An Urgent Call for Studies That Address the Cardiovascular Consequences of Legalization of Marijuana.

In about a decade, half of the United States has legalized marijuana for recreational use. The drug has been associated with acute myocardial infarction, acute stroke, congestive heart failure, and various cardiac arrythmias. Data have shown that legalization of the drug led to an increase of its use as well as an increase in tetra hydro cannabinoid positive tests in patients admitted to emergency departments. In Colorado, one of the earlier states to implement legalization, there was an increase in traffic accidents, suicide rates, and even total mortality. However, there is a paucity of data on the effect of marijuana legalization on various cardiovascular events. It is prudent to have well-designed studies with enough power to provide consumers and health care providers the information they need to decide whether the risks of marijuana, especially on the cardiovascular front, are worth the "high" or potential benefits that have been described for other medical conditions.

Effects of Electronic Cigarette Vaping on Cardiac and Vascular Function, and Post-myocardial Infarction Remodeling in Rats.

The effect of electronic cigarette (E-cig) vaping on cardiac and vascular function during the healing phase of myocardial infarction (MI), and post-MI remodeling was investigated. Sprague Dawley rats were subjected to left coronary artery ligation to induce MI. One week later, rats were randomized to receive either 12 weeks of exposure to purified air (n = 37) or E-cig vapor (15 mg/ml of nicotine) (n = 32). At 12 weeks, cardiac and vascular function, and post-MI remodeling were assessed. Baseline blood flow in the femoral artery did not differ between groups, but peak reperfusion blood flow was blunted in the E-cig group (1.59 ± 0.15 ml/min) vs. the air group (2.11 ± 0.18 ml/min; p = 0.034). Femoral artery diameter after reperfusion was narrower in the E-cig group (0.54 ± 0.02 mm) compared to the air group (0.60 ± 0.02 mm; p = 0.023). Postmortem left ventricular (LV) volumes were similar in the E-cig (0.69 ± 0.04 ml) and air groups (0.73 ± 0.04 ml; p = NS); and myocardial infarct expansion index did not differ between groups (1.4 ± 0.1 in E-cig group versus 1.3 ± 0.1 in air group; p = NS). LV fractional shortening by echo did not differ between groups at 12 weeks (E-cig at 29 ± 2% and air at 27 ± 1%; p = NS). Exposure to E-cig during the healing phase of MI was associated with altered vascular function with reduced femoral artery blood flow and diameter at reperfusion, but not with worsened LV dilation or worsened cardiac function.

The association of tadalafil exposure with lower rates of major adverse cardiovascular events and mortality in a general population of men with erectile dysfunction.

BACKGROUND: Tadalafil is a long-acting phosphodiesterase-5 inhibitor (PDE-5i) indicated for erectile dysfunction (ED). HYPOTHESIS: Our hypothesis was that tadalafil will reduce the risk of major adverse cardiovascular events (MACE: composite of cardiovascular death, myocardial infarction, coronary revascularization, unstable angina, heart failure, stroke) and all-cause death in men with ED. METHODS: A retrospective observational cohort study was conducted in a large US commercial insurance claims database in men with a diagnosis of ED without prior MACE within 1 year. The exposed group (n = 8156) had ≥1 claim for tadalafil; the unexposed group (n = 21 012) had no claims for any PDE-5i. RESULTS: Primary outcome was MACE; secondary outcome was all-cause death. Groups were matched for cardiovascular risk factors, including preventive therapy. Over a mean follow-up of 37 months for the exposed group and 29 months for the unexposed group, adjusted rates of MACE were 19% lower in men exposed to tadalafil versus those unexposed to any PDE-5i (hazard ratio [HR] = 0.81; 95% confidence intervals [CI] = 0.70-0.94; p = .007). Tadalafil exposure was associated with lower adjusted rates of coronary revascularization (HR = 0.69; 95% CI = 0.52-0.90; p = .006); unstable angina (HR = 0.55; 95% CI = 0.37-0.81; p = .003); and cardiovascular-related mortality (HR = 0.45; CI = 0.22-0.93; p = .032). Overall mortality rate was 44% lower in men exposed to tadalafil (HR = 0.56; CI = 0.43-0.74; p < .001). Men in the highest quartile of tadalafil exposure had the lowest rates of MACE (HR: 0.40; 95% CI: 0.28-0.58; p < .001) compared to lowest exposure quartile. CONCLUSION: In men with ED, exposure to tadalafil was associated with significant and clinically meaningful lower rates of MACE and overall mortality.

