Citations

BACKGROUND: The financial burden linked to the diagnosis and treatment of patients with chest pain on the health care system is considerable. Angina and nonobstructive coronary artery disease (ANOCA) is common, associated with adverse cardiovascular events, and may lead to repeat testing or hospitalizations. Diagnostic certainty can be achieved in patients with ANOCA using coronary reactivity testing (CRT); however, its financial effect on the patient has not been studied. Our goal was to assess the effect of CRT on health care–related cost in patients with ANOCA. METHODS: Patients with ANOCA who underwent diagnostic coronary angiography (CAG) and CRT (CRT group) were matched to controls who had similar presentation but only underwent a CAG without CRT (CAG group). Standardized inflation-adjusted costs were collected and compared between the 2 groups on an annual basis for 2 years post the index date (CRT or CAG). RESULTS: Two hundred seven CRT and 207 CAG patients were included in the study with an average age of 52.3±11.5 years and 76% females. The total cost was significantly higher in the CAG group as compared with the CRT group ($37 804 [$26 933–$48 674] versus $13 679 [$9447–$17 910]; P <0.001). When costs are itemized and divided based on the Berenson-Eggers Type of Service categorization, the largest cost difference occurred in imaging (any type, including CAG; P <0.001), procedures (eg, percutaneous coronary intervention/coronary artery bypass grafting/thrombectomy) ( P =0.001), and test (eg, blood tests, EKG; P <0.001). CONCLUSIONS: In this retrospective observational study, assessment of CRT in patients with ANOCA was associated with significantly reduced annual total costs and health care utilization. Therefore, the study may support the integration of CRT into clinical practice.

Abstract Mesenchymal stem/stromal cells (MSCs), a class of cells with proliferative, immunomodulatory, and reparative functions, have shown therapeutic potential in a variety of systemic diseases, including metabolic syndrome (MetS). The cluster of morbidities that constitute MetS might be particularly amenable for the application of MSCs, which employ an arsenal of reparative actions to target multiple pathogenic pathways simultaneously. Preclinical studies have shown that MSCs can reverse pathological changes in MetS mainly by inhibiting inflammation, improving insulin resistance, regulating glycolipid metabolism, and protecting organ function. However, several challenges remain to overcome before MSCs can be applied for treating MetS. For example, the merits of autologous versus allogeneic MSCs sources remain unclear, particularly with autologous MSCs obtained from the noxious MetS milieu. The distinct characteristics and relative efficacy of MSCs harvested from different tissue sources also require clarification. Moreover, to improve the therapeutic efficacy of MSCs, investigators have explored several approaches that improved therapeutic efficacy but may involve potential safety concerns. This review summarized the potentially useful MSCs strategy for treating MetS, as well as some hurdles that remain to be overcome. In particular, larger-scale studies are needed to determine the therapeutic efficacy and safety of MSCs for clinical application.

Introduction: The mechanistic link between early coronary artery disease (CAD) and atrial fibrillation (AF) continues to be explored. Clonal hematopoiesis of indeterminate potential (CHIP) is increasingly recognized as a risk factor for cardiovascular disease. We hypothesize CHIP further increases the risk for AF in early CAD. Methods: 184 participants underwent invasive coronary angiogram with endothelial function testing. Buffy coat was used for whole exosome sequencing to identify CHIP (variant allele frequency > 2% and minor allele frequency ≤ 0.1%). Early CAD was defined by the presence of coronary endothelial dysfunction (CED) in the absence of obstructive CAD. Invasive coronary angiography with endothelial function testing characterized CED as ≥ 20% increase in coronary artery diameter or ≤ 50% increase in coronary blood flow in response to acetylcholine. AF was identified by ICD-10 code or patient survey and confirmed by an independent investigator by chart review. Cox proportional hazard regression was adjusted for age, sex, and conventional cardiovascular comorbidities (hypertension, diabetes, and total cholesterol). Results: Of the 184 participants, we identified 23 cases with both early CAD and CHIP and 62 normal controls without CHIP or CAD. Case patients were significantly older (mean 60 ±9 vs 52 ±10 years, p = 0.004 years) and predominantly female (74% vs 81%, p = 0.506). AF was more likely among case participants when compared to normal controls (29% vs 10%, p = 0.036). Mean time to AF or last follow-up was 11 ±7 years. Case patients with both early CAD and CHIP were nearly 10 times more likely to develop AF when compared to normal controls in a Cox regression model adjusted for age, sex, and conventional cardiovascular comorbidities (HR 9.52, 95% CI 1.93 - 47.02, p = 0.006). The risk for AF was not significant if we defined cases by only the presence of CHIP (n = 30) or early CAD (n = 122). Conclusions: Patients with both CHIP and early CAD may have greater risk for developing AF beyond the presence of CHIP or CAD alone. Our findings suggest an added mechanistic role of CHIP that further increases the risk for AF in early CAD.

