The role of substance use in structural heart disease among women living with HIV

Abstract

BACKGROUND:

People living with HIV have increased risk of cardiovascular disease, but few studies focus on women with HIV (WWH) and few account for the use of multiple substances

SETTING:

We recruited WWH from San Francisco shelters, free meal programs, street encampments and a safety net HIV clinic.

METHODS:

Between 2016 and 2019, participants completed six monthly interviews, specimen collection, and a transthoracic echocardiogram. We assessed associations between three echocardiographic indices of cardiac hypertrophy (concentric hypertrophy, concentric remodeling, and eccentric hypertrophy) and study factors, including cardiovascular risk factors, substance use, and HIV-specific factors (CD4+ count, viral load, HIV medication).

RESULTS:

Among 62 participants, the average age was 53 years and 70% were ethnic minority women. Just over 70% had elevated blood pressure (BP). Toxicology-confirmed substance use included tobacco (63%), cannabis (52%), cocaine (51%), methamphetamine (29%), and alcohol (26%). Concentric hypertrophy was detected in 26% of participants. It was positively associated with cocaine use (adjusted Relative Risk [aRR]= 32.5, p<0.01) and negatively associated with cannabis use (aRR=0.07, p<0.01). Concentric remodeling was detected in 40% of participants. It was positively associated with cocaine use (aRR=11.2, p<0.01) and negatively associated with cannabis use (aRR=0.17, p=0.02). Eccentric hypertrophy was not significantly associated with factors studied here.

CONCLUSIONS:

Routine evaluation of stimulant use as a contributing factor to cardiovascular risk may improve risk assessment in WWH. Whether cannabis use mitigates the impact of cocaine use on structural heart disease among WWH merits further investigation.

INTRODUCTION

People living with HIV (PWH) have increased risk for cardiovascular disease (CVD) and echocardiographic abnormalities, which is partly due to a higher prevalence of CVD risk factors, such as high blood pressure and diabetes, particularly in low-income PWH.¹ While many studies elucidate the underlying mechanisms of CVD risk in PWH, the majority include sample populations composed mostly of men. Given sex-specific conditions linked to CVD, such as premature menopause,² and given sex differences in the impact of conditions like left ventricular (LV) hypertrophy on mortality,³ the current evidence base surrounding evaluation of women with HIV and CVD may be incomplete.

Data from a multi-site national study of PWH suggest that women living with HIV (WWH) are more likely than men to live in poverty and use substances.⁴ Substance use is an important factor in HIV-related outcomes, particularly in lower-income PWH. For example, stimulant toxicity is the most common cause of death among safety net HIV clinic patients⁵ as well as unstably housed women living with or at risk for HIV.⁶

In one of the few studies to focus on the cardiovascular health of WWH, a recent investigation reported that those with CD4+ counts<200 cells/mm³ had a significantly higher prevalence of LV hypertrophy compared to women without HIV.⁷ Here we build on this line of investigation by evaluating whether current stimulant use influences the relationship between CD4+ count and structural heart disease in WWH who experience homelessness and unstable housing.

METHODS

Study Design

The current study used data from baseline interviews, as well as a transthoracic echocardiogram completed within the subsequent two months. Data were provided by WWH participating in “Polysubstance Use and Health Outcomes Evaluation” (PULSE), a cohort study of women living in San Francisco. PULSE study data were collected between June 2016 and January 2019 to examine the influences of polysubstance use on cardiac dysfunction, and study details have been described elsewhere.⁸

Study Participant Recruitment

Trained study team members recruited a sample of San Francisco women who experienced homelessness and unstable housing from shelters, free meal programs, single room occupancy (SRO) hotels and street encampments. Additional WWH were recruited from the Zuckerberg San Francisco General Hospital HIV clinic (“Ward 86”).

Inclusion criteria included female sex at birth, age ≥ 18 years and a history of housing instability (i.e., slept in public, a homeless shelter, or place not meant for human habitation; or stayed with a series of associates because there was no other place to sleep [“couch-surfed”]). HIV testing was conducted at screening and WWH were over-sampled. Only WWH were included in the current study. CVD status at enrollment was unknown. Participants provided informed consent at baseline and were reimbursed $40 for each study visit. All study procedures were approved by the Institutional Review Board at the University of California, San Francisco.

