Increased plasma BMP-2 levels are associated with atherosclerosis burden and coronary calcification in type 2 diabetic patients.

BACKGROUND: Although Bone morphogenetic protein-2 (BMP-2) is a known mediator of bone regeneration and vascular calcification, to date no study has investigated the relationship between BMP-2 and type 2 diabetes mellitus (T2DM) and its possible role in coronary artery disease (CAD). The purpose of this study is to evaluate the relationship of BMP-2 with atherosclerosis and calcification in patients with T2DM. METHODS: 124 subjects were enrolled in this study: 29 patients with T2DM and CAD; 26 patients with T2DM and without CAD; 36 patients with CAD and without T2DMand 34 without T2DM or CAD (control group). Severity of coronary lesions was assessed using coronary angiography and intravascular ultrasound (IVUS). Plasma BMP-2 levels were quantified using a commercially available ELISA kit. RESULTS: Compared to the control group, the mean plasma BMP-2 level was significantly higher in T2DM patients with or without CAD (20.1 ± 1.7 or 19.3 ± 1.5 pg/ml, vs 17.2 ± 3.3 pg/ml, P < 0.001). In a multivariable linear regression analysis, both T2DM and CAD were significantly and positively associated with BMP-2 (Estimate, 0.249; standard error (SE), 0.063; p <0.0001; Estimate, 0.400; SE, 0.06; p < 0.0001). Plasma BMP-2 was also strongly correlated with glycosylated hemoglobin A1c (HbA1c) (Spearman ρ = -0.31; p = 0.0005). SYNTAX score was also significantly associated with BMP-2 (Spearman ρ = 0.46; p = 0.0002). Using the results from IVUS, plasma BMP-2 levels were shown to positively correlate with plaque burden (Spearman ρ = 0.38, P = 0.002) and plaque calcification (Spearman ρ =0.44, P = 0.0003) and to negatively correlate with lumen volume (Spearman ρ =0.31, P = 0.01). CONCLUSIONS: Our study demonstrates that patients with T2DM had higher circulating levels of BMP-2 than normal controls. Plasma BMP-2 levels correlated positively with plaque burden and calcification in patients with T2DM.

Coronary Vasomotor Dysfunction Is Associated With Cardiovascular Events in Patients With Nonobstructive Coronary Artery Disease.

BACKGROUND: Coronary vasomotor dysfunction (CVDys) can be comprehensively classified on the basis of anatomy and functional mechanisms. OBJECTIVES: The aim of this study was to evaluate the association between different CVDys phenotypes and outcomes in patients with angina and nonobstructive coronary artery disease (ANOCA). METHODS: Patients with ANOCA who underwent coronary reactivity testing using an intracoronary Doppler guidewire to assess microvascular and epicardial coronary endothelium-dependent and endothelium-independent function were enrolled. Endothelium-dependent microvascular and epicardial coronary dysfunction were defined as a <50% change in coronary blood flow in response to intracoronary acetylcholine (Ach) infusion and a <-20% change in coronary artery diameter in response to Ach. Endothelium-independent microvascular and epicardial coronary dysfunction were defined as coronary flow reserve < 2.5 during adenosine-induced hyperemia and change in cross-sectional area in response to intracoronary nitroglycerin administration < 20%. Major adverse cardiac and cerebrovascular events (cardiovascular death, nonfatal MI, heart failure, stroke, and late revascularization) served as clinical outcomes. RESULTS: Among the 1,196 patients with ANOCA, the prevalence of CVDys was 24.5% and 51.8% among those with endothelium-independent and endothelium-dependent microvascular dysfunction, respectively, and 47.4% and 25.4% among those with endothelium-independent and endothelium-dependent epicardial coronary dysfunction, respectively. During 6.3 years (Q1-Q3: 2.5-12.9 years) of follow-up, patients with endothelium-dependent microvascular dysfunction, endothelium-dependent epicardial coronary dysfunction, or endothelium-independent microvascular dysfunction showed significantly higher event rates compared with those without (19.5% vs 12.0% [P < 0.001], 19.7% vs 14.6% [P = 0.038] and 22.2% vs 13.8% [P = 0.001], respectively). Coronary flow reserve (HR: 0.757; 95% CI: 0.604-0.957) and percentage change in coronary blood flow in response to Ach infusion (HR: 0.998; 95% CI: 0.996-0.999) remained significant predictors of major adverse cardiac and cerebrovascular event after adjustment for conventional risk factors. CONCLUSIONS: CVDys phenotype is differentially associated with worse outcomes, and endothelium-dependent and endothelium-independent microvascular function provide independent prognostic information in patients with ANOCA.