Choriocapillaris and Retinal Vascular Alterations in Presymptomatic Alzheimer's Disease.

Purpose: To compare optical coherence tomography angiography (OCTA) retina metrics between cognitively healthy subjects with pathological versus normal cerebrospinal fluid (CSF) Aß42/tau ratios. Methods: Swept-source OCTA scans were collected using the Zeiss PLEX Elite 9000 and analyzed on 23 cognitively healthy (CH) subjects who had previously undergone CSF analysis. Thirteen subjects had a pathological Aß42/tau (PAT) ratio of <2.7132, indicative of presymptomatic Alzheimer's disease (AD), and 10 had a normal Aß42/tau (NAT) ratio of ≥2.7132. OCTA en face images of the superficial vascular complex (SVC) and deep vascular complex were binarized and skeletonized to quantify the perfusion density (PD), vessel length density (VLD), and fractal dimension (FrD). The foveal avascular zone (FAZ) area was calculated using the SVC slab. Choriocapillaris flow deficits (CCFDs) were computed from the en face OCTA slab of the CC. The above parameters were compared between CH-PATs and CH-NATs. Results: Compared to CH-NATs, CH-PATs showed significantly decreased PD, VLD, and FrD in the SVC, with a significantly increased FAZ area and CCFDs. Conclusions: Swept-source OCTA analysis of the SVC and CC suggests a significant vascular loss at the CH stage of pre-AD that might be an indicator of a neurodegenerative process initiated by the impaired clearance of Aß42 in the blood vessel wall and by phosphorylated tau accumulation in the perivascular spaces, a process that most likely mirrors that in the brain. If confirmed in larger longitudinal studies, OCTA retinal and inner choroidal metrics may be important biomarkers for assessing presymptomatic AD.

Impact of symptom-to-reperfusion-time on transmural infarct extent and left ventricular strain in patients with ST-segment elevation myocardial infarction: a 3D view on the wavefront phenomenon.

AIMS: We examined the association between the symptom-to-reperfusion-time and cardiovascular magnetic resonance (CMR)-derived global strain parameters and transmural infarct extent in ST-segment elevation myocardial infarction (STEMI) patients. METHODS AND RESULTS: The study included 108 STEMI patients who underwent successful primary percutaneous coronary intervention (PPCI). Patients were categorized according to the median symptom-to-reperfusion-time: shorter (<160 min, n = 54) and longer times (>160 min, n = 54). CMR was performed 2-7 days after PPCI and at 1 month. CMR cine imaging was performed for functional assessment and late gadolinium enhancement to evaluate transmural infarct extent. Myocardial feature-tracking was used for strain analysis. Groups were comparable in relation to incidence of LAD disease and pre- and post-PPCI thrombolysis in myocardial infarction (TIMI) flow grades. The mean transmural extent score at follow-up was lower in patients with shorter reperfusion time (P < 0.01). Both baseline and follow-up maximum transmural extent scores were smaller in patients with shorter reperfusion time (P = 0.03 for both). Patients with shorter reperfusion time had more favourable global left ventricular (LV) circumferential strain (baseline, P = 0.049; follow-up, P = 0.01) and radial strain (baseline, P = 0.047; follow-up, P < 0.01), whilst LV longitudinal strain appeared comparable for both baseline and follow-up (P > 0.05 for both). In multi-variable regression analysis including all three strain directions, baseline LV circumferential strain was independently associated with the mean transmural extent score at follow-up (ß=1.89, P < 0.001). CONCLUSION: In STEMI patients, time-to-reperfusion was significantly associated with smaller transmural extent of infarction and better LV circumferential and radial strain. Moreover, infarct transmurality and residual LV circumferential strain are closely linked.

Association of the COVID-19 Pandemic on Treatment Times for ST-Elevation Myocardial Infarction: Observations from the Los Angeles County Regional System.

