Innovative approaches to cardiovascular safety pharmacology assessment.

This editorial prefaces the annual themed issue on safety pharmacology (SP) methods which has been published since 2004 in the Journal of Pharmacological and Toxicological Methods (JPTM). Here we highlight content derived from the 2023 Safety Pharmacology Society (SPS) meeting held in Brussels, Belgium. The meeting generated 138 abstracts, reproduced in the current volume of JPTM. As in prior years, the manuscripts reflect various areas of innovation in SP including in silico modeling of stroke volume, cardiac output and systemic vascular resistance, computational approaches that compare drug-induced proarrhythmic sensitivity of human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), an evaluation of the utility of the corrected J-Tpeak and Tpeak-to-Tend parameters from the ECG as potential proarrhythmia biomarkers, and the applicability of nonclinical concentration-QTc (C-QTc) modeling of data derived from the conduct of the in vivo QTc study as a component of the core battery of safety pharmacology studies.

Mechanistic Assessment of Cardiovascular State Informed by Vibroacoustic Sensors.

Monitoring blood pressure, a parameter closely related to cardiovascular activity, can help predict imminent cardiovascular events. In this paper, a novel method is proposed to customize an existing mechanistic model of the cardiovascular system through feature extraction from cardiopulmonary acoustic signals to estimate blood pressure using artificial intelligence. As various factors, such as drug consumption, can alter the biomechanical properties of the cardiovascular system, the proposed method seeks to personalize the mechanistic model using information extracted from vibroacoustic sensors. Simulation results for the proposed approach are evaluated by calculating the error in blood pressure estimates compared to ground truth arterial line measurements, with the results showing promise for this method.

Arterial stiffness assessment using PPG feature extraction and significance testing in an in vitro cardiovascular system.

Cardiovascular diseases (CVDs) remain the leading cause of global mortality, therefore understanding arterial stiffness is essential to developing innovative technologies to detect, monitor and treat them. The ubiquitous spread of photoplethysmography (PPG), a completely non-invasive blood-volume sensing technology suitable for all ages, highlights immense potential for arterial stiffness assessment in the wider healthcare setting outside specialist clinics, for example during routine visits to a General Practitioner or even at home with the use of mobile and wearable health devices. This study employs a custom-manufactured in vitro cardiovascular system with vessels of varying stiffness to test the hypothesis that PPG signals may be used to detect and assess the level of arterial stiffness under controlled conditions. Analysis of various morphological features demonstrated significant (p < 0.05) correlations with vessel stiffness. Particularly, area related features were closely linked to stiffness in red PPG signals, while for infrared PPG signals the most correlated features were related to pulse-width. This study demonstrates the utility of custom vessels and in vitro investigations to work towards non-invasive cardiovascular assessment using PPG, a valuable tool with applications in clinical healthcare, wearable health devices and beyond.

Autonomic activity and cardiovascular system risk assessment in pediatric patients with hemolytic uremic syndrome.

In pediatric patients with hemolytic uremic syndrome (HUS), cardiac involvement and autonomic nervous system function can be evaluated by a non-invasive method called heart rate variability (HRV). This study aims to evaluate heart rate variability and electrocardiography findings in patients with HUS by comparing a healthy group. Patients who are diagnosed with HUS at a university hospital from December 2020 to June 2022 are screened by electrocardiography (ECG), echocardiography, and 24-h Holter ECG. A healthy control group, compatible in age and gender with the patient group, was selected from healthy subjects. HRV parameters, laboratory values, and ECG findings were analyzed and compared with the healthy group and each other. There were 25 patients with HUS and 51 participants in the healthy control group. Statistically significant differences were found in some HRV parameters: standard deviation of normal to normal intervals, the mean of the 5-min RR interval standard deviations, the standard deviation of 5-min RR interval means, the triangular interpolation of normal to normal interval, and very-low-frequency power. HUS patients had impaired and declined HRV values compared to the healthy group. There was a significant decrease in the PR distance, while a significant increase in the corrected QT and QT dispersion values was detected in the electrocardiographic findings of the patient group. HRV values impaired as renal failure parameters increased.  Conclusion: Patients with HUS may have autonomic nervous system dysfunction. HRV measurement is a non-invasive method that can evaluate this. It can be thought that there may be an increased risk of cardiovascular events and arrhythmias in some patients with HUS. ECG should be also considered to detect arrhythmia. What is Known: • Hemolytic uremic syndrome (HUS) primarily effects the hematologic parameters and kidney. • Secondary cardiomyopathy with hypertension and renal failure could be observed in these patients. • Rhythm problems are not expected primarily in these patients. • There is very limited data in evaluating autonomic function and arrhythmia risk for these patients. What is New: • Patients with HUS may have autonomic nervous system dysfunction. • HRV measurement is a non-invasive method that can evaluate this. • Cardiovascular events and arrhythmias due to the deterioration of the balance between the sympathetic and parasympathetic systems could manifest in patients with HUS. • An ECG and screening patients for cardiac events, and monitoring them closely should be considered.