Prognostic Implications of Resistive Reserve Ratio in Patients With Nonobstructive Coronary Artery Disease With Myocardial Bridging.

BACKGROUND: Myocardial bridging (MB) is accompanied by the dynamic extravascular compression of epicardial coronary arteries, leading to intracoronary hemodynamic disturbance with abnormal coronary flow profiles. We aimed to evaluate the prognostic implications of resistive reserve ratio (RRR), a composite measure of flow and pressure parameters that represents the vasodilatory capacity of the coronary arteries, in patients with angina with nonobstructive coronary artery disease (ANOCA) and MB, in comparison with coronary flow reserve (CFR). METHODS AND RESULTS: In this retrospective cohort study, we included patients with ANOCA who underwent coronary reactivity testing, where MB was identified by transient constriction in coronary artery segments between systole and diastole. Abnormal CFR and RRR were defined as <2.5 and <2.62, respectively. Major adverse cardiac events, including cardiovascular death, stroke, myocardial infarction, heart failure, and late revascularization, served as outcomes. Among 1251 patients with ANOCA, 191 (15.3%) had MB. The prevalence of abnormal CFR or RRR was not significantly different between patients with and without MB (P=0.144 and P=0.398, respectively). Over a median follow-up time of 6.9 years, abnormal RRR predicted major adverse cardiac events in patients with MB (hazard ratio [HR], 4.38 [95% CI, 1.71-11.21]; P=0.002) and without MB (HR, 1.91 [95% CI, 1.38-2.64]; P<0.001). Abnormal CFR predicted major adverse cardiac events in patients without MB (HR, 2.15 [95% CI, 1.54-3.00]; P<0.001), whereas it was not predictive of major adverse cardiac events in patients with MB (HR, 2.29 [95% CI, 0.93-5.65]; P=0.073). CONCLUSIONS: In patients with ANOCA and MB, impaired RRR was superior to impaired CFR in distinguishing patients at a higher risk of future adverse events, suggesting that RRR may serve as a risk stratification tool in patients with MB and ANOCA.

Predictive Value of Artificial Intelligence-Enabled Electrocardiography in Patients With Takotsubo Cardiomyopathy.

BACKGROUND: Recent studies have indicated high rates of future major adverse cardiovascular events in patients with Takotsubo cardiomyopathy (TC), but there is no well-established tool for risk stratification. This study sought to evaluate the prognostic value of several artificial intelligence-augmented ECG (AI-ECG) algorithms in patients with TC. METHODS AND RESULTS: This study examined consecutive patients in the prospective and observational Mayo Clinic Takotsubo syndrome registry. Several previously validated AI-ECG algorithms were used for the estimation 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, defined as cardiovascular death, recurrence of TC, nonfatal myocardial infarction, hospitalization for congestive heart failure, and stroke. In the final analysis, 305 patients with TC were studied over a median follow-up of 4.8 years. Patients with future major adverse cardiac events were more likely to be older, have a history of hypertension, congestive heart failure, worse renal function, as well as high-risk AI-ECG findings compared with those without. Multivariable Cox proportional hazards analysis indicated that the presence of 2 or 3 high-risk findings detected by AI-ECG remained a significant predictor of major adverse cardiac events in patients with TC after adjustment by conventional risk factors (hazard ratio, 4.419 [95% CI, 1.833-10.66], P=0.001). CONCLUSIONS: The combined use of AI-ECG algorithms derived from a single 12-lead ECG might detect subtle underlying patterns associated with worse outcomes in patients with TC. This approach might be beneficial for stratifying high-risk patients with TC.

What Can Biologic Aging Tell Us About the Effects of Mental Stress on Vascular Health.