Previous studies have documented longer treatment times and worse outcomes for patients with ST-elevation myocardial infarction (STEMI) who underwent primary percutaneous coronary intervention (PCI) during the COVID-19 pandemic. The objective of the present study was to evaluate the impact of the COVID-19 pandemic on treatment times and outcomes for patients with STEMI who underwent primary PCI within a regional system of care. This was a retrospective study using data from the Los Angeles County Emergency Medical Services Agency. Data on the emergency medical service activations were abstracted for patients with STEMI from March 19, 2020 to January 31, 2021, during the COVID-19 pandemic and for the same interval the previous year. All adult patients (≥18 years) with STEMI who underwent emergent coronary angiography were included. The primary end point was the first medical contact (FMC) to device time. The secondary end points included treatment time intervals, vascular complications, need for emergent coronary artery bypass surgery, length of hospital stay, and in-hospital mortality. During the study period, 3,017 patients underwent coronary angiography for STEMI, 1,893 patients pre-COVID-19 and 1,124 patients during COVID-19 (40% lower). A total of 2,334 patients (77%) underwent PCI. During the COVID-19 period, rates of PCI were significantly lower compared with the control period (75.1% vs 78.7%, p = 0.02). FMC to device time was shorter during the COVID-19 period compared with the control period (median 77.0 vs 81.0 minutes, p = 0.004). For patients with STEMI complicated by out-of-hospital cardiac arrest, FMC to device time was similar during the COVID-19 period compared with the control period (median 95.0 [33.0] vs 100.0 [40.0] minutes, p = 0.34). Vascular complications, the need for emergent bypass surgery, length of hospital stay, and in-hospital mortality were similar between the periods. In conclusion, in this large regional system of care, we found a relatively small but significant decrease in treatment times, yet overall, similar clinical outcomes for patients with STEMI who underwent primary PCI and were treated during the COVID-19 period compared with a control period. These findings suggest that mature cardiac systems of care were able to maintain efficient care despite the challenges of the COVID-19 pandemic.

Princeton IV consensus guidelines: PDE5 inhibitors and cardiac health.

BACKGROUND: In 1999, 1 year after the approval of the first oral phosphodiesterase type 5 (PDE5) inhibitor for the treatment of erectile dysfunction (ED), the first Princeton Consensus Conference was held to address the clinical management of men with ED who also had cardiovascular disease. These issues were readdressed in the second and third conferences. In the 13 years since the last Princeton Consensus Conference, the experience with PDE5 inhibitors is more robust, and recent new data have emerged regarding not only safety and drug-drug interactions, but also a potential cardioprotective effect of these drugs. AIM: In March 2023, an interdisciplinary group of scientists and practitioners met for the fourth Princeton Consensus Guidelines at the Huntington Medical Research Institutes in Pasadena, California, to readdress the cardiovascular workup of men presenting with ED as well as the approach to treatment of ED in men with known cardiovascular disease. METHOD: A series of lectures from experts in the field followed by Delphi-type discussions were developed to reach consensus. OUTCOMES: Consensus was reached regarding a number of issues related to erectile dysfunction and the interaction with cardiovascular health and phosphodiesterase-5 inhibitors. RESULTS: An algorithm based on recent recommendations of the American College of Cardiology and American Heart Association, including the use of computed tomography coronary artery calcium scoring, was integrated into the evaluation of men presenting with ED. Additionally, the issue of nitrate use was further considered in an algorithm regarding the treatment of ED patients with coronary artery disease. Other topics included the psychological effect of ED and the benefits of treating it; the mechanism of action of the PDE5 inhibitors; drug-drug interactions; optimizing use of a PDE5 inhibitors; rare adverse events; potential cardiovascular benefits observed in recent retrospective studies; adulteration of dietary supplements with PDE5 inhibitors; the pros and cons of over-the-counter PDE5 inhibitors; non-PDE5 inhibitor therapy for ED including restorative therapies such as stem cells, platelet-rich plasma, and shock therapy; other non-PDE5 inhibitor therapies, including injection therapy and penile prostheses; the issue of safety and effectiveness of PDE5 inhibitors in women; and recommendations for future studies in the field of sexual dysfunction and PDE5 inhibitor use were discussed. CLINICAL IMPLICATIONS: Algorithms and tables were developed to help guide the clinician in dealing with the interaction of ED and cardiovascular risk and disease. STRENGTHS AND LIMITATIONS: Strengths include the expertise of the participants and consensus recommendations. Limitations included that participants were from the United States only for this particular meeting. CONCLUSION: The issue of the intersection between cardiovascular health and sexual health remains an important topic with new studies suggesting the cardiovascular safety of PDE5 inhibitors.