Preclinical cardiovascular safety assessment of pharmacology-toxicology relationship for a set of novel kinase inhibitors.

Cardiovascular toxicity is one of the more common causes of attrition in preclinical and clinical drug development. Preclinical cardiovascular safety assessment involves numerous in vitro and in vivo endpoints which are being continually reviewed and improved to lower the incidence of cardiovascular toxicity that manifests only after the initiation of clinical trials. An example of notable preclinical toxicity is necrosis in the papillary muscle of the left ventricle in dogs that is induced by exaggerated pharmacological effects of vasodilators or positive inotropic/vasodilating off-target drug effects. Two distinct, small-molecule inhibitors that target an intracellular kinase, Compound A and Compound B, were profiled in 2-week dose-range finding and 4-week toxicity studies. Serum cardiac troponin (cTnI) was evaluated after a single dose and after 2-week and 4-week repeat dose studies with each kinase inhibitor. Acute effects on hemodynamic (heart rate, blood pressures, left ventricular contractility) and electrocardiographic (QTcV, PR, QRS intervals) endpoints by each inhibitor were assessed in an anesthetized dog cardiovascular model. Cardiovascular degeneration/necrosis with and without fibrosis was observed in dogs and correlated to increases in serum cTnI in repeat-dose toxicity studies. At the same doses used in toxicologic assessments, both kinase inhibitors produced sustained increases in heart rate, left ventricular contractility, and cardiac output, and decreases in mean arterial pressure. Cardiac pathology findings associated with these 2 kinase inhibitors were accompanied not only by cardiac troponin elevations but also associated with hemodynamic changes, highlighting the importance of the link of the physiologic-toxicologic interplay in cardiovascular safety assessment.

Post-transplant outcomes and financial burden of donation after circulatory death donor liver transplant after the implementation of acuity circle policy.

BACKGROUND: After implementation of the Acuity Circles (AC) allocation policy, use of DCD liver grafts has increased in the United States. METHODS: We evaluated the impact of AC on rates of DCD-liver transplants (LT), their outcomes, and medical costs in a single practice. Adult LT patients were classified into three eras: Era 1 (pre-AC, 1/01/2015-12/31/2017); Era 2 (late pre-AC era, 1/01/2018-02/03/2020); and Era 3 (AC era, 05/10/2020-09/30/2021). RESULTS: A total of 520 eligible LTs were performed; 87 were DCD, and 433 were DBD. With each successive era, the proportion of DCD increased (Era 1: 11%; Era 2: 20%; Era 3: 24%; p < .001). DCD recipients had longer ICU stays, higher re-admission/re-operation rates, and higher incidence of ischemic cholangiopathy compared to those with DBD. Direct, surgical, and ICU costs during first admission were higher with DCD than DBD (+8.0%, p < .001; +4.2%, p < .001; and +33.3%, p = .001). DCD-related costs increased after Era 1 (Direct: +4.9% [Era 2 vs. 1] and +12.4% [Era 3 vs. 1], p = .04; Surgical: +17.7% and +21.7%, p < .001). In the AC era, there was a significantly higher proportion of donors ≥50 years, and more national organ sharing. Compared to DCD from donors <50 years, DCD from donors ≥50 years was associated with significantly higher total direct, surgical, and ICU costs (+12.6%, p = .01; +9.5%, p = .01; +84.6%, p = .03). CONCLUSIONS: The proportion of DCD-LT, especially from older donors, has increased after the implementation of AC policies. These changes are likely to be associated with higher costs in the AC era.

Cardiovascular Outcomes of α-Blockers vs 5-α Reductase Inhibitors for Benign Prostatic Hyperplasia.

