Heart Valve Research Articles

Comparison of the effects of pre-dilatation with conventional versus larger balloon sizes on clinical outcomes in transcatheter aortic valve implantation with self-expandable valves

Abstract Background Transcatheter aortic valve implantation (TAVI) is considered an established treatment option for patients with severe aortic stenosis. When implanting self-expandable valve, pre-dilatation is often necessary to facilitate optimal transcatheter heart valve (THV) deployment. Traditionally, balloon sizes chosen for pre-dilatation are smaller than the minimum annulus diameter. Insufficient pre-dilatation can result in under-expansion of the THV, necessitating post-dilatation, and can increase the risk of complications. However, this conventional approach may not always yield the best outcomes, prompting a reassessment of balloon sizing strategies to improve procedural success and patient outcomes. Purpose The aim of this study was to investigate the impact on procedural outcomes of using larger balloons, sized less than the mean annulus diameter, for pre-dilatation compared to the traditional practice of using balloons sized less than the minimum annulus diameter during the implantation of self-expandable valves. Methods We analyzed 785 patients who underwent TAVI with self-expandable valve with pre-dilatation out of a consecutive 3880 cases at 6 centers from 2010 to 2023 (Figure 1). Among them, we divided the patients into two groups: those who underwent pre-dilation with balloons smaller than the minimum annulus diameter defined as the Conventional-size group and those who underwent pre-dilatation with balloons smaller than the mean annulus diameter defined as the Large-size group. The primary endpoint of this study was procedural success, stroke and need for permanent pacemaker implantation as designated by the VARC-3criteria. Results Of patients (69% female; mean age 84.9), there were 563 (71.7%) patients in the Conventional-size group and 222 (28.2%) patients in the Large-size group. There was no annulus rupture in either group. The incidence of post-dilatation was significantly higher in the Conventional-size group than in the Large-size group (109 of 563 [19.4%] vs. 23 of 222 [10.3%], p=0.001) (Figure 2). There was no significant difference in the incidence of primary endpoints (all p > 0.05). In post-echocardiographic outcomes, there was no significant difference in effective orifice area, mean pressure gradient, patients-prosthesis mismatch, or paravalvular leakage between the groups (P > 0.05). Conclusions This study demonstrates that a large-size strategy using a balloon smaller than the mean annulus diameter in the deployment of self-expandable valves is safe and may avoid the need for post-dilatation compared to the traditional strategy using a balloon smaller than the smallest diameter.

Rheumatic heart disease: an ongoing public health concern in vulnerable communities

Abstract Background Acute rheumatic fever (ARF) results from an autoimmune response triggered by group A streptococcus (GAS) infection (1). Severe or recurrent ARF episodes can cause permanent heart valve damage, leading to complications including heart failure, stroke, arrhythmias, carditis, and decompensation during pregnancy (2). Purpose Rheumatic fever (RF) remains a public health concern in Australia, particularly among Indigenous, migrant populations and socioeconomically disadvantaged communities. Europe and various regions worldwide have experienced significant migration from areas with a high prevalence of RHD (3). Amongst the more than 1 million asylum seekers who arrived in Europe in 2015, an estimated 1% could potentially be affected by RHD (3). This migration influx underscores the pressing need for the implementation of strategies in health policy and practice. We aimed to outline the attributes of our RF-RHD cohort to aid in the formulation of a Model of Care (MoC). Methods Cases were identified on a quarterly basis either through the NSW Public Health Rapid, Emergency, Disease, and Syndromic Surveillance (PHREDSS) system or via clinical diagnoses reported to the Public Health Unit (PHU) from January 2015 to June 2023. Demographic profiles, clinical particulars, and patient outcomes were collected from patients in the South Western Sydney Local Health District (SWSLHD), NSW, Australia. Results A total of 45 cases were reported (Table 1). This consisted predominantly of females with an average age at diagnosis of 14 years. A majority were obese (69%). Most were in the Maori and Pacific Islander populations (62%), while a smaller portion of patients were of Aboriginal or Torres Strait Islander descent (9%) (Australian Indigenous community). Notably, 84% of patients diagnosed with ARF subsequently progressed to RHD. Among the reported cases, 16 patients underwent valvular surgery, 2 patients progressed to end-stage heart failure, and there was 1 mortality. 39% (11) of female patients were pregnant during the study period, with 6 (55%) of these patients decompensating during their pregnancy (Table 2). Conclusion Rheumatic fever persists as a public health concern on a global scale. Our findings emphasize the need for a high index of clinical awareness in considering RF/RHD in socioeconomically disadvantaged communities. In our setting, there is a disproportionate burden of disease among the Pacific Islander population. The high occurrence of cardiac decompensation during pregnancy, underscores the need for close monitoring in this demographic. Despite the prevalence of rheumatic fever predominantly affecting young patients in vulnerable groups, we found a significant proportion of individuals lost to follow-up or not connected with Cardiology services. Addressing rheumatic fever requires a comprehensive approach that encompasses improved healthcare accessibility, targeted health education initiatives, and socioeconomic interventions.

