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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.

INTRODUCTION: Prior consensus meetings have addressed the relationship between phosphodiesterase type 5 (PDE5) inhibition and cardiac health. Given significant accumulation of new data in the past decade, a fourth consensus conference on this topic was convened in Pasadena, California, on March 10 and 11, 2023.

OBJECTIVES: Our meeting aimed to update existing knowledge, assess current guidelines, and make recommendations for future research and practice in this area.

METHODS: An expert panel reviewed existing research and clinical practice guidelines.

RESULTS: Key findings and clinical recommendations are the following: First, erectile dysfunction (ED) is a risk marker and enhancer for cardiovascular (CV) disease. For men with ED and intermediate levels of CV risk, coronary artery calcium (CAC) computed tomography should be considered in addition to previous management algorithms. Second, sexual activity is generally safe for men with ED, although stress testing should still be considered for men with reduced exercise tolerance or ischemia. Third, the safety of PDE5 inhibitor use with concomitant medications was reviewed in depth, particularly concomitant use with nitrates or alpha-blockers. With rare exceptions, PDE5 inhibitors can be safely used in men being treated for hypertension, lower urinary tract symptoms and other common male disorders. Fourth, for men unresponsive to oral therapy or with absolute contraindications for PDE5 inhibitor administration, multiple treatment options can be selected. These were reviewed in depth with clinical recommendations. Fifth, evidence from retrospective studies points strongly toward cardioprotective effects of chronic PDE5-inhibitor use in men. Decreased rates of adverse cardiac outcomes in men taking PDE-5 inhibitors has been consistently reported from multiple studies. Sixth, recommendations were made regarding over-the-counter access and potential risks of dietary supplement adulteration. Seventh, although limited data exist in women, PDE5 inhibitors are generally safe and are being tested for use in multiple new indications.

CONCLUSION: Studies support the overall cardiovascular safety of the PDE5 inhibitors. New indications and applications were reviewed in depth.

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.

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.

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.

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.

Early screening to determine patient risk of developing Alzheimer's will allow better interventions and planning but necessitates accessible methods such as behavioral biomarkers. Previously, we showed that cognitively healthy older individuals whose cerebrospinal fluid amyloid/tau ratio indicates high risk of cognitive decline experienced implicit interference during a high-effort task, signaling early changes in attention. To further investigate attention's effect on implicit interference, we analyzed two experiments completed sequentially by the same high- and low-risk individuals. We hypothesized that if attention modulates interference, practice would affect the influence of implicit distractors. Indeed, while both groups experienced a strong practice effect, the association between practice and interference effects diverged between groups: stronger practice effects correlated with more implicit interference in high-risk participants, but less interference in low-risk individuals. Furthermore, low-risk individuals showed a positive correlation between implicit interference and EEG low-range alpha event-related desynchronization when switching from high- to low-load tasks. This suggests that lower attention on the task was correlated with stronger interference, a typical phenomenon in the younger population. These results demonstrate how attention impacts implicit interference and highlight early differences in perception between high- and low-risk individuals.

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 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 favorable 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), while LV longitudinal strain appeared comparable for both baseline and follow-up (p > 0.05 for both). In multivariable regression analysis including all 3 strain directions, baseline LV circumferential strain was independently associated with the mean transmural extent score at follow-up (β=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.

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.

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.