Cardiovascular disease is often a disease of aging. Considerable advances in our understanding of the biological mechanisms of aging have been made; yet, cardiovascular disease remains the leading cause of death in the United States urging a continued search for novel risk factors to target for preventing and treating disease. Mental stress (MS) is emerging as an important risk factor, and while progress has been made in understanding the link between MS and cardiovascular disease, the precise mechanisms of a putative causal relationship require greater clarification. In the current review, we (1) summarize our current understanding of the pathological effects of MS on vascular health; (2) describe important aspects of the pathobiology of vascular aging including inflammation, oxidative stress, mitochondrial dysfunction as well as novel processes such as genomic instability, epigenetic alterations, and nutrient signal pathways; (3) highlight similarities in the downstream biologic effects of aging and MS on vascular health with an emphasis on cellular and molecular processes that could be used to develop novel prognostic markers and treatment strategies for cardiovascular disease; (4) discuss lifestyle and pharmacological methods that target indicators of aging whose role could be translated into approaches managing the effects of MS; and (5) outline important future steps that should be considered in this area of research including the need for prospective clinical trials and for creating greater collaboration between preclinical aging researchers and clinical investigators managing MS.

Guess What We Can Hear-Novel Voice Biomarkers for the Remote Detection of Disease.

The advancement of digital biomarkers and the provision of remote health care greatly progressed during the coronavirus disease 2019 global pandemic. Combining voice/speech data with artificial intelligence and machine-based learning offers a novel solution to the growing demand for telemedicine. Voice biomarkers, obtained from the extraction of characteristic acoustic and linguistic features, are associated with a variety of diseases and even coronavirus disease 2019. In the current review, we (1) describe the basis on which digital voice biomarkers could facilitate "telemedicine," (2) discuss potential mechanisms that may explain the association between voice biomarkers and disease, (3) offer a novel classification system to conceptualize voice biomarkers depending on different methods for recording and analyzing voice/speech samples, (4) outline evidence revealing an association between voice biomarkers and a number of disease states, and (5) describe the process of developing a voice biomarker from recording, storing voice samples, and extracting acoustic and linguistic features relevant to training and testing deep and machine-based learning algorithms to detect disease. We further explore several important future considerations in this area of research, including the necessity for clinical trials and the importance of safeguarding data and individual privacy. To this end, we searched PubMed and Google Scholar to identify studies evaluating the relationship between voice/speech features and biomarkers and various diseases. Search terms included digital biomarker, telemedicine, voice features, voice biomarker, speech features, speech biomarkers, acoustics, linguistics, cardiovascular disease, neurologic disease, psychiatric disease, and infectious disease. The search was limited to studies published in English in peer-reviewed journals between 1980 and the present. To identify potential studies not captured by our database search strategy, we also searched studies listed in the bibliography of relevant publications and reviews.

Position statement and updated international guideline for safe and effective whole-body electromyostimulation training-the need for common sense in WB-EMS application.

Whole-Body Electromyostimulation (WB-EMS) is a training technology that enables simultaneous stimulation of all the main muscle groups with a specific impulse intensity for each electrode. The corresponding time-efficiency and joint-friendliness of WB-EMS may be particularly attractive for people unable or unmotivated to conduct (intense) conventional training protocols. However, due to the enormous metabolic and musculoskeletal impact of WB-EMS, particular attention must be paid to the application of this technology. In the past, several scientific and newspaper articles reported severe adverse effects of WB-EMS. To increase the safety of commercial non-medical WB-EMS application, recommendations "for safe and effective whole-body electromyostimulation" were launched in 2016. However, new developments and trends require an update of these recommendations to incorporate more international expertise with demonstrated experience in the application of WB-EMS. The new version of these consensus-based recommendations has been structured into 1) "general aspects of WB-EMS", 2) "preparation for training", recommendations for the 3) "WB-EMS application" itself and 4) "safety aspects during and after training". Key topics particularly addressed are 1) consistent and close supervision of WB-EMS application, 2) mandatory qualification of WB-EMS trainers, 3) anamnesis and corresponding consideration of contraindications prior to WB-EMS, 4) the participant's proper preparation for the session, 5) careful preparation of the WB-EMS novice, 6) appropriate regeneration periods between WB-EMS sessions and 7) continuous interaction between trainer and participant at a close physical distance. In summary, we are convinced that the present guideline will contribute to greater safety and effectiveness in the area of non-medical commercial WB-EMS application.