Incidence of cardiovascular diseases among breast cancer patients: a nationwide registry study 2013-2020

Abstract Background and aims There is evidence to suggest that breast cancer (BC) treatment is associated with an increased risk of developing cardiovascular disease (CVD). Several countries have introduced clinical measures to reduce the impact of breast cancer treatment on cardiovascular function including activated breathing control during radiotherapy, lower radiation doses, and maximum anthracycline doses. The overall aim of this study was therefore to investigate whether breast cancer patients still exhibit higher rates of cardiovascular disease than the general population. Methods We conducted a registry-based cohort study using linked data from four nationwide health registries. Out study population included all Norwegian patients diagnosed with BC between 2013-2020 and matched them by age to 10 controls without BC. Health outcomes were measured from 2008 to 2021. We estimated the cumulative incidence from index date, for ten selected CVDs. For BC patients, the index date was defined as date of BC diagnosis. For controls, the index date was defined as the date of BC diagnosis for the matched BC patient. A wash-out period of 5 years was applied to identify incident cases of CVD. Results The study population included 27,535 patients with BC and 269,9994 matched controls. Median age in both groups was 62 years (IQR: 20). Prior to index date, there were no significant differences in the prevalence of heart valve disease, chronic ischemic heart disease heart failure and peripheral vascular disease in BC patients compared to controls (p>0.05) (Table 1). Hypertensive heart disease, pulmonary embolism, atrial fibrillation, and other cardiac arrythmias were more prevalent in BC patients, while angina pectoris and acute myocardial infarction were more prevalent among controls. After the index date, the incidence proportion for heart valve disease, hypertensive heart disease, pulmonary embolism, atrial fibrillation, other cardiac arrythmias, and heart failure were higher in BC patients compared to controls (p<0.001) (Table 2). No significant differences were found for angina pectoris, acute myocardial infarction, chronic ischemic heart disease, and peripheral vascular disease. Conclusion Breast cancer is still associated with an increased risk of developing several CVDs in current clinical practice, compared to matched controls without breast cancer.Baseline characteristicsIncidence of CVD

Assessment of a new index of myocardial strain for the diagnosis of cardiac sarcoidosis

Abstract Background The diagnosis of cardiac involvement in sarcoidosis is challenging and often expensive. Purpose The aim of this study is to assess whether a new strain index proposed by the authors has incremental value in the evaluation of cardiac involvement, compared to the use of left ventricular (LV) global longitudinal strain (GLS). Methods This is a single-center, non-blinded, pilot cross-sectional study. Patients of both genders, >18 years old, with confirmed diagnosis of cardiac sarcoidosis according to the Heart Rhythm Society criteria, and controls consisting of individuals diagnosed with systemic sarcoidosis without cardiac involvement, were included. Patients with obesity grade 2 or higher , moderate or severe primary heart valve disease, myocardial diseases of other etiologies, established coronary artery disease, and inadequate acoustic window were excluded. All patients underwent transthoracic echocardiography, with subsequent measurements performed on a workstation. The following LV indexes were evaluated: GLS and the new proposed index, calculated by the ratio between LVEF and the sum of the two segments with the lowest absolute strain values. ROC curves were calculated for both parameters using an online dedicated software, with determination of the optimal cutoff point for both variables, corresponding to the point of highest sensitivity and specificity. Confidence intervals were established by the DeLong method, and curves were compared using the Bonferroni method. A two-tailed p value of 0.05 was considered significant. Results Twenty patients with cardiac involvement and twenty patients without cardiac involvement were evaluated. The results of the variables are presented in table 1. Conclusions The new index showed a larger area under the curve compared to isolated GLS, as well as higher sensitivity and specificity for the identified cutoff point, although without statistical significance, possibly due to the small sample size. Further studies are needed for subsequent validation of this innovative index.

The association of obesity and in-hospital outcomes among patients undergoing ablation for atrial fibrillation: a propensity-score matched analysis

Abstract Background Obesity is a strong risk factor for atrial fibrillation (AF), and it can affect the prognosis of AF. However, the impact of obesity (BMI≥30 kg/m²) on postoperative complications after AF ablation has not been extensively studied. We aimed to evaluate the association of obesity with in-hospital outcomes among patients with AF who ablation procedures. Methods The study utilized the National Inpatient Sample (NIS) database 2016-2020. Patients were divided into obese and non-obese groups and matched with propensity score matching (1:1). This matching involved adjusting for baseline variables (including age, gender, primary expected payer, race, and median household income) and comorbidities (including diabetes, hypertension, hyperlipidemia, history of coronary artery bypass grafting (CABG), chronic kidney disease, hyperthyroidism, cardiomyopathy, prior stroke or transient ischemic attack, heart failure with preserved ejection fraction (HFpEF), heart failure with reduced ejection fraction (HFrEF), heart valve disease, coronary artery disease, chronic obstructive pulmonary disease (COPD), alcohol misuse, anemia, and smoking). Furthermore, a weighted analysis was conducted utilizing weights provided by the NIS, and multivariate logistic regression was used to calculate the odds ratio. Results A total of 29,440 patient with AF who underwent ablation were included. After propensity matching, (8,110 in obese and 8,110 in non-obese group) the baseline characteristics were not significantly different between the two groups. Obesity was independently associated with higher risk of pseudoaneurysm, hematoma, postoperative anemia, acute kidney injury, vasopressor need, mechanical ventilation, pulmonary embolism, and ischemic stroke in patients who underwent ablation for AF (Figure 1). In addition, obese group had significantly higher length of stay (median and IQR 2 [1-3] vs 2 [1-4]) and total charges (median and IQR: 131,248$ [95,303-197,784] vs 143,693$ [102,720-206728]) compared to non-obese group (p<0.001). However, in-hospital mortality was not significantly different between the two groups. Conclusion In patients who underwent AF ablation, obesity is associated with significantly higher risk of post-operative complications, as well as increased LOS and total hospital charges.

