.01 ng/mL experienced this phenomenon (P=.03). Five of the 6 converters presented with LBBB, while only 1 of the 19 nonconverters had this abnormality (P=.0007). Four of the 6 converters had an initial EF >50%. Myocardial degradation and LBBB predicted systolic conversion in HFPSF patients with nonsignificant coronary disease.

Thymoglobulin induction and steroid avoidance in cardiac transplantation: results of a prospective, randomized, controlled study.

BACKGROUND: Chronic use of corticosteroids (CS) following transplantation is associated with significant long-term morbidities. Minimizing exposure to CS to improve long-term outcomes, without compromising allograft function, remains an important goal in transplantation. OBJECTIVES: This single-center, prospective, randomized, open-label study was designed to evaluate the efficacy of Thymoglobulin as part of a CS-sparing regimen in cardiac transplantation. METHODS: Thirty-two low-risk cardiac transplant patients were randomized in a 1:1 ratio to receive either a Thymoglobulin-based CS-avoidance regimen (CS-avoidance group; n = 16) or a long-term CS-based regimen with no antibody induction (control group; n = 16). Pulse CS therapy was used for the treatment of acute cellular rejection in both groups. RESULTS: Baseline characteristics were similar between groups. At one yr, there was no significant difference in the mean incidence of acute cellular rejection (>or=3A) episodes between the CS-avoidance and control groups, 0.81+/-1.05 and 1.07+/-1.03, respectively. Importantly, the CS-avoidance patients had significant improvement in muscle strength and less bone loss compared with the control patients during the first six months post-transplant. CONCLUSIONS: CS-avoidance regimen with Thymoglobulin induction appeared to be safe and effective in cardiac transplantation. Further studies are required to demonstrate the long-term safety and benefits of such a regimen.

Coronary angiography for follow-up of heart transplant recipients: insights from TIMI frame count and TIMI myocardial perfusion grade.

BACKGROUND: The aim of this study was to evaluate the course of Thrombolysis in Myocardial Infarction (TIMI) frame count (TIMI FC) and myocardial perfusion grade (TIMI MPG) in heart transplant recipients and whether these parameters could predict mortality. METHODS: Sixty-two heart transplant recipients were enrolled in this study. All patients had coronary angiography at baseline and at 1 year, which were evaluated for TIMI FC and TIMI MPG. Also, 50 vessels in 35 patients were analyzed with volumetric intravascular ultrasound (IVUS) at baseline and at 1 year. Rejection episodes and mortality were recorded during the follow-up period. RESULTS: The mean follow-up interval was 51.5 +/- 17.2 months (range 12.2 to 78.4 months). TIMI FCs of all three coronary arteries and global TIMI FC (gTIMI FC) significantly increased from baseline during the first year (p < 0.0001). TIMI MPG deteriorated significantly (p < 0.0001 for left anterior descending and circumflex coronary arteries, p = 0.002 for right coronary artery). There was no correlation between changes in TIMI FC and progression of transplant vasculopathy as assessed by IVUS. Episodes of Grade > or = 3A rejection were significantly more frequent in the stable gTIMI FC group (p = 0.03). Mortality rate was significantly higher in the group with increasing gTFC (p = 0.02). CONCLUSIONS: gTIMI FCs and TIMI FCs of coronary arteries increase, and TIMI MPG gradually deteriorates during the first year after transplantation. Mortality rate is significantly higher in patients whose gTIMI FC increases from baseline. Change in gTIMI FC is a simple quantitative predictor of long-term mortality in heart transplant recipients.

Heart transplantation: a magnified model of heart-brain interactions.

The human heart transplant model unmasks the heart-brain link as an active process that is clinically demonstrated and confirmed at the tissue level. Further studies are needed to elucidate the relative contribution of each of these isolated observations to the pathogenesis of coronary allograft vasculopathy, which remains enigmatic. Recent studies have suggested that mTOR inhibitors may have the ability to attenuate this lethal process that limits the long-term survival of cardiac transplant recipients. The observations we have discussed here suggest that other targeted therapies, including glycoprotein IIb/IIIa inhibitors, tissue metalloproteinase inhibitors, and angiotensin receptor blockers, may facilitate the attenuation of cardiac transplant vasculopathy, but clinical trials are difficult to conduct in this relatively small population of patients. These observations may shed insight, however, into the pathophysiology of hypertension and its impact on the vascular system, as cardiac transplantation provides a setting in which heart-brain interactions are magnified and the pathophysiology occurs over years rather than decades.