Flavoring Agents in E-cigarette Liquids: A Comprehensive Analysis of Multiple Health Risks.

The availability of a wide range of flavored e-cigarettes is one of the primary reasons for vaping initiation and persistent use among adolescents and young people. This plethora of flavors available on the market are crafted using different flavoring agents such as cinnamaldehyde, vanillin, benzaldehyde, ethyl maltol, menthol, and dimethylpyrazine. Recent studies have brought to light the potential risks associated with e-cigarette flavoring agents and their effects on various organ systems, both with and without nicotine. Research has demonstrated that flavoring agents can induce inflammation, endothelial dysfunction, epithelial barrier disruption, oxidative stress, DNA damage, electrophysiological alterations, immunomodulatory effects, and behavioral changes, even independently of nicotine. Notably, these negative outcomes adversely affect cardiovascular system by reducing cell viability, decreasing endothelial nitric oxide synthase, nitric oxide bioavailability, soluble guanylyl cyclase activity and cyclic guanosine monophosphate accumulation, impairing endothelial proliferation and tube formation, and altering vasoreactivity resulting in vascular dysfunction. In the heart, these agents decrease parasympathetic activity, induce depolarization of resting membrane potential, loss of rhythmicity, increase isovolumic relaxation time, and change in ventricular repolarization and ventricular tachyarrhythmias. It is found that the specific response elicited by flavoring agents in different organ systems varies depending on the flavor used, the concentration of the flavoring agent, and the duration of exposure. However, the literature on the effects of flavoring agents is currently limited, emphasizing the need for more preclinical and randomized clinical trials to gain a deeper understanding and provide further evidence of the harmful effects of flavored e-cigarette use. In summary, recent research suggests that flavoring agents themselves can have detrimental effects on the body. To fully comprehend these effects, additional preclinical and clinical studies are needed to explore the risks associated with flavored e-cigarette usage.

Instantaneous detection of acute myocardial infarction and ischaemia from a single carotid pressure waveform in rats.

Aims: Myocardial infarction (MI) is one of the leading causes of death worldwide. It is well accepted that early diagnosis followed by early reperfusion therapy significantly increases the MI survival. Diagnosis of acute MI is traditionally based on the presence of chest pain and electrocardiogram (ECG) criteria. However, around 50% of the MIs are without chest pain, and ECG is neither completely specific nor definitive. Therefore, there is an unmet need for methods that allow detection of acute MI or ischaemia without using ECG. Our hypothesis is that a hybrid physics-based machine learning (ML) method can detect the occurrence of acute MI or ischaemia from a single carotid pressure waveform. Methods and results: We used a standard occlusion/reperfusion rat model. Physics-based ML classifiers were developed using intrinsic frequency parameters extracted from carotid pressure waveforms. ML models were trained, validated, and generalized using data from 32 rats. The final ML models were tested on an external stratified blind dataset from additional 13 rats. When tested on blind data, the best ML model showed specificity = 0.92 and sensitivity = 0.92 for detecting acute MI. The best model's specificity and sensitivity for ischaemia detection were 0.85 and 0.92, respectively. Conclusion: We demonstrated that a hybrid physics-based ML approach can detect the occurrence of acute MI and ischaemia from carotid pressure waveform in rats. Since carotid pressure waveforms can be measured non-invasively, this proof-of-concept pre-clinical study can potentially be expanded in future studies for non-invasive detection of MI or myocardial ischaemia.

Resting heart rate (variability) and cognition relationships reveal cognitively healthy individuals with pathological amyloid/tau ratio.

