Young at heart? Drugs of abuse cause early onset cardiovascular disease in the young.

We are all familiar with them, from alcohol and tobacco to methamphetamine and cannabis. While drugs of abuse are often used as important medications (e.g., opioids for pain management), the non-medical use of these substances has been trending upward globally [1], which is likely to be accelerated by the global coronavirus pandemic and its concomitant mental health crisis. There has been a particularly notable increase in the abuse of synthetic opioids (e.g. fentanyl) and stimulants (e.g. methamphetamine), with growing evidence of an epidemic of simultaneous polysubstance abuse of opioids with methamphetamine. In the United States, the emerging methamphetamine crisis has led to congressional introduction of the Methamphetamine Response Act to forestall or prevent the development of this crisis in its early stages.

Substance use and premature cardiovascular disease.

Since the advent of antibiotics in the early 20^th century, cardiovascular disease has been the leading cause of death in the United States. While therapeutic advances have reduced the incidence of cardiovascular diseases over the past 30 years, we have recently seen an uptick in the incidence of cardiovascular disease. Although prevalent in the aged population, atherosclerotic cardiovascular diseases (ASCVDs), such as ischemic heart disease (IHD), ischemic cerebrovascular disease (ICVD), and peripheral arterial disease (PAD), have shown an alarming rise in young patients [2]. However, the causal factors contributing to this premature ASCVD remain undefined.

Substance use disorders have been associated with an acceleration of the aging process. Use of cocaine and methamphetamine have been associated with accelerated cellular aging and neurocognitive decline with greater than normal age-related cortical gray matter loss [3, 4, 5]. In parallel to accelerated aging, growing evidence suggest that the substance use disorder epidemics may accelerate vascular aging and contribute to early onset ASCVD. Cannabis use has been associated with accelerated cardiovascular aging, and cardiovascular aging has been viewed as a surrogate for organismal aging [6]. Lifetime opioid exposure predicts vascular stiffness and accelerated vascular aging [7]. Both cocaine and methamphetamine can have adverse and potentially fatal effects on arteries and blood vessels, including elevated blood pressure, acute vasospasm, and atherosclerotic cardiovascular disease [8, 9]. Posthumous studies show a clear increased risk for ASCVD and IHD in cocaine and methamphetamine users, particularly notable in young patients that normally show minimal ASCVD [8, 10, 11]. Additionally, methamphetamine induced structural and electrical remodeling of cardiac tissue leading to arrhythmias and heart failure [9, 12]. With the dramatic recent increase in substance use trends, especially of stimulants and opioids, this suggests than an entire cohort of individuals may show dramatic increases in early onset ASCVD. As young adults age into their middle and elder years, a subset of them will begin to experience the clinical manifestations of ASCVDs and will thus further burden a struggling healthcare system.

In this issue of Heart, Mahtta et al. performed a comprehensive analysis of clinical and administrative datasets obtained from the nationwide Veteran’s Affairs (VA) Healthcare System to create the Veterans wIth premaTure AtheroscLerosis (VITAL) nationwide registry. The age of first ASCVD-related event, according to current cardiovascular guidelines, was used to mark whether a patient developed extremely premature (male and female <40yrs; n=7,716), premature (male: <55yrs; female: <65yrs; n=135,703), or non-premature ASCVD (male: ≥55yrs; female: ≥65yrs; n=1,112,455). Using the VITAL registry dataset and VA clinical data sources, patient demographic variables were identified, including patients’ medical history their diagnosis cost group relative risk score (DCG-RRS), a well-validated surrogate marker for overall illness and the burden of subsequent healthcare costs. To assess any potential correlation between diagnosis of premature ASCVD and the use of non-medical substances, multivariable logistics regression models were created to examine the association between non-medical substance use (tobacco, alcohol, and illicit drugs: cocaine, amphetamines (e.g. methamphetamine), cannabis, other/unspecified) and incidence of extremely premature and premature ASCVD. Patients diagnosed with both extremely premature and premature ASCVD reported significantly greater proportion of non-medical substance users versus those diagnosed with non-premature ASCVD. Fully adjusted models reveal an independent association between non-medical substance use and incidence of premature and extremely premature ASCVD, meaning the use of tobacco, alcohol, amphetamine, cocaine, cannabis, and other drugs are each independently associated with increased risk of premature and extremely premature ASCVD. Further evaluation of the statistical models reveal an independent association of non-medical substance use with incidence of each subcategory of ASCVD (Figure 1A).

Figure 1.