Effect of patient prosthesis mismatch on clinical outcomes following surgical aortic valve replacement

Abstract Introduction Patient prosthesis mismatch (PPM) after surgical aortic valve replacement (SAVR) occurs when the valve’s effective orifice area (EOA) does not allow appropriate cardiac output to meet demand, causing increased transvalvular gradients. The literature is conflicting regarding the effect of PPM on long-term mortality and other adverse outcomes. Purpose To characterise the effect of PPM on all-cause mortality, cardiovascular death, heart failure hospitalisation and major adverse cardiac events (MACE; a composite of cardiovascular death, myocardial infarction, and stroke) following SAVR, stratified by sex. Methods This retrospective cohort study uses data from the Western Australia Heart Valves Study linked to administrative health data and includes all patients who underwent SAVR in Western Australian public hospitals between 2010-2020. PPM was defined according to the Valve Academic Research Consortium 3 criteria. The indexed EOA was derived from body surface area and published in-vivo EOA’s calculated for each prosthesis model and size. Results During the study period 1837 patients underwent SAVR (mean age 65 ± SD 14 years, 31% female). Median follow-up was 3.76 years (IQR 1.73-6.62). A mechanical prosthesis was implanted in 579 (32%) patients. Moderate or severe PPM was present in 250 (14%) patients, whilst no significant PPM was present in 1587 (86%) patients. Compared to those without significant PPM, patients with PPM were older (69 ± 14 vs 64 ± 11 years; p<0.001); included more women (101/250; 40% vs 459/1587; 29%; p<0.001) and were more likely to have bioprosthetic SAVR (213/250; 85% vs 1045/1587; 66%; p<0.001). The presence of PPM (moderate or severe vs no significant PPM) was associated with increased all-cause death (Hazard Ratio (HR) 1.74, 95% CI 1.09-2.75), cardiovascular death (HR 2.44, 95% CI 1.33-4.48) and MACE (HR 1.89, 95 CI 1.17-3.04) in females in adjusted analyses, but not males (table). The presence of PPM was not associated with heart failure hospitalisation, overall or in either sex. Conclusion The presence of moderate or severe PPM is associated with increased all-cause death, cardiovascular death, and MACE in females only. These results highlight the importance of patient selection, valve choice and operative technique to minimise PPM, particularly in female patients.Table 1

Real-world analysis of transcatheter aortic valve replacement in patients with prostate cancer and severe aortic stenosis

Abstract Background Patients with prostate cancer have a high prevalence of cardiovascular disease, including degenerative heart valve diseases such as aortic stenosis. It is not uncommon in clinical practice to perform transcatheter aortic valve replacement (TAVR) in patients with severe aortic stenosis and active prostate cancer. Still, the prognosis after this procedure in this population is not well known. Purpose To evaluate 1-year and 3-year survival rates after TAVR in patients with prostate cancer who have undergone TAVR when compared with patients without active cancer. Methods Data were extracted from electronic medical records of a large multinational collaborative network (TriNetX) that currently englobes 113 healthcare organizations worldwide with more than 100 million patients. Patients aged 18 years or older with prostate cancer documented up to 12 months before TAVR as well as controls undergoing TAVR without oncologic history before the proceeding were included. The survival analysis for 1 year and 3 years was performed with Kaplan Meier survival plots and log-rank test. Propensity score matching, using clinical and demographic variables, was performed to pair the cohorts. Results From a cohort of 26,656 men who had undergone TAVR, we identified 1,040 with prostate cancer diagnosed up to 1 year before TAVR ( prostate cancer group) and 20,231 patients without oncologic history before TAVI (control group). After propensity score matching, analyzing 1,040 patients in each group, the 1-year and 3-year survival probabilities were not different between the prostate cancer group versus the control group ( 89.5% vs 88.9%, log-rank test P=0.70 and 72.6% vs 68.7%, log-rank test P=0.22, respectively). Considering a subgroup of patients with metastatic prostate cancer ( n=229) under androgen deprivation therapy vs the control group ( n =229), we have also not observed a survival difference between the two groups at 1-year and 3-year follow-up ( 88.1 vs 89.1%, log-rank test P=0.69 and 58.7% vs 67.4%, log-rank test P=0.25). Conclusions In this real-world analysis, patients with prostate cancer and severe aortic stenosis who underwent TAVR, including patients with metastatic disease, the 1-year and 3-year survival rates were not significantly different when compared to patients without oncologic hystory who underwent TAVR.

Anticoagulation control challenges in patients with rheumatic heart disease and mechanical heart valves operated at a cardiac surgery center in a low-income country

Abstract Background Rheumatic heart disease (RHD) prevalence is very high in many low-income countries and valve replacement surgery can sometimes be the only available therapeutic strategy for the affected patients. Mechanical valves require lifelong anticoagulation and this can be very challenging in many poor countries where several barriers to effective anticoagulation monitoring and management are faced. Methods This is a retrospective study on 145 patients with RHD who underwent valve replacement surgery at a cardiac surgery center (CSC) in a low-income country between 2001 and 2022. The study aimed to evaluate the effectiveness of anticoagulation treatment to prevent thromboembolic events in patients with RHD with mechanical valves. The patients’ information such as social and demographic data, clinical features, surgical data and international normalized ratio (INR) records were collected and analyzed. Descriptive statistics were applied to the data and expressed as mean with standard deviation or simple frequencies and percentages. Results The mean age of the operated patients was 25.9 years (± 12.6) and 60% of them were female. Most of the patients (54%) were able to monitor their anticoagulation at the center and 8.2% of them monitored it in other hospitals. Three percent (3%) of the patients use a portable device to monitor their INR. These devices are provided by the CSC to help patients that live in distant provinces and are unable to go to the capital regularly. The device is held by one patient that is a focal point and helps monitor the INR of the other patients living in the same province. The INR results are communicated to the CSC by telephone text message. Seven percent (7%) of the operated patients haven’t monitored their INR for more than one year and 24.8% of them were lost to follow-up. Sixty-four percent (64%) of the patients who monitor their INR at the center have an optimal control of their anticoagulation therapy. Most of the patients that were lost to follow-up (N=20) and most of the patients that haven’t checked their INR for more than one year (N=7) are patients who had aortic valve replacements. At least 20% of the patients that live in capital of the country and close to the CSC don’t monitor their anticoagulation regularly. Conclusion The surgical outcomes in RHD patients who undergo mitral valve repair are usually satisfactory. However, valve replacement is often the only feasible alternative and anticoagulation monitoring and management in these patients can become a serious problem especially to those coming from areas with limited resources. Illiteracy and poverty play a major role as barriers to effective monitoring of anticoagulation therapy. Efforts must be made to increase access to facilities where INR can be monitored. Our experience showed us that providing portable devices for INR monitoring to the patients living in remote areas can be a favorable short-term solution.