Data Collection

Participants completed study visits consisting of an interview, serum/urine collection, vital sign assessment, and a transthoracic echocardiogram. Median time between the baseline study visit and the echocardiogram was 76.5 days. With the exception of blood pressure, all data were from the baseline interview, toxicology, and echocardiogram. We averaged blood pressure across all study visits to reduce bias from a single transient spike. In addition, we reviewed electronic health records to assess the most recent CD4+ count prior to the echocardiogram.

Dependent Outcome Measures

Structural heart disease was measured as LV geometry. It was classified based on LV mass index (LVMI) and right wall thickness (RWT) as follows: normal geometry (RWT<= 0.42 AND LVMI<= 95 g/m2), eccentric hypertrophy (RWT<= 0.42 AND LVMI> 95 g/m2), concentric remodeling (RWT> 0.42 AND LVMI<= 95 g/m2), and concentric hypertrophy (RWT> 0.42 AND LVMI> 95 g/m2).⁹ Echocardiograms were read by a single cardiologist who was blinded to clinical characteristics.

Independent Exposure Measures

Primary study exposures were toxicology-confirmed use of substances. Additional covariates included toxicology-confirmed prescribed pharmaceutical drugs influencing cardiovascular health; demographic variables; self-reported chronic health conditions; and CVD risk factors, including body mass index, systolic and diastolic blood pressure, total cholesterol (Cholesterol_2, Siemens ADVIA^® Chemistry XPT), HDL cholesterol (Direct HDL cholesterol, Siemens ADVIA^® Chemistry XPT), calculated LDL cholesterol (Friedewald equation). A full list of substances and additional study factors is shown in Table 1.

Table 1.

Study characteristics of women living with HIV who experience homelessness and unstable housing (N=62)

	Prevalence
Age (per 10 years)	53.3 (45.5–59.3)
Race
White	19 (30.6%)
Black/AA	30 (48.4%)
Latina	8 (12.9%)
Multiracial	3 (4.8%)
Other	2 (3.2%)
Post-Menopausala	43 (69.4%)
Body Mass Inex (kg/m2)	Mean=28.5 (SD: 22.3–35.3)
LDL Cholesterol (mg/dL) per SD	Mean=92 (SD: 75–117)
HDL Cholesterol (mg/dL) per SD	Mean=59 (SD: 45–71)
Diabetesb	6 (9.7%)
Prior MIb	6 (9.7%)
Prior Strokeb	8 (12.9%)
Hep Cb	30 (48.4%)
Cocained,e	32 (51.6%)
Methamphetamined	18 (29.0%)
Heroind,f	2 (3.2%)
Fentanyld	2 (3.2%)
Opioid Analgesicsd,g	17 (27.4%)
Alcohold,h	16 (25.8%)
Cannabisd,i	32 (51.6%)
Cotinined	38 (61.3%)
Methadonej	15 (24.2%)
Benzodiazapinesj,k	10 (16.1%)
Beta Blockersj,l	7 (11.3%)
Calcium Channel Blockersj,m	3 (4.8%)
Other Antihypertensive Agentsj,n	1 (1.6%)
Statins	0
Lidocainej	9 (14.5%)
Tenofovirj	8 (12.9%)
Emtricitabinej	19 (30.6%)
Darunavirj	5 (8.1%)
Raltegravirj	1 (1.6%)
Dolutegravirj	25 (40.3%)
CD4+ counts < 200 cells/mm3	8 (13.6%)
HIV viral load
<50	32 (62.7%)
50–199	4 (7.8%)
200–499	4 (7.8%)
500–999	3 (5.9%)
1000+	8 (15.7%)
Systolic Blood Pressure (per 10 mmHg)	Mean=125 (SD: 112–142)
Diastolic Blood Pressure (per 10 mmHg)	Mean=84.5 (SD: 76–92)

^a>1 year since last menstrual period.

^bSelf-reported history

^cImmunoassay positive result

^dToxicology-confirmed

^eCocaine, Benzoylecgonine, Ecgonine methyl ester or Norcocaine

^f6-Monoacetylmorphine, Heroin

^gMorphine, Codeine, Hydrocodone, Hydromorphone, Dihydrocodeine, Morphine Glucuronide, Codeine Glucuronide, Oxycodone or Oxymorphone.