Introduction: Increasing evidence unravels the role of loneliness and social connection in cardiovascular diseases potentially mediating accelerated biological aging. The present study aims to explore the association between social connection and biological aging as determinate by artificial intelligence-enabled electrocardiography (ECG). Methods: This is an observational retrospective cohort of adults aged ≥18 seen at Mayo Clinic from 2019-2022 who completed the social determinants of health questionnaire and had a 12-lead ECG within one year of completing the questionnaire. Five questions were asked to understand each patient’s social connection . The answers were scored to assess their level of social connection from socially isolated (score of 0) to socially connected (score of 4). The biological age was predicted from ECGs using the previously developed convolutional neural network (AI-ECG age). Delta age (Δage) was defined as AI-ECG age minus chronological age, where positive values reflect an older than expected age. Results: We included 280,323 subjects (chronological age 59.7±16.4 years, 51% female). The average AI-ECG age was 59.5±13.5 year. Better social connection status correlated with lower delta age (β=-0.33 (95%CI, -0.38 and -0.28, p<0.001, adjusted to chronological age and sex). Conversely, individuals reporting the least social connection were an average of 2 years older than expected whereas those with the most social connection were 2 years younger than expected by AI-ECG (Figure 1). Conclusions: Social connection is strongly associated with slower biological aging compared to chronological aging, independent of the conventional cardiovascular risk factors. This observation underscores the need to address social connection as a healthcare determinant.

Introduction: The physiological changes associated with aging have deleterious effects on cardiovascular function. In addition, increasing evidence showed the effect of exercise on improving cardiovascular health and reducing the aging process. The present study sought to demonstrate the association between exercise and biological age, estimated by our previously reported method using artificial intelligence-enabled electrocardiography (ECG). Methods: This retrospective observational study enrolled adults aged ≥18 years who have been evaluated at Mayo Clinic between 2019-2022 and completed the exercise questionnaire. The total time spent in moderate to strenuous exercise was calculated by multiplying the number of days engaging in exercise per week by the average minutes per day. The biological age was determined by applying our previously developed convolutional neural network model on the 12-lead ECG records (AI-ECG). The ECG records were within one year of subjects’ visits (in case of multiple visits, the closest one to the questionnaire was chosen). Positive Age-Gap (AI-ECG minus chronological age) reflects a person identified as being older by AI-ECG compared to his/her chronological age. Results: A total of 268,002 subjects (51% female) were recruited (mean age 59.7±16.4 years). Of those, 25.7% were not engaged in any exercise. The median day of engaging in exercise was 3 (Interquartile range, 2,5) per week, and the average time of exercising was 31.3±30 minutes/day. Age-Gap diminished progressively with increased duration of moderate to strenuous exercise (Figure 1). Linear regression analysis revealed exercise is an independent predictor of Age-Gap, (β= -0.043, 95%CI, -0.045 and -0.041, p<0.001). Conclusions: Engaging in moderate to strenuous exercise is associated with slower biological aging relative to chronological age as determined by AI-enabled ECG.

Introduction: Peripheral microvascular endothelial dysfunction (PMED) is a marker and precursor of atherosclerosis and is associated with an increased risk of cardiovascular events. The present study aims to identify the best cut-off value of PMED, assessed by the reactive hyperemia index, in predicting major adverse cardiovascular events (MACE). Additionally, we investigate whether integrating PMED to CHA2DS2-Vasc score improves the predicting accuracy of cardiovascular disease. Methods: this is a retrospective study of patients who underwent reactive hyperemia peripheral arterial tonometry (PAT). The optimal cut-off value of reactive hyperemia index associated with MACE was calculated using the area under the receiver-operating curve and the maximum Youden index. Traditional cardiovascular risk factors such as age, sex, congestive heart failure, hypertension, diabetes, stroke, vascular disease were determined to calculate the CHA2DS2-VASc score. MACE was defined as myocardial infarction, heart failure hospitalization, and cerebrovascular events. Results: 1,690 patients were enrolled (average age 51.1±13.9, 64.1% female). The optimal cut-off value of the reactive hyperemia index was 2.0 in the overall population and females and 2.17 in males. The risk of MACE during 10 (Interquartile range: 4,16) years of follow-up was 15.3%. Multivariable logistic regression revealed that PMED as an independent predictor of MACE (PMED: OR, 3.6, 95% CI, 2.6-4.9, p<0.001) (Table1). Furthermore, integrating PMED to CHA2DS2-VASc significantly improved the predictive accuracy (area under the curve, 0.747 vs. 0.708, p<0.001). Conclusion: PMED is a strong predictor of cardiovascular events. Non-invasive assessment of peripheral endothelial function may be useful in early detection and improving the stratification of high-risk patients for cardiovascular events.