Influence of prior heart valve intervention on treatment and disease trajectory after diagnosis of heart failure with reduced ejection fraction

Abstract Background and aim Among patients with heart failure with reduced ejection fraction (HFrEF), knowledge is scarce on whether patients with prior valvular heart disease (VHD) intervention are distinct regarding clinical characteristics, treatment, and prognosis. Methods Using the Danish Heart Failure Registry and nationwide administrative registries, we identified patients with new-onset HFrEF from 2008 to 2021. Within this cohort, patients with a prior VHD intervention were identified and matched 1:5 on age-, sex-, in/outpatient presentation, and year of HFrEF diagnosis with remaining patients (controls). Outcomes were 1) baseline use and up-titration of guidelines-directed medical therapy (GDMT) and implementation of implantable cardioverter-defibrillator or cardiac resynchronization therapy with pacemaker/defibrillator (ICD/CRT-P/D) at 6 months follow-up, and 2) a composite of HF hospitalization or all-cause death at 3 years follow-up. The Kaplan-Meier estimator and Cox regression models, adjusted for HF severity, socioeconomic status, and major comorbidities, were used to compare the composite outcome, with patients without prior heart valve intervention as reference. Results The study cohort comprised 32,713 patients, of whom 1196 (3.6%) underwent a prior VHD intervention (median time since intervention 10 months). After matching, the study population were 1151 cases (median age 74 years, 82% men), and 3769 matched controls. Among cases and controls, median left ventricular ejection fraction was similar (30% vs. 30%) and the proportion in New York Heart Association (NYHA) class II was alike (82% vs 83%). At the time of HFrEF diagnosis, numerically more cases were on a beta-blocker (62% vs. 53%), ACEi/ARB/ARNI (48% vs. 44%), MRA (19% vs. 14%), and more had an implementation of (ICD/CRT-P/D) (17 % vs. 7%) (Figure 1). At 6 months, ≥ 50% of the daily target dose was achieved in (46% vs. 46%) for beta-blockers, (47% vs. 47%) for ACEi/ARBs/ARNI, (31% vs. 33%) for MRA, and implementation of ICD/CRT-P/D was attained in (28% vs. 18%), among cases and controls, respectively (Figure 1). The 3-year risk of HF hospitalization or all-cause death was 25% in cases and 24% in controls (Figure 2) with no significant differences (hazard ratio (HR) 0.95 , 95% confidence interval (CI) 0.84-1.08) compared to controls. Conclusions Patients with new-onset HFrEF and prior VHD interventions received more GDMT and had a higher implementation of ICD/CRT-P/D at the time of HFrEF diagnosis. However, following diagnosis, no major differences in GDMT initiation and up-titration, implementation of ICD/CRT-P/D, and the adjusted rates of HF hospitalization or all-cause death were observed among patients with and without prior heart valve intervention.Figure 1 Guideline-directed medicationFigure 2 Crude cumulative risk

Evaluation of myocardial work indexes in patients with cardiac sarcoidosis

Abstract Background Cardiac involvement is associated with worse prognosis and mortality in sarcoidosis. Diagnosis often requires expensive and less available tests. Purpose The aim of this study is to evaluate whether non-invasive measurement of myocardial work by transthoracic echocardiogram has incremental value in the diagnosis of cardiac involvement compared to left ventricular (LV) global longitudinal strain (GLS). Methods This is a cross-sectional, non-blinded, single-center pilot study. Patients of both genders > 18 years old, with confirmed diagnosis of cardiac sarcoidosis according to the Heart Rhythm Society criteria, and controls consisting of individuals diagnosed with systemic sarcoidosis without cardiac involvement, were included. Patients with obesity grade 2 or higher , moderate or severe primary heart valve disease, myocardial diseases of other etiologies, established coronary artery disease, and inadequate acoustic window were excluded. All patients underwent transthoracic echocardiography and non-invasive blood pressure measurement, followed by subsequent analysis involving the construction of a pression-strain curve. The following LV indexes were calculated: GLS, global work index, global constructive work, global wasted work, and global work efficiency. ROC curves were calculated for all variables using the EasyROC online tool (v 1.3.1), and these were later compared to GLS. Confidence intervals were established by the DeLong method, and curves were compared by the Bonferroni method. A two-tailed p value of 0.05 was considered significant. Results Twenty patients with cardiac involvement and twenty patients without cardiac involvement were evaluated. The results of the variables are presented in table 1. Conclusions With exception of wasted work, all other LV myocardial work variables showed statistical correlation with cardiac involvement in sarcoidosis patients. However, there was no incremental value of myocardial work indexes compared to the isolated use of GLS.