^hDetermined by Ethyl Glucuronide

ⁱTetrahydrocannabinol (THC) −COOH and THC−COOH glucuronide

^jDrug level confirmed

^k7-Aminoclonazepam, Clonazepam, Diazepam, Lorazepam, Nordiazepam, Temazepam, Oxazepam, Alprazolam, alpha-hydroxyalprazolam, Flurazepam, 2-Hydroxyethlflurazepam, Desalkylflurazepam, Flunitrazepam, 7-aminoflunitrazepam, N-Desmethylflunitrazepam, Midazolam, 7-aminontrazepam or Etizolam

^lMetoprolol, Atenolol, Carvedilol, Labetolol

^mAmlodipine, Diltiazem, Verapamil

ⁿClonidine, Lisinopril or Losartan

We tested hydrolyzed urine samples for the use of substances and prescribed pharmaceutical drugs using a qualitative liquid chromatography-high resolution mass spectrometry (LC-HRMS) method. Data acquisition and generation of mass spectra took place using an SCIEX 5600 TripleTOF^® LC-HRMS system. We used HRMS full scan mode with information-dependent acquisition of HRMS product ion spectra, which were searched against a mass spectral library for positive identification of each substance.¹⁰ To increase test sensitivity, we conducted separate urine THC screening, which uses a liquid chromatography tandem mass spectrometry (LC-MS/MS) method to detect THC−COOH (>0.5 ng/mL) and THC-COOH-glucuronide (2.5 ng/mL).¹¹

Analysis

We used multinomial logistic regression to analyze associations between independent variables and LV geometric outcomes (eccentric hypertrophy, concentric remodeling, and concentric hypertrophy) compared with “normal geometry.” We used backward deletion to arrive at a final adjusted model in which variable significance was assessed at the p< 0.05 level. All analyses were done using Stata Version 15.0 (Stata Corp., LLC, College Station, TX).

RESULTS

Among 62 WWH with complete data, including information from an additional echocardiogram study visit, the average age of participants was 53.3 years (SD: 45.5–59.3), 48% were Black, and 69% were post-menopausal (Table 1). Over one-third (37%) of participants had a detectable viral load and 14% had a CD4+ count<200 cells/mm³. Prior physician-diagnosed heart attack was reported by 10% of participants, and 68% had Stage 1 hypertension or higher (i.e., systolic >130 mm Hg or diastolic >80 mm Hg) (Table 1).

The prevalence of toxicology-confirmed substances included cotinine (61%), cocaine (52%), cannabis (52%), methamphetamine (29%), glucuronide/alcohol (26%), and heroin (3%). The use of multiple substances was detected in 82% of participants. The prevalence of prescription drugs included methadone (24%), beta blockers (11%), calcium channel blockers (5%), statins (0%), and HIV drugs, dolutegravir (40%) and emtricitabine (31%) (Table 1).

Most participants had a normal LV ejection fraction (LVEF: 63%, IQR: 58%−68% [normal range 50%−70%]), and 68% had normal diastolic function.

“Normal” geometry was observed in 17 participants, while eccentric hypertrophy was detected in 4%, concentric remodeling in 25, and concentric hypertrophy in 16. Factors significantly associated with concentric remodeling include increasing age (relative risk ratio [RR]=1.95 per 10 years; 95% confidence interval [CI]:1.03,3.70), post-menopausal status (RR: 5.81; 95% CI: 1.5, 22.5), cocaine use (11.2; 95% CI: 2.1, 60.3), and cannabis use (0.17; 95% CI: 0.04, 0.74). Factors significantly associated with concentric hypertrophy include increased age (relative risk ratio: 4.1 per 10 years; CI: 1.59, 10.6), post-menopausal status (RR: 27.5; 95% CI: 2.88, 262), cocaine use (RR: 32.5; 95% CI: 4.68, 226), opioid analgesic use (RR: 0.1; 95% CI: 0.01, 0.9), cannabis use (RR: 0.07; 95% CI: 0.01, 0.39), and diastolic blood pressure (RR: 1.96 per 10 mmHg; 95% CI 1.05, 3.66) (Table 2).