Corrigendum: Position statement and updated international guideline for safe and effective whole-body electromyostimulation training-the need for common sense in WB-EMS application.

[This corrects the article DOI: 10.3389/fphys.2023.1174103.].

Lessons from a crisis-opportunities for lasting public health change from the COVID-19 pandemic.

The coronavirus 2019 (COVID-19) global pandemic has wrought hardship and disrupted lives across all strata of humanity, giving rise to a variety of social, psychological, and medical challenges to individuals in almost every country in the world. Yet for all the difficulties the pandemic has inflicted, it has forced us to examine previously accepted practices at home, work, and society more broadly and has led to innovative changes in the way we communicate and collaborate. These novel approaches to contemporary challenges were devised primarily to allow continued productivity despite the need for social distancing, but have offered secondary advantages that could provide society with lasting benefits. In the following review, we outline three aspects of working life and public health which could experience lasting improvement on the back of lessons learnt from the current crisis.

Noninvasive Voice Biomarker Is Associated With Incident Coronary Artery Disease Events at Follow-up.

OBJECTIVE: To evaluate the association between a preidentified voice biomarker and incident coronary artery disease (CAD) events. METHODS: Patients referred for clinically indicated coronary angiography underwent a total of three 30-second voice recordings using the Vocalis Health smartphone application between January 1, 2015, and February 28, 2017. A pre-established voice biomarker was derived from each individual recording, and the mean biomarker value was calculated for each patient. Individuals were clinically observed through December 31, 2019. The prespecified primary outcome was a composite of presenting to the emergency department with chest pain, being admitted to the hospital with chest pain, or having an acute coronary syndrome; the prespecified secondary outcome was a composite of a positive stress test result at follow-up or the presence of CAD at follow-up coronary angiography. RESULTS: In the final analysis, 108 patients were included (mean age, 59.47±11.44 years; male, 59 [54.6%]). The median follow-up time was 24 months (range, 1 to 60 months). In multivariable Cox proportional hazards models adjusting for CAD grade on baseline angiography, a high baseline mean voice biomarker was significantly associated with both the primary (hazard ratio, 2.61; 95% CI, 1.42 to 4.80; P=.002) and secondary (hazard ratio, 3.13; 95% CI, 1.13 to 8.68; P=.03) composite outcomes. CONCLUSION: This study found a significant association between a noninvasive voice biomarker and incident CAD events at follow-up. These results may have important clinical implications for the remote and noninvasive screening of patients to identify those at risk of coronary disease and its complications.

Mental Stress and Its Effects on Vascular Health.

Coronary artery disease continues to be a major cause of morbidity and mortality despite significant advances in risk stratification and management. This has prompted the search for alternative nonconventional risk factors that may provide novel therapeutic targets. Psychosocial stress, or mental stress, has emerged as an important risk factor implicated in a higher incidence of cardiovascular events, and although our understanding of this far ranging and interesting phenomenon has developed greatly over recent times, there is still much to be learned regarding how to measure mental stress and how it may impact physical health. With the current coronavirus disease 2019 global pandemic and its incumbent lockdowns and social distancing, understanding the potentially harmful biological effects of stress related to life-changing events and social isolation has become even more important. In the current review our multidisciplinary team discusses stress from a psychosocial perspective and aims to define psychological stress as rigorously as possible; discuss the pathophysiologic mechanisms by which stress may mediate cardiovascular disease, with a particular focus to its effects on vascular health; outline existing methods and approaches to quantify stress by means of a vascular biomarker; outline the mechanisms whereby psychosocial stressors may have their pathologic effects ultimately transduced to the vasculature through the neuroendocrine immunologic axis; highlight areas for improvement to refine existing approaches in clinical research when studying the consequences of psychological stress on cardiovascular health; and discuss evidence-based therapies directed at reducing the deleterious effects of mental stress including those that target endothelial dysfunction. To this end we searched PubMed and Google Scholar to identify studies evaluating the relationship between mental or psychosocial stress and cardiovascular disease with a particular focus on vascular health. Search terms included "myocardial ischemia," "coronary artery disease," "mental stress," "psychological stress," "mental∗ stress∗," "psychologic∗ stress∗," and "cardiovascular disease∗." The search was limited to studies published in English in peer-reviewed journals between 1990 and the present day. To identify potential studies not captured by our database search strategy, we also searched studies listed in the bibliography of relevant publications and reviews.