Fibroblast activation in cardio-oncology

Abstract Introduction Carcinoid heart disease is a rare disease affecting the right sided heart valves (1) while anthracycline cardiotoxicity is a dreaded sequelae of a common chemotherapeutic agent that can occur early or even years after exposure (2). Activated fibroblasts, a key factor in these diseases, can be imaged with 68Gallium-fibroblast activation protein inhibitor (68Ga-FAPI). Method 12 patients with carcinoid syndrome, 12 patients with previous anthracycline exposure and 10 healthy volunteers underwent hybrid 68Ga-FAPI positron emission tomography and magnetic resonance imaging. Areas of fibroblast activation were quantified as mean and maximum target-to-background ratios (TBRmean and TBRmax). Results Carcinoid syndrome: 2 of the 12 patients had carcinoid heart disease [mean age 70, 50% female] (CHD) (Figure 1A). 68Ga-FAPI uptake was seen in the liver lesions of all patients with known carcinoid liver tumours. Of the 10 patients without cardiac involvement, 6 had significant tricuspid valve 68Ga-FAPI uptake (CHD- FAPI+) (Figure 1B) and 4 did not (CHD- FAPI-). Median tricuspid TBRmax was significantly higher in CHD + [2.38 (IQR 2.35-2.42)], than CHD- patients [CHD- FAPI+: 1.68 (IQR 1.65-1.73), CHD- FAPI-: 1.55 (IQR 1.53-1.65)], although this was higher than healthy volunteers [1.45 (IQR 1.43- 1.61; p<0.05). CHD- FAPI+ patients had significantly elevated urinary 5-HIAA levels compared to CHD- FAPI- patients [Median =188 mg/24hr (IQR 151-196) in CHD- FAPI+ vs 32mg/24hr ( IQR 12-73); p=0.03]. Anthracycline chemotherapy: 3 of the 12 patients had cardiotoxicity [mean age 61, 67% female]. Anthracycline patients had higher left ventricular myocardial 68Ga-FAPI uptake than healthy volunteers with cardiotoxicity patients having the highest. [TBRmean: Cardiotoxicity 1.46 (IQR 1.36- 1.53), No cardiotoxicity 1.37 (IQR 1.19- 1.49), Healthy volunteers 0.73 (IQR 0.66 - 0.81); p<0.01 (Figure 1E). Across the cohort a moderate negative correlation was observed between Left ventricular ejection fraction and 68Ga-FAPI activity (LV TBRmean r =-0.46 and TBRmax (r= -0.66) Discussion 68 Ga-FAPI provides us the ability to assess fibroblast activation and for the first time demonstrated the key role of these cells in both these cardio-oncology conditions. Increased fibroblast activation is observed around the tricuspid valve in patients with carcinoid syndrome both in those with and without overt clinical disease. Similarly increased myocardial fibroblast activation is observed in patients exposed to anthracyclines even many years after exposure and where there is no overt evidence of cardiotoxicity. Conclusion 68Ga-FAPI imaging holds promise in evaluating the role of activated fibroblasts in the pathology of both carcinoid heart disease and cardiotoxicity, providing information beyond the current resolution of current clinical approaches.

The association between exercise-induced ventricular premature contractions and long-term mortality in patients without coronary artery disease

Abstract Background/Introduction The treadmill exercise test is widely used clinical test to determine cardiovascular risk and mortality, regardless of clinical risk factors (1). ST-segment changes detected in the exercise test are shown to predict myocardial ischemia (2) and premature ventricular complexes (PVCs) are frequently observed during exercise stress testing (3). Exercise-related PVC is observed in 14% to 23% of healthy individuals without significant heart disease (4,5). The literature on the role of PVCs observed during treadmill exercise testing in predicting prognosis is controversial. Purpose Therefore, we aimed to evaluate the clinical results of PVCs seen during exercise testing in patients who had been diagnosed with non-obstructive coronary artery disease after coronary angiography. Methods The study population consisted of 1624 consecutive patients who were considered high risk according to the Duke treadmill risk score and had no significant stenosis on coronary angiogram from January 2016 to April 2021. Patients with previous history of coronary revascularization, previous myocardial infraction, heart failure, moderate or severe heart valve disease, congenital heart disease, cardiomyopathy, bundle branch block, and left ventricular hypertrophy were excluded from the study. The primary endpoints of the study were long-term all-cause mortality of patients who had PVCs during the exercise test or during the resting phase. Results The long-term mortality was observed in 53 patients out of 1624 patients in the mean follow-up of 47 months. PVCs was observed in 293 (18.7%) patients without long-term mortality, while PVCs was observed in 24 (45.3%) patients with long-term mortality (p<0.001). The model adjusted for all covariates showed that the presence of PVCs in the recovery phase (p<0.007, HR (95% CI) 2.244 (1.244 – 4.047)) and advanced age (p<0.001, HR (95% CI) 1.194 (1.143 – 1.247)) were associated with long-term all-cause mortality (Figure 1). Considering Kaplan-Meier curve, individuals with PVCs in recovery had significantly higher risk of long-term mortality compared with those with without PVCs (log-rank statistic: 22.47, p<0.001) (Figure 2). Conclusion(s) The study highlights that PVCs monitored in the recovery phase of the treadmill exercise test were associated with long -term mortality in patients without structural heart disease and coronary artery disease.Figure 2Figure 1

Prevention of mechanical valve thrombosis with a combination of the factor Xa inhibitor edoxaban plus aspirin in swine: intermediate results from the EdoValves project

Abstract Background Patients with an implanted mechanical heart valve (MHV) currently have a contraindication to the use of non-vitamin K antagonist oral anticoagulants (NOACs) based on the unfavorable results of the RE-ALIGN trial with dabigatran. We hypothesized that the combination of a Factor Xa inhibitor, acting upstream of thrombin generation, plus aspirin, may effectively prevent valve thrombosis, providing a much more friendly and viable alternative to vitamin K antagonists for such patients. We tested this in a swine model with a recently implanted mechanical valve prosthesis in the mitral position, combining the most unfavorable conditions promoting mechanical valve thrombosis, based on (a) the implanting position; (b) recent surgery; (c) the high thrombogenicity of the animal model. The study was approved by the Animal Ethics Committee of the University of Pisa and the Italian Ministry of Health and conducted according to Good Clinical Practices for Animal Experiments. Methods 17 farm male pigs, weighing ≈30 kg at the beginning, underwent cardiac surgery under general anesthesia and with extracorporeal circulation to receive a 25 mm or 27 mm bileaflet Corcym Bicarbon mechanical heart valve replacement in the mitral position. Pigs were given 1 mg/kg enoxaparin immediately after surgery and started with the oral daily administration of edoxaban 1 mg/kg (30 mg, then escalated to 60 mg with the animal growth) + aspirin 100 mg, both given as crushed tablets with a food pellet since the animal awakening from anesthesia. An initially planned warfarin control group was quickly abandoned because of the extreme difficulty of controlling warfarin activity. Animals were submitted to blood sampling and transthoracic echocardiography at least twice in the follow-up when uneventful for up to three months or in case of health deterioration. The autopsy was performed by a certified pathologist after each spontaneous death or procured sacrifice. Results (Figure 1): Excluding 5 peri-operative deaths, 12 animals survived surgery. Of those, 6 died within the second month: pulmonary edema occurred in 3 cases, due to prosthesis-mismatch in the growing animals; pulmonary infection occurred in 1 subject; heart failure due to valve thrombosis occurred in 2 cases. Six swine were full-term survivors in good health status up to the 3-month planned observational time. No hemorrhagic events were ever documented. Conclusion The combination of edoxaban + aspirin effectively avoided valve thrombosis events in 10 out of 12 (83%) analyzable animals and was safe from bleeding complications. The study is ongoing up to a predicted sample size of ≥20 animals. If further confirmed, these data may open the possibility of an alternative to vitamin K antagonists in humans with the fixed-dose drug combination here used, without the need for continuous anticoagulation monitoring and with expected greater safety.Figure 1