Importance: The most prescribed class of medications for benign prostatic hyperplasia (BPH) is α-blockers (ABs). However, the cardiovascular safety profile of these medications among patients with BPH is not well understood. Objective: To compare the safety of ABs vs 5-α reductase inhibitors (5-ARIs) for risk of adverse cardiovascular outcomes. Design, Setting, and Participants: This active comparator, new-user cohort study was conducted using insurance claims data from a 20% random sample of Medicare beneficiaries from 2007 to 2019 to evaluate the 1-year risk of adverse cardiovascular outcomes. Males aged 66 to 90 years were indexed into the cohort at new use of an AB or 5-ARI. Twelve months of continuous enrollment and at least 1 diagnosis code for BPH within 12 months prior to initiation were required. Data were analyzed from January 2007 through December 2019. Exposures: Exposure was defined by a qualifying prescription fill for an AB or 5-ARI after at least 12 months without a prescription for these drug classes. Main Outcomes and Measures: Follow-up began at a qualified refill for the study drug. Primary study outcomes were hospitalization for heart failure (HF), composite major adverse cardiovascular events (MACE; hospitalization for stroke, myocardial infarction, or death), composite MACE or hospitalization for HF, and death. Inverse probability of treatment and censoring-weighted 1-year risks, risk ratios (RRs), and risk differences (RDs) were estimated for each outcome. Results: Among 189 868 older adult males, there were 163 829 patients initiating ABs (mean [SD] age, 74.6 [6.2] years; 579 American Indian or Alaska Native [0.4%], 5890 Asian or Pacific Islander [3.6%], 9179 Black [5.6%], 10 610 Hispanic [6.5%], and 133 510 non-Hispanic White [81.5%]) and 26 039 patients initiating 5-ARIs (mean [SD] age, 75.3 [6.4] years; 76 American Indian or Alaska Native [0.3%], 827 Asian or Pacific Islander [3.2%], 1339 Black [5.1%], 1656 Hispanic [6.4%], and 21 605 non-Hispanic White [83.0%]). ABs compared with 5-ARIs were associated with an increased 1-year risk of MACE (8.95% [95% CI, 8.81%-9.09%] vs 8.32% [95% CI, 7.92%-8.72%]; RR = 1.08 [95% CI, 1.02-1.13]; RD per 1000 individuals = 6.26 [95% CI, 2.15-10.37]), composite MACE and HF (RR = 1.07; [95% CI, 1.03-1.12]; RD per 1000 individuals = 7.40 [95% CI, 2.88-11.93 ]), and death (RR = 1.07; [95% CI, 1.01-1.14]; RD per 1000 individuals = 3.85 [95% CI, 0.40-7.29]). There was no difference in risk for HF hospitalization alone. Conclusions and Relevance: These results suggest that ABs may be associated with an increased risk of adverse cardiovascular outcomes compared with 5-ARIs. If replicated with more detailed confounder data, these results may have important public health implications given these medications' widespread use.

Neighborhood Factors, Individual Stressors, and Cardiovascular Health Among Black and White Adults in the US: The Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study.

Importance: Chronic stress has been posited to contribute to racial disparities in cardiovascular health. Investigation of whether neighborhood- and individual-level stressors mediate this disparity is needed. Objective: To examine whether racial differences in ideal cardiovascular health (ICH) are attenuated by experiences with neighborhood- and individual-level stressors within a racially and geographically diverse population sample. Design, Setting, and Participants: This cross-sectional study examined data from 7720 participants in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study who completed the second in-home visit (2013-2016). The REGARDS study is a population-based, longitudinal study of 30 239 non-Hispanic Black and non-Hispanic White adults aged 45 years or older at baseline (2003-2007). Data for the present study were analyzed from June to July 2021 and in March 2022. Exposures: Neighborhood physical environment (eg, excessive noise, violence; scored from 7-28, with higher scores indicating more problems), neighborhood safety (scored as very safe, safe, or not safe), neighborhood social cohesion (eg, shared values; scored from 5-25, with higher scores indicating higher cohesion), perceived stress (eg, coping; scored from 0-16, with higher scores indicating greater perceived stress), and the experience of discrimination (yes or no). Main Outcomes and Measures: Ideal cardiovascular health (ICH), measured as a composite of 4 health behaviors (cigarette smoking, diet, physical activity, body mass index) and 3 health factors (blood pressure, cholesterol, and glucose levels). Results: The sample included 7720 participants (mean [SD] age, 71.9 [8.3] years; 4390 women [56.9%]; 2074 Black participants [26.9%]; and 5646 White participants [73.1%]). Black participants compared with White participants reported higher perceived stress (mean [SD] score, 3.2 [2.8] vs 2.8 [2.7]) and more often reported discrimination (77.0% vs 24.0%). Black participants also reported poorer neighborhood physical environment (mean [SD] score, 11.2 [3.8] vs 9.8 [2.9]) and social cohesion (mean [SD] score, 15.5 [2.0] vs 15.7 [1.9]) and more often reported their neighborhoods were unsafe (54.7% vs 24.3%). The odds of having a high total ICH score (ie, closer to ideal) were lower for Black adults compared with White adults, both overall (adjusted odds ratio [AOR], 0.53; 95% CI, 0.45-0.61) and by gender (men: AOR, 0.73 [95% CI, 0.57-0.93]; women: AOR, 0.45 [95% CI, 0.37-0.54]). In mediation analyses, the racial disparity in total ICH score was attenuated by neighborhood physical environment (5.14%), neighborhood safety (6.27%), neighborhood social cohesion (1.41%), and discrimination (11.01%). In stratified analyses, the factors that most attenuated the racial disparity in total ICH scores were neighborhood safety among men (12.32%) and discrimination among women (14.37%). Perceived stress did not attenuate the racial disparity in total ICH scores. Conclusions and Relevance: In this cross-sectional study of Black and White US adults aged 45 years and older, neighborhood-level factors, including safety and physical and social environments, and individual-level factors, including discrimination, attenuated racial disparities in cardiovascular health. Interventional approaches to improve ICH that separately target neighborhood context and discrimination by gender and race are warranted.