Introduction: Resting heart rate (HR) and heart rate variability (HRV) have been linked with cognition in the general population and in older individuals. The knowledge of this aspect of heart-brain relationship is relatively absent in older individuals with early Alzheimer's disease (AD) pathology. This study explores relationships of the HR, HRV, and cognition in cognitively healthy individuals with pathological amyloid/tau ratio (CH-PATs) in cerebral spinal fluid (CSF) compared to those with normal ratio (CH-NATs). Methods: We examined therelationshipsbetween1) resting HR and Mini-Mental State Examination (MMSE); 2) resting HR and brain processing during Stroop interference; and 3) resting vagally mediated HRV (vmHRV) and task switching performance. Results: Our studies showed that compared to CH-NATs, those CH-PATs with higher resting HR presented with lower MMSE, and less brain activation during interference processing. In addition, resting vmHRV was significantly correlated with task switching accuracy in CH-NATs, but not in CH-PATs. Discussion: Thesethreedifferenttestsindicatedysfunctionalheart-brainconnections in CH-PATs, suggesting a potential cardio-cerebral dysfunctional integration.

Invasive versus Conservative Management in Coronary Artery Disease.

Background: In patients with ST-elevation myocardial infarction, immediate coronary angiography and intervention is the best practice, if an experienced laboratory is available. In non-Q-wave infarction most, but not all, studies suggest that early invasive strategy is superior to conservative management. Complete revascularization is preferred.Methods: A literature search regarding management of coronary artery disease was conducted in PubMed between January 1985 to January 2021. Articles published in English were reviewed, and those relevant were selected by both authors. Special focus was on the ISCHEMIA trial and related articles.Results: The utility of coronary angiography in patients with stable coronary artery disease is challenging. All patients should undergo optimal medical therapy. Patients with angina should not only receive approved anti-anginal agents but should also receive lifestyle modifications and pharmacologic therapy to control risk factors such as diabetes, hypertension, dyslipidemia, and smoking; and should consider organized physical activity programs. Low density lipoprotein should be reduced to 70 mg/dL or less. Non-invasive studies such as coronary computed tomography angiography (CCTA) are preferred. If expert CCTA is not available, then stress test, preferably with imaging, is recommended. If the results of CCTA show high risk, then coronary angiography and intervention are usually indicated. In patients with left main disease, left ventricular dysfunction, or symptoms of congestive heart failure, early invasive strategy is recommended. If none of these conditions exist, then initial medical therapy may be initiated, and invasive therapy should be utilized only if clinically indicated. In patients with chronic stable angina, continue with medical therapy and risk factor modification. If the frequency or severity of angina episodes change, coronary angiography and revascularization should be considered, as appropriate. In patients with significant renal dysfunction, angiogram may be indicated only if there is complete failure of medical therapy.Conclusion: Optimal medical therapy should be initially utilized in all patients. Early invasive management and revascularization should be utilized in patients with left ventricular dysfunction, congestive heart failure, and failure of medical therapy. A shared decision-making process should always be utilized.

The connection between heart rate variability (HRV), neurological health, and cognition: A literature review.

The heart and brain have bi-directional influences on each other, including autonomic regulation and hemodynamic connections. Heart rate variability (HRV) measures variation in beat-to-beat intervals. New findings about disorganized sinus rhythm (erratic rhythm, quantified as heart rate fragmentation, HRF) are discussed and suggest overestimation of autonomic activities in HRV changes, especially during aging or cardiovascular events. When excluding HRF, HRV is regulated via the central autonomic network (CAN). HRV acts as a proxy of autonomic activity and is associated with executive functions, decision-making, and emotional regulation in our health and wellbeing. Abnormal changes of HRV (e.g., decreased vagal functioning) are observed in various neurological conditions including mild cognitive impairments, dementia, mild traumatic brain injury, migraine, COVID-19, stroke, epilepsy, and psychological conditions (e.g., anxiety, stress, and schizophrenia). Efforts are needed to improve the dynamic and intriguing heart-brain interactions.

Effect of phosphodiesterase type 5 inhibitors on major adverse cardiovascular events and overall mortality in a large nationwide cohort of men with erectile dysfunction and cardiovascular risk factors: A retrospective, observational study based on healthcare claims and national death index data.