Temporal trends in mitral valve surgery in Denmark: changes in patient characteristics and outcomes from 1996 to 2021

Abstract Background Mitral valve regurgitation (MR) is associated with increased morbidity and mortality. Mitral valve surgery (MVS) is recommended in severe MR, which is the second most common cause of heart valve surgery in the Western world. Data on national practice patterns are lacking and are essential for the continuous epidemiologic surveillance of the disease. Purpose To investigate temporal trends in patient characteristics, incidence and mortality in patients undergoing MVS for MR in Denmark from 1996 to 2021. Methods Using Danish nationwide registries, we identified all patients ≥18 years undergoing MVS for MR. Patients operated due to infective endocarditis were excluded. The study population was grouped into one 6-year and four 5-year calendar bands and type of MVS (mitral valve repair, mechanical or biological valve replacement and transcatheter-edge-to-edge repair (TEER)). Temporal trends in patient characteristics were computed. Annual incidence rates were calculated while considering the total Danish population ≥18 years at risk. For one-year postoperative mortality analysis, the reverse Kaplan-Meier estimator and a multivariable Cox proportional hazard analysis were used. Results We identified 7,813 patients (median age 67.3 years, 65.6% males) undergoing MVS. Over calendar time, burden of comorbidities decreased while median age increased, Table 1. From 1996 to 2021, a stepwise increase was seen in the overall incidence rate for MVS from 3.87 [95% CI 3.32-4.51] to 7.06 [95% CI 6.34-7.58] per 100,000 person-years (p<0.001). The incidence of mechanical valve replacement statistically significantly decreased (p<0.001), while the incidence of mitral valve repair (p=0.004), biological replacement (p≤0.001) and TEER statistically increased (p=0.015), Figure 1. For the overall study period, one-year mortality was 5.0% for mitral valve repair, 12.7% for mechanical valve replacement, 15.7% for biological valve replacement and 19.0% for TEER. Demographics and one-year mortality stratified by calendar period are shown in Table 1. In the mitral valve repair group, adjusted analysis showed a stepwise statistically significant decrease in one-year mortality with HR 0.30 (95% CI 0.17-0.53, p≤0.001) in 2017-2021 as compared to 1996-2001. In the remaining surgical groups, trends were towards decreasing one-year mortality over calendar periods but did not reach statistical significance. Conclusion(s) In this Danish nationwide cohort study, we observed an increase in the incidence of overall mitral valve surgery from 1996 to 2021. The incidence of mechanical valve replacement decreased, while the incidence of mitral valve repair, biological replacement and TEER increased. Mortality rates significantly improved for mitral valve repair patients over calendar time. Continuous epidemiological surveillance of this patient group is required in an era of development in treatment guidelines, surgical methods and patient demographics.Table 1Figure 1

Dexmedetomidine Ameliorates Myocardial Ischemia-Reperfusion Injury by Inhibiting MDH2 Lactylation via Regulating Metabolic Reprogramming.

Myocardial ischemia-reperfusion injury (MIRI) significantly worsens the outcomes of patients with cardiovascular diseases. Dexmedetomidine (Dex) is recognized for its cardioprotective properties, but the related mechanisms, especially regarding metabolic reprogramming, have not been fully clarified. A total of 60 patients with heart valve disease are randomly assigned to Dex or control group. Blood samples are collected to analyze cardiac injury biomarkers and metabolomics. In vivo and vitro rat models of MIRI are utilized to assess the effects of Dex on cardiac function, lactate production, and mitochondrial function. It is found that postoperative CK-MB and cTNT levels are significantly lower in the Dex group. Metabolomics reveals that Dex regulates metabolic reprogramming and reduces lactate level. In Dex-treated rats, the myocardial infarction area is reduced, and myocardial contractility is improved. Dex inhibits glycolysis, reduces lactate, and improves mitochondrial function following MIRI. Lactylation proteomics identifies that Dex reduces the lactylation of Malate Dehydrogenase 2（MDH2), thus alleviating myocardial injury. Further studies reveal that MDH2 lactylation induces ferroptosis, leading to MIRI by impairing mitochondrial function. Mechanistic analyses reveal that Dex upregulates Nuclear Receptor Subfamily 3 Group C Member 1（NR3C1)phosphorylation, downregulates Pyruvate Dehydrogenase Kinase 4 (PDK4), and reduces lactate production and MDH2 lactylation. These findings provide new therapeutic targets and mechanisms for the treatment for MIRI.