Plasma Ceramide Levels Are Elevated in Patients With Early Coronary Atherosclerosis and Endothelial Dysfunction.

Background Elevated plasma ceramides are independent predictors of cardiovascular disease and mortality in patients with advanced epicardial coronary artery disease. Our understanding of plasma ceramides in early epicardial coronary artery disease, however, remains limited. We examined the role of plasma ceramides in early coronary atherosclerosis characterized by coronary endothelial dysfunction. Methods and Results Participants presenting with chest pain and nonobstructive epicardial coronary artery disease underwent coronary endothelial function. Patients (n=90) demonstrated abnormal coronary endothelial function with acetylcholine (≥20% decrease in coronary artery diameter or ≤50% increase in coronary blood flow). A total of 30 controls had normal coronary endothelial function. Concentrations of plasma ceramide 18:0 (P=0.038), 16:0 (P=0.021), and 24:0 (P=0.019) differed between participants with normal and abnormal coronary endothelial function. Ceramide 24:0 (odds ratio [OR], 2.23 [95% CI, 1.07-4.66]; P=0.033) and 16:0 (OR, 1.91×106 [95% CI, 11.93-3.07×1011]; P=0.018) were independently associated with coronary endothelial dysfunction. Among participants with endothelium-dependent coronary dysfunction (n=78), ceramides 16:0 (OR, 5.17×105 [95% CI, 2.83-9.44×1010]; P=0.033), 24:0 (OR, 2.98 [95% CI, 1.27-7.00]; P=0.012), and 24:1/24:0 (OR, 4.39×10-4 [95% CI, 4×10-7-0.48]; P=0.030) were more likely to be elevated. Conclusions The current study demonstrated an association between increased circulating ceramide levels and coronary endothelial dysfunction in the absence of epicardial coronary artery disease. This study supports the role of plasma ceramides as a potential biomarker or a therapeutic target for early coronary atherosclerosis in humans.

Systemic lupus erythematosus multiorgan flare with quiescent serologic markers.

Systemic lupus erythematosus (SLE) can affect almost every organ with differing degrees of severity. Typically, SLE activity is associated with hypocomplimentaemia and elevated double-stranded DNA (dsDNA) levels. We describe a case of a severe multiorgan lupus flare including lupus cerebritis, autoimmune haemolytic anaemia, lupus nephritis and lupus myopericarditis with normal complement and dsDNA levels. This highlights the importance of understanding the heterogeneous nature of SLE flares.

Non-invasive vocal biomarker is associated with pulmonary hypertension.

Emerging data suggest that noninvasive voice biomarker analysis is associated with coronary artery disease. We recently showed that a vocal biomarker was associated with hospitalization and heart failure in patients with heart failure. We evaluate the association between a vocal biomarker and invasively measured indices of pulmonary hypertension (PH). Patients were referred for an invasive cardiac hemodynamic study between January 2017 and December 2018, and had their voices recorded on three separate occasions to their smartphone prior to each study. A pre-established vocal biomarker was determined based on each individual recording. The intra-class correlation co-efficient between the separate voice recording biomarker values for each individual participant was 0.829 (95% CI 0.740-0.889) implying very good agreement between values. Thus, the mean biomarker was calculated for each patient. Patients were divided into two groups: high pulmonary arterial pressure (PAP) defined as ≥ 35 mmHg (moderate or greater PH), versus lower PAP. Eighty three patients, mean age 61.6 ± 15.1 years, 37 (44.6%) male, were included. Patients with a high mean PAP (≥ 35 mmHg) had on average significantly higher values of the mean voice biomarker compared to those with a lower mean PAP (0.74 ± 0.85 vs. 0.40 ± 0.88 p = 0.046). Multivariate logistic regression showed that an increase in the mean voice biomarker by 1 unit was associated with a high PAP, odds ratio 2.31, 95% CI 1.05-5.07, p = 0.038. This study shows a relationship between a noninvasive vocal biomarker and an invasively derived hemodynamic index related to PH obtained during clinically indicated cardiac catheterization. These results may have important practical clinical implications for telemedicine and remote monitoring of patients with heart failure and PH.