BACKGROUND: Treatment with phosphodiesterase type 5 inhibitors (PDE-5is) is effective in treating erectile dysfunction (ED). AIM: The objective of this study was to determine the effect of PDE-5is on the incidence of major adverse cardiovascular (CV) events (MACE; composite outcome of CV death, hospitalization for myocardial infarction, coronary revascularization, stroke, heart failure, and unstable angina pectoris) and overall mortality. METHODS: A retrospective observational cohort study was conducted in a large US claims database in men with ≥1 diagnosis of ED without prior MACE within 1 year, from January 1, 2006, to October 31, 2020. The exposed group had ≥1 claim for PDE-5i and the unexposed group had no claims for PDE-5i, and the groups were matched up to 1:4 on baseline risk variables. OUTCOME: The primary outcome was MACE and the secondary outcomes were overall mortality and individual components of MACE, determined by multivariable Cox proportional hazard modeling. RESULTS: Matched plus multivariable analyses showed that MACE was lower by 13% in men exposed (n = 23 816) to PDE-5is (hazard ratio [HR] 0.87; 95% CI 0.79-0.95; P = .001) vs nonexposure (n = 48 682) over mean follow-up periods of 37 and 29 months, respectively, with lower incidence of coronary revascularization (HR 0.85; 95% CI 0.73-0.98; P = .029), heart failure (HR 0.83; 95% CI 0.72-0.97; P = .016), unstable angina (HR 0.78; 95% CI 0.64-0.96; P = .021), and CV death (HR 0.61; 95% CI 0.41-0.90; P = .014) with PDE-5i exposure. Phosphodiesterase type 5 inhibitor-exposed men had a 25% lower incidence of overall mortality (HR 0.75; 95% CI 0.65-0.87; P < .001). Men without coronary artery disease (CAD) but with CV risk factors at baseline showed a similar pattern. In the main study cohort, men in the highest quartile of PDE-5i exposure had the lowest incidence of MACE (HR 0.45; 95% CI 0.37-0.54; P < .001) and overall mortality (HR 0.51; 95% CI 0.37-0.71; P < .001) vs the lowest exposure quartile. In a subgroup with baseline type 2 diabetes (n = 6503), PDE-5i exposure was associated with a lower MACE risk (HR 0.79; 95% CI 0.64-0.97; P = .022). CLINICAL IMPLICATIONS: PDE-5is may have cardioprotective effects. STRENGTHS AND LIMITATIONS: Strengths are the large numbers of participants and consistency of the data; limitations include the retrospective nature of the study and unknown confounders. CONCLUSIONS: In a large population of US men with ED, PDE-5i exposure was associated with lower incidence of MACE, CV death, and overall mortality risk compared to non-exposure. Risk reduction correlated with PDE-5i exposure level.

Effects of Electronic Cigarette Exposure on Myocardial Infarction and No-Reflow, and Cardiac Function in a Rat Model.

PURPOSE: We investigated the effects of exposure to electronic cigarettes (E-cig) vapor on the sizes of the no-reflow and myocardial infarction regions, and cardiovascular function compared to exposure to purified air and standard cigarette smoke. METHODS AND RESULTS: Sprague Dawley rats (both male and female, 6 weeks old) were successfully exposed to filtered air (n = 32), E-cig with nicotine (E-cig Nic+, n = 26), E-cig without nicotine (E-cig Nic-, n = 26), or standard cigarette smoke (1R6F reference, n = 31). All rats were exposed to inhalation exposure for 8 weeks, prior to being subjected to 30 minutes of left coronary artery occlusion followed by 3 hours of reperfusion. Exposure to E-cig vapor with or without nicotine or exposure to standard cigarettes did not increase myocardial infarct size or worsen the no-reflow phenomenon. Exposure to E-cig Nic+ reduced the body weight gain, and increased the LV weight normalized to body weight and LV wall thickness and enhanced the collagen deposition within the LV wall. E-cig exposure led to cardiovascular dysfunction, such as reductions in cardiac output, LV positive and negative dp/dt, suggesting a reduction in contractility and relaxation, and increased systemic arterial resistance after coronary artery occlusion and reperfusion in rats compared to air or cigarette exposure. CONCLUSIONS: E-cig exposure did not increase myocardial infarct size or worsen the no-reflow phenomenon, but induced deleterious changes in LV structure leading to cardiovascular dysfunction and increased systemic arterial resistance after coronary artery occlusion followed by reperfusion.