Table 2.

Multinomial associations between toxicology-confirmed substance use and cardiac geometry among women living with HIV who experience homelessness and unstable housing (N=62)

Exposure Variables	Eccentric Hypertrophy		Concentric Remodeling		Concentric Hypertrophy
	Relative Risk Ratio (95% CI)	p value	Relative Risk Ratio (95% CI)	p value	Relative Risk Ratio (95% CI)	p value
Cocained,e	7.5 (0.65 – 87.2)	0.11	11.2 (2.1 – 60.3)	<0.01 *	32.5 (4.68 – 226)	<0.01 **
Methamphetamined	1.56 (0.12 – 20.6)	0.74	3.11 (0.71 – 13.7)	0.13	1.56 (0.29 – 8.38)	0.61
Heroind,f	2.33e-07 (0 - .)ǂ	0.98	0.67 (0.04 – 11.4)	0.78	2.33e-07 (0 - .)ǂ	0.99
Fentanyld	1 (0 - .)ǂ	1.0	781938 (0 - .)ǂ	0.99	1249669 (0 - .)ǂ	0.99
Opioid Analgesicsd,g	0.48 (0.04 – 5.58)	0.56	0.67 (0.19 – 2.42)	0.54	0.1 (0.01 – 0.9)	0.04 **
Alcohold,h	7.03e-07 (0 - .)ǂ	0.99	0.93 (0.24 – 3.64)	0.92	0.80 (0.17 – 3.73)	0.78
Cannabisd,i	0.64 (0.05 – 8.52)	0.74	0.17 (0.04 – 0.74)	0.02 *	0.07 (0.01 – 0.39)	<0.01 **
Cotinined	0.55 (0.06 – 4.91)	0.59	0.69 (0.20 – 2.47)	0.57	1.2 (0.28 – 5.12)	0.81
Methadonej	7.5 (0.65 – 87.2)	0.11	4.22 (0.78 – 22.8)	0.09	1.07 (0.13 – 8.67)	0.95
Benzodiazapinesj,k	6.28e-06 (0 - .)ǂ	0.99	5.05 (0.55 – 46.5)	0.15	3.69 (0.34 – 39.9)	0.28

^a>1 year since last menstrual period.

^bSelf-reported history

^cImmunoassay positive result

^dToxicology-confirmed

^eCocaine, Benzoylecgonine, Ecgonine methyl ester or Norcocaine

^f6-Monoacetylmorphine, Heroin

^gMorphine, Codeine, Hydrocodone, Hydromorphone, Dihydrocodeine, Morphine Glucuronide, Codeine Glucuronide, Oxycodone or Oxymorphone.

^hDetermined by Ethyl Glucuronide

ⁱTetrahydrocannabinol (THC) −COOH and THC−COOH glucuronide

^jDrug level confirmed

^k7-Aminoclonazepam, Clonazepam, Diazepam, Lorazepam, Nordiazepam, Temazepam, Oxazepam, Alprazolam, alpha-hydroxyalprazolam, Flurazepam, 2-Hydroxyethlflurazepam, Desalkylflurazepam, Flunitrazepam, 7-aminoflunitrazepam, N-Desmethylflunitrazepam, Midazolam, 7-aminontrazepam or Etizolam

^lMetoprolol, Atenolol, Carvedilol, Labetolol

^mAmlodipine, Diltiazem, Verapamil

ⁿClonidine, Lisinopril or Losartan

^ǂModel would not converge

^*Concentric Remodeling, Final Model: cocaine and cannabis use

^**Concentric Hypertrophy, Final Model: cocaine and cannabis use

In adjusted analysis, final models for both concentric remodeling and concentric hypertrophy only included cocaine and cannabis use. Cocaine was positively associated with both concentric remodeling (RR=17, 95% CI: 2.7–107) and concentric hypertrophy (RR=59.9, 95% CI: 6.53–548), while cannabis had a negative (protective) association with both concentric remodeling (RR=0.10, 95% CI: 0.03–0.56) and concentric hypertrophy (RR=0.04, 95% CI: <0.01–0.28) (Table 2). All other factors, including viral load and systolic blood pressure, were not retained in the final models. When viral load and systolic blood pressure were forced into a final model, cocaine and cannabis associations were strong and still reached levels of statistical significance (data not shown).