Vascular reactivity to mental stress is associated with poor cardiovascular disease outcomes in females following acute coronary syndrome.

BACKGROUND: We aimed to test the hypothesis that peripheral endothelial dysfunction induced by mental stress may predict cardiovascular events after acute coronary syndrome beyond traditional cardiovascular disease risk factors. METHODS: This was a prospective study in which 417 patients who had acute coronary syndrome were enrolled in two sites at the US and Qatar. Cardiovascular disease risk factors such as past medical history, blood pressure, heart rate, peripheral endothelial dysfunction, and response to three different mental stress examinations (Stroop Color Word, Arithmetic, and Spiral Omnibus) as assessed by ratio of reactive hyperemia tonometry (EndoPAT) with stress over EndoPAT at rest were obtained at baseline. Major adverse cardiac events were then recorded at 1 year after the index event. RESULTS: There were no differences in baseline peripheral endothelial dysfunction or vascular response to mental stress between the US vs. Qatar patients. Women were more likely to experience major adverse cardiac events in the year following acute coronary syndrome (relative risk 2.42, 95% confidence interval 1.53-3.84, P = 0.044), and had a significantly lower mental stress ratio compared to women who did not (1.0 ± 0.17 vs. 1.20 ± 0.17, P = 0.04). In multivariate analyses stratified by sex, baseline peripheral endothelial dysfunction (EndoPAT < 1.7) (χ = 8.0, P = 0.005) and mental stress ratio (χ = 7.7, P = 0.006), were independently predictive of major adverse cardiac events in women, but not men. CONCLUSION: The current study demonstrates that in women both baseline endothelial function and vascular function in response to mental stress ratio are predictive of worse cardiovascular disease outcomes 1 year after acute coronary syndrome. The study may suggest an important mechanism for adverse clinical outcomes in women following acute coronary syndrome.

CPAP is associated with decreased risk of AF recurrence in patients with OSA, especially those younger and slimmer: a meta-analysis.

PURPOSE: Obstructive sleep apnea (OSA) is associated with the management of atrial fibrillation (AF). This manuscript aims to discuss the effects of continuous positive airway pressure (CPAP) in patients with rhythm control strategies and patients with different ages, weights and length of follow-up. METHODS: We searched Embase, PubMed, Cochrane, Web of Science and Ovid for relevant studies (from inception to 7 July 2019; English). The primary outcome was documented AF recurrence in CPAP users and nonusers. We assessed pooled data by use of a random-effects model. RESULTS: Nine prospective cohort studies with a total of 2134 participants met the inclusion criteria. Results showed that complementary CPAP therapy reduced AF recurrence (RR = 0.63; 95% CI, 0.56-0.72). In subgroup analyses, the benefits of CPAP were stronger in patients younger than 60 years old (< 60 years old: RR, 0.59; 95% CI, 0.50-0.68 vs. ≥ 60 years old: RR, 0.73; 95% CI, 0.59-0.91), with a body mass index (BMI) of less than 30 (< 30: RR, 0.53; 95% CI, 0.37-0.77 vs. ≥ 30: RR, 0.65; 95% CI, 0.55-0.77) or with less follow-up time (≤ 1 year: RR, 0.57; 95% CI, 0.42-0.79 vs. > 1 year: RR, 0.64; 95% CI, 0.53-0.78). CONCLUSIONS: Complementary CPAP therapy reduces the risk of AF recurrence in OSA patients with rhythm control strategies. In addition to weight control and early AF intervention, CPAP compliance should be recommended along with periodic adjustments as necessary.

Amyloidosis: a unifying diagnosis for nephrotic syndrome and congestive cardiac failure.

Diagnosing patients simply with heart failure or nephrotic syndrome is insufficient, and clinicians should always search for the underlying causes of these syndromes. Amyloidosis represents a rare group of diseases in which abnormal protein, namely amyloid fibrils, build up in various organs. Presentation depends on which organ systems are involved, and symptoms could include breathlessness associated with fluid overload suggestive of cardiac and/or renal involvement and diarrhoea and weight loss, suggestive of gastrointestinal involvement. The authors present a case of congestive cardiac failure and nephrotic range proteinuria in a patient with persistent fluid overload secondary toamyloid light-chain (AL) amyloidosis.