ACRT Journal

Introduction

Long lasting alcohol intake has been progressively recognized as a leading cause of non-ischemic dilated cardiomyopathy, affecting near 10% of all alcoholic people [1]. Nowadays chronic alcohol intake and abuse are more and more frequently associated with the assumption of other drugs such as cannabinoids, cocaine and others, and undoubtedly these associations may amplify the cardiac damage [2]. While Left ventricular (LV) dilatation, together with severely impaired systolic function and increased LV mass, represent the symptomatic end-stage of the disease, a great number of subjects are asymptomatic for a long time and in these patients, it is of huge importance to succeed in identifying earlier markers of cardiac impairment in order to stop the intake of harmful substances and to undertake the appropriate therapeutic strategies thus improving prognosis [2-4]. Due to the fact that Echocardiography represents the most widely-available and easy to perform non-invasive diagnostic test to evaluate cardiac function this study was undertaken to determine which echocardiographic parameters, either derived from traditional echocardiographic exam or derived from the newest echocardiographic approach based on strain analysis, allow to predict better LV dysfunction even in subclinical stages in asymptomatic subjects who take alcohol plus other drugs.

Alcohol plus other drugs

It has been demonstrated that long-lasting alcohol intake is associated with important effects on cardiovascular system. Chronic abuse of alcohol is often associated with abuse of other substances including Cannabinoids. In this regard various studies conducted both on animal models [5-6] and on humans [7-8] have shown that cannabinoids exert many cardiovascular effects through the interaction with CB1 receptors which are located in the myocardium, aorta, vascular endothelium, in platelets, central and peripheral nervous system. Main cardiovascular effects of cannabinoids could be summarized as enhanced sympathetic tone, increased catecholamine levels and increased heart rate at lower doses, and bradycardia/hypotension at higher doses due to parasympathetic stimulation occurring at these doses [9]. Other cardiovascular effects which may be identified are platelet activation, endothelial dysfunction and oxidative stress [10].

In addition, smoking marijuana may cause an increase in the amount of carboxyhemoglobin due to combustion, so causing an additional decrease in oxygen supply [11]. Furthermore, multiple case reports have linked marijuana use to procoagulant effect so causing thrombus formation leading to acute myocardial infarction in young adults [12-13]. On the other hand, in many reported cases of cannabis induced AMI coronary angiography showed clean coronaries and documentation of coronary spasm [14].

Although the evidence is weaker, there are also links to a higher risk of atrial fibrillation or ischemic stroke immediately following marijuana use [15-16].

Alcohol intake may be also associated to the assumption of cocaine which presents important cardiovascular effects [17]. Long-term cocaine use, as well as acute cocaine use, is associated with adverse cardiovascular consequences, including arrhythmias, angina, myocardial infarction, heart failure, and other conditions [18]. Over the long term, cocaine can result in structural changes to the heart such as increased left- ventricular mass and decreased left-ventricular end-diastolic volume. Cocaine, ecstasy, and amphetamines share similar adverse effects on the cardiovascular system, related predominantly to activation of the sympathetic nervous system [19].

Finally, Morphine and its semisynthetic analogue heroin may cause cardiovascular damage by determining the occurrence of various bradyarrhythmia’s and tachyarrhythmias [20]. Their main effects are due to the fact that they act centrally to increase parasympathetic and reduce sympathetic activity, resulting in bradycardia and hypotension. On the other side the intake of hallucinogens lysergic acid (LSD) and psichedelics is instead characterized by both sympathomimetic effects and serotonergic hyperactivity thus determining the occurrence of supraventricular tachiarrhythmias and of acute coronary syndromes and pulmary hypertension [21].

Echocardiography

As we have already underlined in the introduction a cardiomyopathy characterized from the echocardiographic point of view by Left ventricular (LV) dilatation, together with severely impaired systolic function and increased LV mass, represents the symptomatic end-stage of the disease which may occur in subjects assuming alcohol and other drugs. Echocardiographic evaluation of left ventricular ejection fraction (LVEF), in addition to the evaluation of the volumes, of the thicknesses of the cardiac chambers, of the morphology and functionality of the valve systems and of the estimation of pressures provides important information regarding myocardial function. In particular LVEF offers important information regarding both myocardial function and prognosis. However, this parameter presents various limitations; LVEF may influenced by hemodynamic load, by geometric assumptions and image quality and it does not reflect myocardial contractility, and in particular it does not allow early detection of myocardial dysfunction [22]. In this regard an important aid may be offered by the evaluation of diastolic function since alterations in LV diastolic function are considered markers of early cardiotoxicity and precede alterations in systolic function [23]. To assess diastolic function Pulsed-wave Doppler mitral velocity curves must be obtained.