Cardiac Effects of Phosphodiesterase-5 Inhibitors: Efficacy and Safety.

The coexistence of cardiovascular disease and erectile dysfunction is widespread, possibly owing to underlying endothelial dysfunction in both diseases. Millions of patients with cardiovascular disease are prescribed phosphodiesterase-5 (PDE5) inhibitors for the management of erectile dysfunction. Although the role of PDE5 inhibitors in erectile dysfunction therapy is well established, their effects on the cardiovascular system are unclear. Preclinical studies investigating the effect of PDE5 inhibitors on ischemia-reperfusion injury, pressure overload-induced hypertrophy, and chemotoxicity suggested a possible clinical role for each of these medications; however, attempts to translate these findings to the bedside have resulted in mixed outcomes. In this review, we explore the biologic preclinical effects of PDE5 inhibitors in mediating cardioprotection. We then examine clinical trials investigating PDE5 inhibition in patients with heart failure, coronary artery disease, and ventricular arrhythmias and discuss why the studies likely have yet to show positive results and efficacy with PDE5 inhibition despite no safety concerns.

The Correlation between COVID-19 Hospitalizations and Emergency Medical Services Responses for Time-Sensitive Emergencies during the COVID-19 Pandemic.

OBJECTIVE: COVID-19 has had significant secondary effects on health care systems, including effects on emergency medical services (EMS) responses for time-sensitive emergencies. We evaluated the correlation between COVID-19 hospitalizations and EMS responses for time-sensitive emergencies in a large EMS system. METHODS: This was a retrospective study using data from the Los Angeles County EMS Agency. We abstracted data on EMS encounters for stroke, ST-elevation myocardial infarction (STEMI), out-of-hospital cardiac arrest (OHCA), and trauma from April 5, 2020 to March 6, 2021 and for the same time period in the preceding year. We also abstracted daily hospital admissions and censuses (total and intensive care unit [ICU]) for COVID-19 patients. We designated November 29, 2020 to February 27, 2021 as the period of surge. We calculated Spearman's correlations between the weekly averages of daily hospital admissions and census and EMS responses overall and for stroke, STEMI, OHCA, and trauma. RESULTS: During the study period, there were 70,616 patients admitted for confirmed COVID-19, including 12,467 (17.7%) patients admitted to the ICU. EMS responded to 899,794 calls, including 9,944 (1.1%) responses for stroke, 3,325 (0.4%) for STEMI, 11,207 (1.2%) for OHCA, and 114,846 (12.8%) for trauma. There was a significant correlation between total hospital COVID-19 positive patient admissions and EMS responses for all time-sensitive emergencies, including a positive correlation with stroke (0.41), STEMI (0.37), OHCA (0.78), and overall EMS responses (0.37); and a negative correlation with EMS responses for trauma (-0.48). ICU COVID-19 positive patient admissions also correlated with increases in EMS responses for stroke (0.39), STEMI (0.39), and OHCA (0.81); and decreased for trauma (-0.53). Similar though slightly weaker correlations were found when evaluating inpatient census. During the period of surge, the correlation with overall EMS responses increased substantially (0.88) and was very strong with OHCA (0.95). CONCLUSION: We found significant correlation between COVID-19 hospitalizations and the frequency of EMS responses for time-sensitive emergencies in this regional EMS system. EMS systems should consider the potential effects of this and future pandemics on EMS responses and prepare to meet non-pandemic resource needs during periods of surge, particularly for time-sensitive conditions.

Gabrb3 endothelial cell-specific knockout mice display abnormal blood flow, hypertension, and behavioral dysfunction.