Impact of atrial fibrillation on mortality and non-fatal clinical outcomes in 28 492 patients who had undergone open-heart aortic versus mitral valve surgery: a statewide population-linkage study

Abstract Background Postoperative atrial fibrillation (AF) is common after cardiac surgery and has been associated with increased mortality and morbidity. Few studies have defined the impact of AF status (New-AF versus Prior-AF) on clinical outcomes during long-term follow-up and compared AF-related clinical outcomes between patients who had undergone isolated aortic valve surgery (AVSx) or mitral valve surgery (MVSx). Purpose This study aims to examine the impact of AF status on clinical outcomes in patients who had undergone AVSx versus MVSx using a statewide-population administrative database. Methods Patients who had open-heart cardiac valve surgery (1 January 2003 to 31 March 2021) identified from the Admitted-Patient-Data-Collection database in an Australian state, were stratified by AF status (No-AF vs New-AF vs Prior-AF during index admission for valve surgery) and followed up to 31 March 2022. A linkage look-back to year-2001 was performed to identify prior-AF history. Kaplan-Meier and multivariable Cox regression were performed to assess the impact of AF status on all-cause mortality. Fine-Gray competing risk analysis to account for the competing death events was used to assess non-fatal clinical outcomes. Results The overall cohort comprised 28 492 patients (median age 71.6yrs [interquartile range (IQR) 62.7–78.3yrs; 65.6% males): AVSx, n=18949; MVSx, n=9543 (Table 1). During a median follow-up of 6.6yrs (3.42–10.5yrs), Prior-AF and New-AF patients had significantly higher all-cause mortality (AVSx – Prior-AF: 1771 (57.9%) vs New-AF: 2854 (41.5%) vs No-AF: 2961 (32.8%); MVSx – Prior-AF: 1126 (41.0%) vs New-AF: 1034 (29.8%) vs No-AF: 747 (22.4%) (both Kaplan-Meier logrank P<0.001). After adjusting for differences in baseline characteristics and admission year-groups, in the AVSx subgroup, both new-AF and prior-AF were independently associated with all-cause mortality (aHR=1.16, 95%CI=1.10–1.22; aHR=1.69, 95%CI=1.59–1.79 respectively, both P<0.001) compared to no-AF patients. In the MVSx subgroup, only prior-AF was associated with increased risk of all-cause mortality (aHR=1.47, 95% CI=1.33–1.61, P<0.001). Competing risk analyses showed higher rehospitalisation rates for AF and congestive cardiac failure for new-AF and prior-AF groups compared to No-AF patients after both AVSx and MVSx, whereas the rehospitalisation rate for ischemic stroke was only significantly higher in the AVSx new-AF and prior-AF subgroups (all p < 0.05) (Table 2). Conclusions Patients undergoing open-heart aortic or mitral valve surgery are at risk of significant adverse clinical outcomes including death, heart failure and ischaemic stroke, with the target valve and baseline AF status having a differential impact on clinical outcomes. Drivers behind these high rates of adverse outcomes should be explored further and strategies should be developed and tailored accordingly to different surgical patient groups to improve their prognosis.

Clinical, echocardiographic, and pathologic characteristics of patients with pathology-proven nonbacterial thrombotic endocarditis

Abstract Background Non-bacterial thrombotic endocarditis (NBTE) is a non-infectious condition characterized by thrombotic and/or inflammatory depositions involving the cardiac valves. It is a challenging diagnosis of exclusion. Purpose This study aimed to better characterize patients with pathologically proven NBTE and assess its clinical, echocardiographic characteristics and prognostic implications. Methods We retrospectively identified patients with pathology-proven NBTE at a single center. Patients with positive preoperative blood cultures, a history of active or treated infective endocarditis, or identification of valvular organisms by special stains were excluded from the study. Patients with pathology reports of valve perforation or chordal rupture were also excluded because of the high likelihood of an infectious etiology for these lesions. Results A total of 53 patients with NBTE (median age 57 years; 61% females) were identified. In this cohort, 22% had a history of malignancy, 30% had connective tissue disease, 32% had coronary artery disease, and 11% prior history of NBTE. Neurological events accounted for 18 (34%) of the presenting symptoms (TIA n=17, CVA n=9), while new valvular dysfunction in 7 (13%) and fever in 8 (15%) of patients. Five patients (9%) had NBTE involving more than one valve. NBTE involved the mitral valve in 64%, aortic valve in 38% prosthetic/mechanical valve in 11%, and tricuspid valve in 5%. NBTE was identified at the time of autopsy in 34% of patients. NBTE recurred in 3 patients during follow-up. Excluding patients diagnosed at the time of autopsy, 9% of patients died within 1 year of NBTE diagnosis. Conclusion NBTE was diagnosed pathologically in the presence of hyper-inflammatory states due to critical illness or immunological diseases. It was predominantly on the left side of the heart and was associated with embolic phenomena, either clinically or on imaging. Patients diagnosed with antemortem with NBTE have a high mortality in the first year (9%).

The incidence of death and risk factors for mortality following major bleeding in patients anticoagulated with factor Xa inhibitors: an observational study in the UK clinical setting (AXIOM UK)