Transplant vasculopathy is associated with increased AlloMap gene expression score.

The AlloMap gene expression test is used for the non-invasive detection of rejection in heart transplant recipients. We evaluated the impact of transplant vasculopathy on AlloMap gene expression analysis. A total of 69 heart transplant recipients, mean age 53 years, were evaluated at a mean 35 months post-transplant. AlloMap score was determined on the same day of the endomyocardial biopsies. Twenty patients had evidence of vasculopathy by coronary angiography (vasculopathy group). These were compared to the remaining 49 patients (control group). The vasculopathy group had a longer mean follow-up duration (48.7 vs 28.8 months, p < 0.01), lower left ventricular ejection fraction (51% vs 60%, p < 0.01) and increased use of sirolimus (40% vs 16%, p = 0.034) compared with controls. Using the logistic regression model and bagging bootstrap approach to adjust for the time factor and potential confounders, the vasculopathy group had a significantly higher AlloMap score than the control group (32.2 +/- 3.9 vs 26.1 +/- 6.5, p < 0.001). There was a correlation of AlloMap score with time after transplantation (r = 0.31, p = 0.01). We found transplant vasculopathy to be associated with increased AlloMap score.

Increased expression of angiotensin II type 1 receptor (AGTR1) in heart transplant recipients with recurrent rejection.

BACKGROUND: Angiotensin II receptor sub-type 1 (AGTR1) plays an important role in the regulation of the cellular immune process. We hypothesized that recurrent acute rejection is associated with increased gene expression of AGTR1 in human heart transplantation. METHODS: We identified a group of 14 heart transplant recipients who had recurrent acute cellular rejection (RAR), defined as three consecutive episodes of acute rejection (Grade > or =3A). These patients were matched to a control group (n = 15). mRNA gene expression of AGTR1 was measured in heart biopsy specimens of controls at 1 week post-transplant. AGTR1 mRNA was determined serially in the RAR group at baseline, each rejection episode, and after resolution of rejection. Angiotensin-converting enzyme (ACE) polymorphism was also evaluated. RESULTS: Both the control and RAR groups had similar mRNA AGTR1 expression at baseline. Compared with baseline, the RAR group had significantly increased mRNA expression of AGTR1 at the first episode of rejection (9-fold, p < 0.001), which increased further at the second episode (12-fold, p < 0.001) and peaked at the third episode (35-fold, p < 0.001). After resolution of rejection, AGTR1 expression was decreased significantly (p < 0.001), but remained elevated above baseline (6-fold, p < 0.001). No difference in ACE polymorphism was noted between the two groups. Compared with controls, the RAR patients had an increased incidence of hypertension, diabetes mellitus, chronic renal insufficiency and transplant vasculopathy during a mean follow-up period of 51.5 +/- 12 months. CONCLUSIONS: This is the first report to describe increased mRNA expression of AGTR1 in response to recurrent cellular rejection. Up-regulation of AGTR1 responds to treatment of rejection but not to complete recovery, a phenomenon that may potentially explain the link between rejection and subsequent clinical outcome.

The impact of hypogammaglobulinemia on infection outcome in patients undergoing ventricular assist device implantation.