Polysubstance Abuse and Atherosclerotic Cardiovascular Disease Risk. A) Odd ratios (OR) for ischemic cerebrovascular disease, ischemic heart disease, and peripheral artery disease associated with the use of cocaine, amphetamine, and cannabis. B) Venn diagram for the OR for premature (black) and extremely premature (purple) atherosclerotic cardiovascular disease (ASCVD) associated with the combined use of cocaine, amphetamine, and cannabis. Adapted from Mahtta et al. in this issue of Heart.

Perils of Polysubstance Use.

The association between substance use and cardiovascular disease is complicated by the high prevalence of polysubstance abuse. Epidemiological studies suggest that 1 in 5 young adults engage in polysubstance abuse, and these polysubstance users start using at younger ages and have more severe disease outcomes [13]. This is dangerous phenomenon, as among other things, polysubstance abuse leads to worse neurocognitive outcomes than abuse of a single agent [3]. According to the study by Mahtta et al., patients with premature and extremely premature ASCVD reported higher rates of polysubstance use, and the multivariable logistics regression models revealed a graded risk associated with polysubstance use, meaning the risk of extremely premature and premature ASCVD increases with each additional substance used (Only 1: odds ratio (OR)-2.05; Only 2: 3.45; Only 3: 6.38; 4 or more: 8.85). These correlations are troublesome, especially when considered the increasing incidence of polysubstance abuse worldwide.

Greater Risk for Women?

A particularly worrisome correlation observed by Mahtta et al. is that non-medical substance use is associated with a significantly greater risk of extremely premature and premature ASCVD incidence in females versus their male counterparts. However, differences in the age limits to define these populations and limitations in the inclusion of females in the VITAL registry call into question the degree of enhanced risk. For instance, this study included 1,112,445 total patients with non-premature ASCVD, but only 0.7% (n=8,137) of those patients were female. Although the sample size is small, the study demonstrates a clear trend for increased incidence of early-onset ASCVD-related events in females with substance use disorder. However, it should be noted that polysubstance abuse may be more common in males than females, which may lead to complicated interaction between sex and individual substance use patterns.

Ilicit Amphetamine Use Demonstrates Greatest Cardiovascular Risk.

While the risk of extremely premature and premature ASCVD is further increased as the number of substances used increases, the specific types of substance combinations appear to show distinct risk profiles (Figure 1B). Comparing combinations of three illicit drugs (amphetamine (A), cannabis (Ca), and cocaine (Co)), Mahtta et al. clearly demonstrate that some drug combinations are more risky than others. The combination with the lowest associated risk is cocaine and cannabis (premature-OR: 4.62; extremely-premature-OR: 3.56). Any group including amphetamine exhibited a much greater risk correlation (premature (A+Co+Ca)=OR: 5.57; (A+Co)=OR: 5.32; (A+Ca)=OR 5.37), with the differences being even greater in patients with extremely-premature ASCVD (A+Co+Ca=OR: 6.99; A+Co=OR: 6.4; A+Ca=OR: 7.2). This finding highlights the growing body of research showing that methamphetamine use results in a particularly detrimental and early form of cardiovascular disease [9, 12]. Moreover, it cautions that a greater early onset ASCVD crisis may be occurring concomitant with the recent steep increase in methamphetamine abuse.

Implications for ASCVD Research and Treatment.

Retrospective studies are limited by the available data. While this study supports the association between substance use disorder and early onset ASCVD, the effect of substance use frequency, dose, and duration cannot be reliably ascertained in this patient sample. Prospective studies will ultimately be necessary to define the effects of dose and duration, to identify specific biomarkers for substance use-associated cardiovascular disease, and to characterize the therapeutic window to limit these chronic effects of substance use disorder. To this end, prospective studies should focus on developing methods of acquiring detailed information from patients regarding their substance use and current cardiovascular function. While this will not provide an immediate solution, the continual gathering of these data will allow for much more detailed risk assessments, disease modeling, and eventually will be integrated with mechanistic data to provide a more complete understanding of the risk posed by various non-medical or prescribed substances.

Additionally, the growing body of literature on substance use disorders and their cardiovascular outcomes suggests the need for a nationwide education campaign on the potential long-term damage being done to the cardiovascular system in patients with substance use disorders. These individuals should be aware of the long term risk of chronic debilitating ASCVD beyond the acute risk of overdose. In addition, clinicians and primary care providers should begin screening their adult and young adult patients with a history of a substance use disorder for symptoms of premature or extremely premature ASCVDs at earlier stages in their patients’ lives. We are only young once, and we should do everything in our power to maintain that state as long as we can.