Abstract Background Major bleeding (MB) in association with anticoagulant use results in significant mortality. Mortality can be directly attributed to bleeding, or may follow bleeding complications such acute kidney injury, myocardial infarction, stroke and other cardiovascular events. Most real-world data relating to bleeding mortality is derived from cohorts receiving vitamin-K antagonists. We investigated all-cause mortality (ACM) after MB in a large cohort anticoagulated with Factor Xa inhibitors (FXai), e.g. direct oral anticoagulants (DOAC) rivaroxaban, apixaban and low-molecular-weight heparins (LMWH). Purpose To describe incidence rates of and risk factors for ACM following MB in patients receiving FXai. To investigate MB related ACM by bleeding site, treatment indication, treatment subgroups and individual and cumulative time periods. Methods Retrospective cohort analysis of new users of FXai, between 2012-2020, for therapeutic indications including atrial fibrillation (AF), venous thromboembolism, bioprosthetic cardiac valves or adult congenital heart disease was conducted. MB was defined by the International Society on Thrombosis and Haemostasis (ISTH) criteria. Incidence rates were reported per 100 person-years. Sub-distribution hazard ratios with 95% confidence intervals (95% CI) were estimated from Fine and Gray regression models accounting for competing risks. Results In 240,357 new users of FXai, 88% used an oral FXai. The most common FXai indication was AF (72%). There were 10,163 patients (4.2%) hospitalised for bleeding events during FXai use. Of these, 3,873 MB events (38%) fulfilled the ISTH definition of MB and 1312 died during 3,542 person years of follow-up (Table 1). ACM incidence rates varied by time, indication, bleeding subtype, and drug type. ACM occurred in 926 patients (23.9%) in the first month. Mortality rates were highest in the first month 607 (95% CI 568-647) per 100 person years, the rates then decreased over the year but remained elevated throughout the first year compared with subsequent years. Those receiving LMWH had higher ACM than those receiving a DOAC, but this was not significant in the adjusted risk factor analysis. Risk factors for ACM following bleeding included age ≥80, and a history of current smoking, myocardial infarction, congestive heart failure, peripheral artery disease, Stage 4 or 5 kidney disease, metastatic cancer, and intracranial haemorrhage. Age<60, bleeding following major trauma, and a history of anaemia were associated with lower risk of ACM (Table 2). Conclusions There is a significant incidence of ACM following MB among FXai users. The incidence rate of ACM in patients treated with FXai was highest in the first month after FXai initiation, declined during the first year and then plateaued. Multiple risk factors associated with ACM have been recognised and these could guide urgent therapies such as antidotes.

Post-operative atrial fibrillation during cardiac rehabilitation: incidence and long-term prognostic value

Abstract Background Postoperative atrial fibrillation (POAF) represents a common complication after cardiac surgery and is associated with longer in-hospital stay and increased in-hospital death and stroke, but its long-term prognostic value, during cardiac rehabilitation (CR), remains not well understood. Purpose The study aimed to assess the incidence and long-term prognostic values of different types of POAF in a cohort of consecutive patients who undergo CR after cardiac surgery. Methods A consecutive registry of patients admitted to our CR after cardiac surgery represents the present study. POAF was defined as any episode of atrial fibrillation occurring in the post-operative period from post-intensive care unit to hospital discharge after CR; moreover, POAF types were classified as Paroxysmal POAF (early and late) and persistent (early and late). Long-term hard end-points were: cardiovascular (CV) mortality and major adverse cardiovascular and cerebrovascular events (MACCEs defined as a composite of cardiovascular death, heart failure hospitalization, non-fatal myocardial infarction, and stroke). Results A total of 2.020 patients were included, mean age was 67 years and male gender was prevalent (71%). CR post-coronary artery bypass graft (CABG) was the indication of CR in 53% of patients, cardiac valve surgery in 35%, while 11% underwent CR after CABG plus valve surgery. All patients were followed for a mean of 50 months. POAF was found in 392 patients (19.4%) divided into 36% paroxysmal POAF and 64% persistent POAF, while 7.7% had permanent atrial fibrillation (figure 1A). Overall POAF was associated with higher rates of CV death (SR 5.0% vs POAF 7.2% vs pAF 16.5%; p<0.001) and MACCEs (SR 12.4% vs POAF 19.6% vs pAF 25.2%; p<0.001 – figure 1B). By analyzing separately paroxysmal, persistent, early, and late POAF, interestingly only late POAF (both persistent or paroxysmal) was associated with a higher long-term CV risk, in particular, both late persistent and late paroxysmal were associated with a higher risk of MACCEs (late persistent: OR 1.65, p=0.004 / late paroxysmal: OR 1.98, p=0.002 – figure 1C), mainly driven by a higher rate of heart failure hospitalization. Interestingly late paroxysmal POAF showed the worst outcomes among all classified POAF (figure 1D). Conclusions POAF after cardiac surgery is associated with long-term adverse outcomes, but not all POAF have the same prognostic value. Late, rather than early, POAF (whether paroxysmal or persistent) is associated with a poor long-term prognosis after cardiac rehabilitation.Figure 1

Characteristics and predictors of persistent somatic symptoms in patients with cardiac disease

Persistent somatic symptoms (PSS) are a diagnostic core criterion of the somatic symptom disorder. This longitudinal study aims to determine the frequency of PSS in patients with cardiac disease, identify potential predictive factors, and investigate its impact on healthcare utilization. Somatic symptoms were assessed with the Somatic Symptom Scale-8 four times over the course of three months in consecutively approached cardiac outpatients. Patients were grouped having PSS vs. not having PSS following a psychometric-driven approach based on the SSS-8 cut-off score and a data-driven approach applying cluster analysis. T-tests were performed to compare the characteristics between patients having vs. not having PSS. To identify predictors of group affiliation, we conducted multivariable logistic regressions. Additionally, analyses of covariance were used to further examine associations between healthcare utilization and group affiliation. The study included 95 patients (30.5% female) with a mean age of 60.5 years (SD = 8.7). All patients had at least one of the following cardiac diseases recorded in their medical history: coronary heart disease (n = 51), myocardial infarction (n = 21), valve disease (n = 22), cardiomyopathy (n = 15), cardiac dysrhythmia (n = 43), and heart failure (n = 12). 30 (32%) were grouped having PSS according to the psychometric-driven approach and 27 (28%) according to the data-driven approach. For both approaches, patients with PSS were more likely to be female, unemployed, reporting angina pectoris, having higher depression, and higher anxiety severity (for all: p ≤ 0.05). Predictors of PSS group affiliation were female gender, higher age, depression severity, and angina pectoris (for all: p ≤ 0.015). Patients with PSS more frequently visited general practitioners and cardiologists compared to patients without PSS (p ≤ 0.013). Enhancing our knowledge of PSS in patients with cardiac disease could help to improve identification of patients’ specific needs and the factors to consider in diagnosis and individualized treatment.