DISCUSSION

In this small sample of polysubstance-using WWH, cocaine use had a strong association with LV hypertrophy and remodeling. The finding that cocaine is especially detrimental to cardiovascular health compared with other substances is consistent with prior non-HIV research showing that, among individuals using cocaine or heroin, those using cocaine have a higher likelihood of LV hypertrophy.¹² Results from this and other studies suggest that stimulant use has an outsized effect on cardiovascular outcomes. However, it often goes unrecognized in clinic settings. For example, silent CVD progression is frequently pronounced in women.¹³ It is also pronounced in people who use cocaine regularly, many of whom remain undiagnosed until they present to an emergency department with an acute event.¹⁴ The existing evidence suggests that routine assessment of stimulant use in WWH who experience housing instability may improve CVD risk assessment.

These results raise the question of whether cannabis use mediates cocaine effects in women who use multiple substances. This study sample was too small for conclusive results based on further stratification. However, exploratory analysis revealed consistently positive estimates for WWH who used cocaine but not cannabis, positive but smaller estimates for those who used both, and negative estimates for those who used cannabis but not cocaine (data not shown). In terms of potential mechanisms and pathways, the relationships are complicated. For example, cannabis activation of the endocannabinoid receptor 1 (CB₁R) can lead to adverse cardiovascular effects through a variety of mechanisms (e.g., endothelial dysfunction, cell death, tissue injury, oxidative stress, smooth muscle proliferation),¹⁶ whereas activation of CB₂R (expressed primarily in immune cells) exerts anti-inflammatory effects.¹⁶ Complicating these relationships is the potential effect modification by the concentration of Δ9-tetrahydrocannabinol (THC) found in cannabis, which may have an atheroprotective effect at low doses.¹⁷ However, dramatic increases in the THC content of available cannabis over the past decade have complicated the assessment of its impact.¹⁶ Whether cannabis use mitigates the impact of cocaine on structural heart disease in WWH merits further investigation.

Unlike Shitole et al., we did not observe a significant difference in hypertrophy by CD4+ count. However, differences in sample populations or study design may explain the discrepancy. First, the current sample was much smaller. Second, the current study defined hypertrophy based on LV geometry (i.e., right wall thickness and LV mass index) while Shitole et al. defined hypertrophy as LV mass index >95 g/m². In addition, Shitole et al. compared WWH with CD4+ counts<200 cells/mm³ to women without HIV, while our comparison groups were WWH with CD4+ counts< and ≥200 cells/mm³. Whether the discrepancy reflects differences in these measurements, or an overriding influence by stimulant use, is currently unclear.

In the general population, LV hypertrophy is associated with hypertension and associated factors like older age and obesity. It also predicts future cardiovascular events, which stresses the importance of modifiable risks in the context of structural cardiac abnormalities in people with HIV. Investigating stimulant use as a potential central CVD risk factor in future larger studies among WWH may help refine results presented here. In the meantime, our findings of cocaine use and hypertrophy in WWH suggest the importance of strategies to address substance use as a means to reduce cardiovascular risk in WWH. Our finding that no women were using statins also points to another modifiable but currently untapped area of prevention, which is gaining traction with the recent REPRIEVE study. Initial REPRIEVE findings suggest that daily statin use leads to a 30% mortality reduction in PWH.¹⁸ However, it is notable that the vast majority of REPRIEVE study participants should have been prescribed statins, even under the current more restrictive guidelines. Results from the REPRIVE study and the current study suggest that more attention to statin use may reduce negative cardiovascular outcomes in PWH.

Findings presented here are based on a small sample, resulting in large confidence intervals. In addition, they are specific to women with a history of housing instability, and prior research suggests a higher risk of stimulant use in women who experience homelessness and unstable housing.¹⁹ Nevertheless, they provide initial evidence suggesting that cocaine use is associated with structural cardiovascular sequelae which are associated with clinical events in the general population, implying a larger role for cocaine in risk assessment and prevention of cardiac events among WWH who experience homelessness and unstable housing. Also, in a setting where multiple substance use is common, our results motivate additional research to investigate whether cannabis use mitigates the impact of cocaine on structural heart disease in WWH.