Introduction: Mechanisms underlying bioprosthetic valve deterioration (BVD) are multifactorial and incompletely elucidated. Reparative circulating progenitor cells (CPCs), and conversely calcification-associated osteocalcin expressing CPCs (CPC-OCN), have been linked to native aortic valve deterioration. However, their role in BVD remains elusive. This study sought to evaluate the contribution of different subpopulations of CPCs in BVD. Methods: This prospective study enrolled 121 patients who had peripheral blood mononuclear cells (PBMC) isolated prior to bioprosthetic aortic valve replacement (surgical 104, transcatheter 17) and had an echocardiographic follow-up ≥2 years after the procedure. Using flow cytometry, fresh PBMC were analyzed for the surface markers CD34, CD133, and osteocalcin (OCN). BVD was evaluated by hemodynamic valve deterioration (HVD) using echocardiography, which was defined as an elevated mean transprosthetic gradient ≥30mmHg and/or at least moderate intraprosthetic regurgitation. Multivariable models were constructed to evaluate the association of each subpopulation of CPCs and other clinical characteristics with HVD. Results: Sixteen patients (13.2%) developed HVD during follow-up for a median of 5.9 years. Patients with HVD showed significantly lower levels of reparative CD34 + CD133 + cells and higher levels of OCN + cells than those without HVD (CD34 + CD133 + cells: 125 [80, 210] vs 270 [130, 420], P=0.002; OCN + cells: 3060 [523, 5528] vs 670 [180, 1930], P=0.005 respectively). Decreased level of CD34 + CD133 + cells was a significant predictor of HVD. Conclusions: Circulating levels of CD34 + CD133 + cells and OCN + cells were significantly associated with the subsequent occurrence of HVD in patients undergoing bioprosthetic aortic valve replacement. CPCs might play a vital role in the mechanism, risk stratification and a potential therapeutic target for patients with bioprosthetic valve deterioration.

Introduction: Recent studies have indicated high rates of future major adverse cardiovascular events in patients with Takotsubo cardiomyopathy (TTC). This study sought to evaluate the prognostic value of our institutional artificial intelligence-augmented electrocardiography (AI-ECG) algorithms in patients with TTC. Methods: This study enrolled consecutive patients in the prospective and observational Mayo Clinic Takotsubo syndrome registry. TTC was diagnosed according to the Mayo Clinic diagnostic. Our clinic’s previously developed and validated AI-ECG algorithms were used for detection of ECG-Age, probability of low ejection fraction, and probability of atrial fibrillation.Multivariable models were constructed to evaluate the association of AI-ECG and other clinical characteristics with major adverse cardiac events (MACE), defined as cardiac death, recurrence of TTC, nonfatal myocardial infarction, hospitalization for congestive heart failure, and stroke. Results: In the final analysis, 305 patients were studied over a median follow-up of 4.8 years. Patients with MACE were more likely to be older, have history of hypertension and chronic heart failure (CHF), worse renal function as well as having high-risk AI-ECG findings compared to those without. In the multivariate Cox proportional hazard analysis, the presence of 3 or 4 high-risk findings detected by AI-ECG, remained a significant predictor of MACE in the patients with TTC after adjusted by conventional risk factors (hazard ratio (HR) 2.17, 95% CI [1.33, 3.53], P=0.002; HR 2.44, 95% CI [1.38, 4.29], P=0.002, respectively). Conclusions: The combined use of developed AI-ECG algorithms derived from a single 12-lead ECG might identify ECG correlates of underlying non-transient myocardial dysfunction and detect subtle underlying patterns associated with worse outcomes in patients with TTC. This approach might be beneficial for stratifying high-risk patients with TTC.