BACKGROUND: Infection is a major comorbidity after ventricular assist device (VAD) placement. Defects in cellular immunity have been reported after VAD placement. However, to our knowledge, quantitative immunoglobulin G (IgG) level determination and the impact of hypogammaglobulinemia (HGG) on infections after VAD implantation have not been evaluated before. METHODS: A total of 76 patients (mean age, 53 years) underwent VAD implantation as a bridge to transplantation and had IgG levels determined as a baseline before transplantation. Patients were divided into 2 groups according to IgG level: Control Group (n = 56, IgG > or = 700 mg/dl) and HGG Group (n = 20, IgG < 700 mg/dl). Infection outcome during the VAD course and after transplantation was analyzed in relation to the IgG level. RESULTS: Baseline characteristics were similar in both groups. The incidence of bacteremia (14/20 [70%] vs 18/56 [32%], p = 0.0032) and major infection (19/20 [95%] vs 31/56 [56%], p = 0.0009) were significantly increased in the HGG Group compared with the Control Group. After transplantation, the episodes of rejection were similar in both groups and survival was similar. The HGG Group experienced more cytomegalovirus infections compared with the Control Group (9/20 [45%] vs 9/56 [16%], p = 0.009). CONCLUSIONS: VAD patients with HGG are at increased risk of infections. After transplantation, these patients also experience increased cytomegalovirus infections. A randomized preemptive IgG replacement trial may be warranted in the future to determine if this intervention will alleviate the risk of infection.

Improved survival after acute myocardial infarction complicated by cardiogenic shock with circulatory support and transplantation: comparing aggressive intervention with conservative treatment.

BACKGROUND: The prognosis for patients with myocardial infarction has steadily improved, but remains poor for those developing cardiogenic shock. Utilization of re-vascularization, mechanical circulatory support and transplantation in these patients may improve survival. METHODS: We retrospectively analyzed the clinical outcome of 138 consecutive patients at the Cleveland Clinic from 1992 to 1998 who met the criteria for cardiogenic shock after acute myocardial infarction. All patients received intensive medical therapy and intra-aortic balloon pump support. Forty-three patients received intensive medical therapy (conservative group) and 95 patients were treated aggressively (aggressive group). The aggressive group comprised patients who were treated with percutaneous intervention/coronary artery bypass grafting (n = 77, re-vascularization group), and patients who received circulatory support/cardiac transplantation (n = 18). RESULTS: The baseline demographics and angiographic and hemodynamic features were comparable for the two groups. The in-hospital mortality rate was significantly reduced in the aggressive group compared with the conservative group (54% vs 81%, p = 0.002). The in-hospital mortality rate of the circulatory support/transplant group was markedly reduced compared with the conservative group (33% vs 81%, p < 0.001), and was also significantly lower than that of the re-vascularization group (33% vs 63%, p= 0.03). The aggressive group had a markedly improved 5-year survival compared with the conservative group (30% vs 6.2%, p = 0.003). CONCLUSIONS: These data suggest that an aggressive strategy, particularly left ventricular assist device support as a bridge to heart transplantation, may improve survival in post-myocardial infarction patients with cardiogenic shock.

Donor or recipient hepatitis B seropositivity is associated with allograft vasculopathy.

BACKGROUND: Increasing interest has focused on possible viral triggers of cardiac allograft vasculopathy. Although much interest has centered on cytomegalovirus, it has recently been noted that donor hepatitis C seropositivity is associated with risk for accelerated vasculopathy. The current study hypothesized that hepatitis B (HBV) might be associated with accelerated vasculopathy. METHODS: Sixty-six patients who received heart transplants between September 1998 and July 2000 were analyzed by intravascular ultrasound within 6 weeks and again at 12 months after transplantation. These patients were divided into 2 groups: the HBV Group (n = 13) in which either the donor or recipient was seropositive for hepatitis B core antibody (HBcAb), and a Control Group (n = 53) in which neither donor nor recipient was positive for HBcAb. RESULTS: Baseline characteristics of the 2 groups were similar. The HBV Group had significant increase in the change in average intimal area (1.59 +/- 1.4 vs 0.46 +/- 0.4 mm2, p = 0.01) per mm length of the vessel compared with controls. Allograft vasculopathy at 1 year (defined as largest maximal intimal thickness increase of > or =0.50 mm) occurred in 46% of the HBV group compared with 24% of the control group (p = 0.05). When measured as an average maximal intimal thickness increase of >0.30 mm, allograft vasculopathy at 1 year occurred in 31% of the HBV Group compared with 5% of Controls (p = 0.01). CONCLUSIONS: These preliminary results suggest that HBV seropositivity in donor or recipient may be associated with an increased risk for cardiac allograft vasculopathy.