Our recent studies uncovered a novel GABA signaling pathway in embryonic forebrain endothelial cells that works independently from neuronal GABA signaling and revealed that disruptions in endothelial GABAA receptor-GABA signaling from early embryonic stages can directly contribute to the origin of psychiatric disorders. In the GABAA receptor ß3 subunit endothelial cell conditional knockout (Gabrb3ECKO) mice, the ß3 subunit is deleted selectively from endothelial cells, therefore endothelial GABAA receptors become inactivated and dysfunctional. There is a reduction in vessel densities and increased vessel morphology in the Gabrb3ECKO telencephalon that persists in the adult neocortex. Gabrb3ECKO mice show behavioral deficits such as impaired reciprocal social interactions, communication deficits, heightened anxiety, and depression. Here, we characterize the functional changes in Gabrb3ECKO mice by evaluating cortical blood flow, examine the consequences of loss of endothelial Gabrb3 on cardiac tissue, and define more in-depth altered behaviors. Red blood cell velocity and blood flow were increased in the cortical microcirculation of the Gabrb3ECKO mice. The Gabrb3ECKO mice had a reduction in vessel densities in the heart, similar to the brain; exhibited wavy, myocardial fibers, with elongated 'worm-like' nuclei in their cardiac histology, and developed hypertension. Additional alterations in behavioral function were observed in the Gabrb3ECKO mice such as increased spontaneous exploratory activity and rearing in an open field, reduced short term memory, decreased ambulatory activity in CLAMS testing, and altered prepulse inhibition to startle, an important biomarker of psychiatric diseases such as schizophrenia. Our results imply that vascular Gabrb3 is a key player in the brain as well as the heart, and its loss in both organs can lead to concurrent development of psychiatric and cardiac dysfunction.

Analysis of integrated clinical safety data of tadalafil in patients receiving concomitant antihypertensive medications.

This pooled safety analysis assessed the incidence of hypotension-related treatment-emergent adverse events (TEAEs) and major adverse cardiovascular events (MACEs) in patients with concomitant use of tadalafil and antihypertensive medications. Data were pooled from seventy-two Phase II-IV studies conducted on patients with a diagnosis of erectile dysfunction (ED) and/or benign prostate hyperplasia (BPH). Studies were categorized as either All placebo-controlled studies or All studies. The incidences of hypotension-related TEAEs and MACEs were analyzed by indication; by use of concomitant antihypertensive medications; and by the number of concomitant antihypertensive medications. A total of 15 030 and 22 825 patients were included in the analyses for All placebo-controlled studies and All studies, respectively. In the All placebo-controlled studies, the incidence of hypotension-related TEAEs and MACEs was ranging between 0.6-1.5% and 0.0-1.0%, respectively, across all indications. Tadalafil was associated with an increase in hypotension-related TEAEs only in the ED as-needed group not receiving any concomitant antihypertensive medications (p-value = .0070); no significant difference was reported between placebo and tadalafil in the groups of patients receiving ≥1 antihypertensive medication (p-values ≥ .7386). Similarly, no significant differences (p-values≥ .2238) were observed in the incidence of MACEs between tadalafil and placebo treatment groups, with or without concomitant use of antihypertensive medications, and across all indication categories. In the All studies group, results were similar. The pooled analysis showed no evidence that taking tadalafil alongside antihypertensive medications increases the risk of hypotension-related TEAEs or MACEs compared with antihypertensive medications alone.

One Acute Exposure to E-Cigarette Smoke Using Various Heating Elements and Power Levels Induces Pulmonary Inflammation.

Background: Electronic cigarettes (eC) may not be entirely benign. There is a lack of data on the effect of a single acute exposure of eC vapor using various heating sources and power settings upon lung injury. The purpose of this study was to determine if an acute exposure with eC vapor heated with different heating elements and power levels induced inflammatory changes in the lungs and heart. Methods: Rats were exposed to pure air or received a single, 4-h exposure to eC vapor. The devices used either a stainless steel (SS) or nichrome (NC) heating element randomized to a low or high atomization power (45 versus 70 W). Rats were euthanized within 48 h of exposure. Results: The eC groups showed accumulation of inflammatory cells in bronchial lumen, near the pleura, and within the alveolar spaces. The numbers of inflammatory cells per field in the lung parenchyma were significantly greater in the rats exposed to eC groups vs. the air group. There were significantly higher inflammatory gene expression changes in the lungs of animals assigned to 70 W power. We observed that eC vapor generated using burnt coils were toxic and could cause acute respiratory distress and myocarditis. Conclusion: In conclusion, one 4-h exposure to eC vapor, in the absence of vitamin E oil or nicotine, significantly increased lung inflammation. Effects were seen after exposures to vapor generated using SS and NC heating elements at either high or low power. Vapor from devices with burnt coils can negatively affect the heart and lung.