CardioNerds (Drs. Amit Goyal and Dan Ambinder) join Dr. Emily Lee (LAC+USC Internal medicine resident) and Dr. Charlie Lin (LAC+USC Cardiology fellow) as the discuss an important case of stimulant-related (methamphetamine) cardiovascular toxicity that manifested in right ventricular dysfunction due to severe pulmonary hypertension. Dr. Jonathan Davis (Director, Heart Failure Program at Zuckerberg San Francisco General Hospital and Trauma Center) provides the ECPR for this episide. Audio editing by CardioNerds Academy Intern, student doctor Akiva Rosenzveig.

With the ongoing methamphetamine epidemic, the incidence of stimulant-related cardiovascular toxicity continues to grow. We discuss the following case: A 36-year-old man was hospitalized for evaluation of dyspnea and volume overload in the setting of previously untreated, provoked deep venous thrombosis. Transthoracic echocardiogram revealed severe right ventricular dysfunction as well as signs of pressure and volume overload. Computed tomography demonstrated a prominent main pulmonary artery and ruled out pulmonary embolism. Right heart catheterization confirmed the presence of pre-capillary pulmonary arterial hypertension without demonstrable vasoreactivity. He was prescribed sildenafil to begin management of methamphetamine-associated cardiomyopathy and right ventricular dysfunction manifesting as severe pre-capillary pulmonary hypertension.

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Case Media – stimulant-related (methamphetamine) cardiovascular toxicity

Pearls – stimulant-related (methamphetamine) cardiovascular toxicity

1. Methamphetamine, and stimulants in general, can have a multitude of effects on the cardiovascular and pulmonary systems. Effects of methamphetamine are thought to be due to catecholamine toxicity with direct effects on cardiac and vascular tissues. Acutely, methamphetamine can cause vascular constriction and vasospasm, while chronic exposure is associated with endothelial damage. Over time, methamphetamine can cause pulmonary hypertension, atherosclerosis, cardiac arrhythmias, and dilated cardiomyopathy.

2. Methamphetamines are the second most commonly misused substances worldwide after opiates. Patients with methamphetamine-associated pulmonary arterial hypertension (PAH) have more severe pulmonary vascular disease, more dilated and dysfunctional right ventricles, and worse prognoses when compared to patients with idiopathic PAH. Additionally, patients with methamphetamine-associated cardiomyopathy and PAH have significantly worse outcomes and prognoses when compared to those with structurally normal hearts without evidence of PAH. Management includes multidisciplinary support, complete cessation of methamphetamine use, and guideline-directed treatment of PAH.

3. The diagnosis of pulmonary hypertension (PH) begins with the history and physical, followed by confirmatory testing using echocardiography and invasive hemodynamics (right heart catheterization). Initial serological evaluation may include routine biochemical, hematologic, endocrine, hepatic, and infectious testing. Though PH is traditionally diagnosed and confirmed in a two-step, echocardiogram-followed-by-catheterization model, other diagnostics often include electrocardiography, blood gas analysis, spirometry, ventilation/perfusion assessment, CT scans, MRIs, and/or genetic testing to evaluate for the myriad of etiologies that may contribute to the development of PH.

4. PH is characterized by remodeling of the pulmonary vasculature and a progressive increase of pulmonary vascular load, often resulting in right ventricular hypertrophy, remodeling, and dysfunction. PH is defined hemodynamically by a mean pulmonary arterial pressure ≥ 20 mmHg at rest when measured by right heart catheterization (RHC). Pre-capillary pulmonary hypertension due to pulmonary vascular disease is further defined by an elevation in pulmonary vascular resistance (PVR) of at least 3 wood units (WU).

5. Medications used to treat pulmonary arterial hypertension fall into four general mechanistic classes: calcium channel blockers, endothelin receptor antagonists, phosphodiesterase-5 inhibitors, and prostacyclin receptor agonists.

Show Notes – stimulant-related (methamphetamine) cardiovascular toxicity

Pulmonary Arterial Hypertension - CardioNerds

How is pulmonary hypertension diagnosed with right heart catheterization (RHC)?

Pulmonary hypertension is defined by mean pulmonary arterial pressure (mPAP) ≥ 20 mmHg at rest. Pulmonary hypertension has three hemodynamic phenotypes – pre-capillary PH, post-capillary PH, and combined pre-/post-capillary PH. Isolated pre-capillary PH is defined by pulmonary vascular resistance (PVR) ≥ 3 woods units and pulmonary artery wedge pressure (PAWP) ≤ 15 mmHg. Isolated post-capillary PH is defined by PVR < 3 woods units and PAWP > 15 mmHg. PVR is calculated by dividing the mean trans-pulmonary gradient (= PAWP – mPAP) by the cardiac output.

	Characteristics	Clinical groups
Isolated pre-capillary PH	mPAP >20 mmHg PAWP ≤ 15 mmHg PVR ≥ 3 WU	WHO 1,3,4, and 5
Isolated post-capillary PH	mPAP >20 mmHg PAWP > 15 mmHg PVR < 3 WU	WHO 2 and 5
Combined pre- & post-capillary PH	mPAP >20 mmHg PAWP > 15 mmHg PVR ≥ 3 WU	WHO 2 and 5

Classification of PAH by WHO Groups:

WHO Group 1 Pulmonary Arterial Hypertension	WHO Group 2 Pulmonary hypertension due to left sided heart disease	WHO Group 3 Pulmonary hypertension due to lung disease or hypoxia	WHO Group 4 Chronic thromboembolic pulmonary hypertension and other pulmonary artery obstructions	WHO Group 5 Pulmonary hypertension with multifactorial mechanisms
Idiopathic	Left ventricular systolic and/or diastolic dysfunction	Chronic obstructive pulmonary disease	Chronic thromboembolic pulmonary hypertension	Hematological Disease (Sickle cell disease)
Hereditary	Left-sided valvular heart disease	Interstitial lung disease	Obstruction of the pulmonary circulation by tumor or inflammation	Systemic disorders (Sarcoidosis, Langerhans cell granulomatosis)
Drug and toxin induced		Other mixed restrictive or obstructive lung disease		Metabolic disorders (Gaucher’s disease)
Associated with connective tissue disease		Sleep-disordered breathing
Associated with HIV infection		Alveolar hypoventilation disorders
Associated with portal hypertension		Chronic exposure to high altitude
Congenital heart disease
Schistosomiasis

What is vasoreactivity testing?

Pulmonary vasoreactivity testing is used to identify patients who may respond favorably to calcium channel blocker (CCB) treatment. Typically, this includes patients with idiopathic pulmonary arterial hypertension, heritable pulmonary arterial hypertension, or substance-related pulmonary arterial hypertension. It is usually performed at the time of RHC. Inhaled nitric oxide (NO) at 10–20 parts per million (ppm) is the standard of care for vasoreactivity testing with alternatives including intravenous adenosine and epoprostenol. A significant response to vasodilator therapy is defined by a reduction of the mean PAP by at least 10 mmHg and concurrent decrement of the absolute value to less than 40 mmHg, without a decrease in cardiac output. Vasoreactive PH should be treated with CCB therapies such as nifedipine, diltiazem, and amlodipine. Vasoreactivity is relatively rare, occurring in 10% or fewer individuals with PH who undergo testing. PH without vasoreactivity of significant response to CCB therapy should be managed with alternative class of medications (see below).

What is the medical treatment for PAH?

Medication treatment of pulmonary arterial hypertension comes in 4 general categories with the general mechanism is listed:

Calcium channel blockers (nifedipine, diltiazem and amlodipine used in high doses) – used in patients with positive vasoreactivity testing.
Endothelin receptor antagonists (ambrisentan, bosentan, macitentan) – inhibit binding of endothelin, a vasoconstrictive peptide, to its receptors on smooth muscle cells, which is enriched in pulmonary vasculature, resulting in vasodilation and subsequent decrease in pulmonary arterial pressure.
Phosphodiesterase 5 inhibitors and guanylate cyclase stimulators (sildenafil, tadalafil, riociguat) – ihibition of the cyclic guanosine monophosphate (cGMP) degrading enzyme phosphodiesterase type 5 results in vasodilation through the NO/cGMP pathway in the pulmonary vasculature, which contains substantial amounts of this enzyme.
Prostacyclin analogues and prostacyclin receptor agonists (epoprostenol, iloprost, treprostinil, beraprost) – prostacyclin is produced predominantly by endothelial cells and induces potent vasodilation of all vascular beds and patients with PAH have been shown to have a reduction of prostacyclin synthase expression in the pulmonary arteries.

References –

Ben-Yehuda O, Siecke N. Crystal Methamphetamine: A Drug and Cardiovascular Epidemic. JACC Heart Fail. Mar 2018;6(3):219-221. doi:10.1016/j.jchf.2018.01.004
Benza RL, Gomberg-Maitland M, Miller DP, et al. The REVEAL Registry risk score calculator in patients newly diagnosed with pulmonary arterial hypertension. Chest. Feb 2012;141(2):354-362. doi:10.1378/chest.11-0676
Benza RL, Gomberg-Maitland M, Elliott CG, et al. Predicting Survival in Patients With Pulmonary Arterial Hypertension: The REVEAL Risk Score Calculator 2.0 and Comparison With ESC/ERS-Based Risk Assessment Strategies. Chest. Aug 2019;156(2):323-337. doi:10.1016/j.chest.2019.02.004
Chin KM, Channick RN, Rubin LJ. Is methamphetamine use associated with idiopathic pulmonary arterial hypertension? Chest. Dec 2006;130(6):1657-63. doi:10.1378/chest.130.6.1657
Galiè N, Humbert M, Vachiery JL, et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Heart J. Jan 1 2016;37(1):67-119. doi:10.1093/eurheartj/ehv317
Hassoun PM. Pulmonary Arterial Hypertension. N Engl J Med. Dec 16 2021;385(25):2361-2376. doi:10.1056/NEJMra2000348
Hoeper MM, Humbert M, Souza R, et al. A global view of pulmonary hypertension. Lancet Respir Med. Apr 2016;4(4):306-22. doi:10.1016/s2213-2600(15)00543-3
Kevil CG, Goeders NE, Woolard MD, et al. Methamphetamine Use and Cardiovascular Disease. Arterioscler Thromb Vasc Biol. Sep 2019;39(9):1739-1746. doi:10.1161/atvbaha.119.312461
Reddy PKV, Ng TMH, Oh EE, Moady G, Elkayam U. Clinical Characteristics and Management of Methamphetamine-Associated Cardiomyopathy: State-of-the-Art Review. J Am Heart Assoc. Jun 2 2020;9(11):e016704. doi:10.1161/jaha.120.016704
Zhao SX, Kwong C, Swaminathan A, Gohil A, Crawford MH. Clinical Characteristics and Outcome of Methamphetamine-Associated Pulmonary Arterial Hypertension and Dilated Cardiomyopathy. JACC Heart Fail. Mar 2018;6(3):209-218. doi:10.1016/j.jchf.2017.10.006

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