Abstract Background and Aims Arterial hypertension (HTN) in association with chronic kidney disease (CKD) is a global healthcare burden, yet clinically proven treatments are limited. electro-Hydraulic Acoustic Therapy (eHAT), using ∼10% of the energy used in shockwave lithotripsy, is a promising technique to ameliorate ischemia and regenerate tissues. eHAT has been demonstrated to enhance healing in tissues such as bone, muscle, and myocardium, via several mechanisms, particularly by promoting neovascularization. Furthermore, previous animal studies demonstrated that eHAT reduces blood pressure (BP) and preserves renal function after ischemic kidney injury. The present pilot study explored the clinical safety and efficacy of eHAT and tested the hypothesis that eHAT would reduce BP and preserve renal function in patients with medically-treated hypertension and CKD. Method So far, a total of 15 patients with HTN and Stage III a/b CKD were enrolled in this prospective, single-arm study. The patients were treated with six sessions of eHAT during a 3-week period. At each session, 2400 shockwaves were applied to each kidney with 0.09 mJ/mm2 at 2.66Hz (NephrospecTM by Curespec LTD, Yehud, Israel). Follow-up (FU) visits were performed at 1, 3, and 6 months. Results The treatment was well tolerated with no major adverse events or need for analgesic treatment. Average Automated Office BP (AOBP) showed a strong tendency for a decrease in diastolic BP from baseline to the Primary Efficacy Objective at FU II (3 months post last treatment), which progressively decreased further at FU III (6 months) (Table 1). Similarly, average Office BP (OBP) detected a strong trend for a progressive decrease in systolic BP from baseline to the Primary Efficacy Objective (Table 1). Levels of eGFR appeared to slightly rise throughout the study, but this change has not reached statistical significance levels (Table 1). Conclusion The current study demonstrates that the eHAT procedure is tolerable and safe in this cohort. Moreover, a 3-week regimen tended to reduce BP and preserve eGFR in patients with controlled HTN and CKD. Therefore, electro-Hydraulic Acoustic Therapy may emerge as a novel, safe, and non-invasive alternative therapeutic approach in the management of HTN in the context of CKD.

Abstract Background and Aims Autologous mesenchymal stem/stromal cells (MSCs) have emerged as a therapeutic option for many chronic diseases. Hypertensive kidney disease (HKD) might impair MSCs’ reparative ability by altering important biomolecular properties of the cell, but the characteristics of this impairment are unclear. In our previous pre-clinical studies, hypoxic preconditioning (HPC) enhanced MSC angiogenesis and reduced senescence through global gene and protein expression. Thus, we hypothesize that HPC would improve human MSCs by enhancing their functionality and angiogenesis, creating an anti-inflammatory and anti-senescence environment in MSCs from healthy control (HC), hypertensive patients (HTN), and hypertensive kidney disease patients (HKD). Method Human MSCs were collected from abdominal subcutaneous fat tissue biopsy of HC, HTN, and HKD patients (n=12 each). Samples were collected from healthy volunteers with no history of hypertension or kidney disease (HC), patients diagnosed with hypertension controlled with antihypertensive drugs (HTN), and hypertensive patients with eGFR&lt;60 mL/min/1.73 m2 (HKD). MSCs were harvested and cultured in Normoxic (20% O2) or Hypoxic (1% O2) conditions for 24-48 hours. MSC functionality was measured by migration and proliferation. Angiogenic and inflammatory secretome in conditioned media was assessed along with MSC senescence by senescence-associated beta-galactosidase (SA-beta-gal) activity. In addition, transcriptome analysis using RNA-sequencing (n=3/group) and quantitative PCR (qPCR) were performed to evaluate gene expression. Results At baseline, Normoxic HTN-MSCs interestingly had higher proliferation compared to HC. HC-MSC subjected to HPC showed increased proliferation (Figure 1A). SA-β-gal activity tended to decrease after HPC, particularly in the HC group (P = .06). HPC did not affect the release of the pro-angiogenic protein VEGF from MSCs, but increased EGF in HC-MSC, and decreased HGF in HC and HKD MSCs. HPC upregulated the pro-angiogenetic genes, inflammatory gene, and a few senescence genes (Figure 1F). Conclusion HPC has a more favorable functional effect on HC- than on HKD-MSC, reflected in increased proliferation and EGF release, and tends to decrease senescence, whereas it has little effect on HTN or HKD MSCs. These observations may assist in developing novel therapeutic strategies to improve the regenerative capacity of MSCs in patients with hypertensive kidney disease.