Assessing social needs among patients with cardiovascular and psychiatric comorbidities in free community health clinics.

BACKGROUND: Community-related health assessments have been shown to improve several outcomes in socioeconomically disadvantaged populations with comorbid chronic health conditions. However, while it is recognized that modifiable social determinant of health (SDH) factors might be responsible for up to 60% of preventable deaths, it is not yet standard of care to routinely screen and address these at preventive health appointments. The objective of this study was to identify the social needs of socioeconomically disadvantaged patients. METHODS: We performed a retrospective review of the socioeconomic screening questionnaires distributed to under- and uninsured patients seen at a medical student-run free primary care-based community clinic. This study included participants of all ages (0 and up), genders, languages, and ethnicities who filled out the social screening questionnaire. Socioeconomic screening questionnaires assessed the need for critical resources such as food, housing, utilities, finances, transportation, childcare, employment, education, legal support, companionship, health literacy, and community assistance. The primary study outcome was to identify unmet social needs of our medical student-run free clinic patients. We secondarily sought to identify associations between these needs and chronic health conditions. We hypothesized that patients with multiple chronic health problems and financial stressors would have the highest requests for resources. RESULTS: Our retrospective review identified 264 uninsured participants who were evaluated for social needs using a screening questionnaire. Participants who reported unmet social needs had significantly more cardiovascular risk factors than those who did not. Cardiovascular comorbidities and a history of psychiatric illness were the two most common medical problems significantly associated with several unmet social needs. CONCLUSION: This study provides support for the preemptive identification and appropriate management of physical, mental, and social care to improve disproportionate disparities in long-term health outcomes.

Assessment of short-term heat effects on cardiovascular mortality and vulnerability factors using small area data in Europe.

BACKGROUND: Short-term associations between heat and cardiovascular disease (CVD) mortality have been examined mostly in large cities. However, different vulnerability and exposure levels may contribute to spatial heterogeneity. This study assessed heat effects on CVD mortality and potential vulnerability factors using data from three European countries, including urban and rural settings. METHODS: We collected daily counts of CVD deaths aggregated at the small-area level in Norway (small-area level: municipality), England and Wales (lower super output areas), and Germany (district) during the warm season (May-September) from 1996 to 2018. Daily mean air temperatures estimated by spatial-temporal models were assigned to each small area. Within each country, we applied area-specific Quasi-Poisson regression using distributed lag nonlinear models to examine the heat effects at lag 0-1 days. The area-specific estimates were pooled by random-effects meta-analysis to derive country-specific and overall heat effects. We examined individual- and area-level heat vulnerability factors by subgroup analyses and meta-regression, respectively. RESULTS: We included 2.84 million CVD deaths in analyses. For an increase in temperature from the 75th to the 99th percentile, the pooled relative risk (RR) for CVD mortality was 1.14 (95% CI: 1.03, 1.26), with the country-specific RRs ranging from 1.04 (1.00, 1.09) in Norway to 1.24 (1.23, 1.26) in Germany. Heat effects were stronger among women [RRs (95% CIs) for women and men: 1.18 (1.08, 1.28) vs. 1.12 (1.00, 1.24)]. Greater heat vulnerability was observed in areas with high population density, high degree of urbanization, low green coverage, and high levels of fine particulate matter. CONCLUSION: This study provides evidence for the heat effects on CVD mortality in European countries using high-resolution data from both urban and rural areas. Besides, we identified individual- and area-level heat vulnerability factors. Our findings may facilitate the development of heat-health action plans to increase resilience to climate change.