Accordingly, to the definition proposed by the European Association of Cardiovascular Imaging [24], in normal conditions, the majority of filling pressures occur during the early LV diastolic phase, then during atrial systole (the ratio between E and A velocities is greater than 1. In case of early reduction of myocardial relaxation (grade I of diastolic dysfunction), the early transmittal pressure gradient is reduced, and increased portion of diastolic filling pressure due to atrial contraction takes place. So, the E/A ratio is less than 1, together with a longer deceleration time (DT) of mitral inflow (normal ranges between 160–240 ms), because of a longer time to equilibrate left-sided chamber pressures. Along with the progression of worsening diastolic dysfunction (grade II of diastolic dysfunction), LA pressure increases with consequent LA sizes enlargement; the rise of early LV diastolic filling pressure is steeper, so the mitral inflow pattern of moderate diastolic dysfunction seems to be similar to that of the true normal diastolic filling pattern of E/A greater than 1 with DT equal or greater than 160 ms (leading to a pseudo-normalized pattern). In case of grade III of diastolic dysfunction (restrictive diastolic dysfunction), early LV diastolic filling is predominant, with a faster rise in filling pressures and very short DT (E/A > 1.5 and DT < 160 ms) [23]. Diastolic function evaluation may be improved recurring to Tissue doppler which has additionally the advantage to be load independent (while the assessment of Pulsed- wave Doppler mitral velocity curves is load-dependent) [25]. Furthermore, through integrated use of echo-Doppler and tissue Doppler imaging (TDI), it is possible to obtain a comprehensive evaluation of both left ventricular (LV) diastolic and longitudinal function indeed the combination of standard Doppler mitral inflow peak early (E) velocity with TDI annular early (e′) velocity (E/e′) is useful to noninvasively estimate the degree of LV filling pressure (LVFP). By averaging e′ velocity of septal and lateral mitral annulus, an E/e′ ≥ 13 accurately predicts elevated LVFP as a result of advanced LVDD [26].

Thus, in asymptomatic subjects, by recurring to the evaluation of these parameters, during standard basal echocardiography, earlier markers of cardiac dysfunction may be detected. A further aid in the evaluation of myocardial function may be given by the newest echocardiographic technique such as strain analysis.

Speckle tracking echocardiography (STE), through the measurement of strain and strain rate, which detect myocardial deformation, allows an even earlier identification of myocardial dysfunction [27]. STE is particularly useful in all conditions in which cardiac dysfunction is not still overt, but a subclinical involvement is undoubtedly present such as in presence of cardiovascular risk factors, in the early stages of chemotherapy induced cardiotoxicity, in asymptomatic subjects with chronic kidney disease [28].

In particular Global longitudinal strain (GLS) represents s probably the most frequent type of strain used to characterize LV systolic function in clinical practice [27]. It is the negative ratio of the maximal change in LV longitudinal length in systole to the original length as assessed by speckle tracking echocardiography. For what regards its prognostic role, previous studies have demonstrated that it proved to be superior to standard LV ejection fraction (EF) in predicting cardiac events and all-cause mortality in the general population [29, 30].

Accordingly, our investigation sought to assess which echocardiographic parameters derived from both standard basal echocardiography and strain analysis could allow to predict cardiac dysfunction in a subset population of chronic, asymptomatic subjects who take alcohol plus other drugs, with no known cardiovascular disease and no comorbidity known to affect cardiovascular function.

Methods

A total of 26 consecutive asymptomatic subjects assuming alcohol and other drugs were enrolled from the Unit of Addiction and Hepatology, Alcohological Regional Centre of our Policlinic. Among the patients, 12 (46%) were suffering from hypertension and all of them were on anti-hypertensive therapy, one patient was previously studied by echography for positive blood cultures without finding any significant alteration. Exclusion criteria were: known coronary arterial disease, severe valve disease, surgical correction of valve diseases, atrial fibrillation, congenital heart disease, chronic renal and liver dysfunction. After a complete physical examination, demographic data and anthropometric measurements of height and weight were provided, in order to calculate the body mass index (BMI, kg/m2) and body surface area (BSA, m2). Details of alcohol and other drugs consumption were obtained from the predefined questionnaires, involving information regarding the pattern, frequency and amount of daily intake of alcohol plus other drugs. Based on the assumption that one standard drink contains 12 g alcohol, the conversion of total alcohol consumption into number of standard drinks on a daily basis was then derived. Conventional transthoracic echocardiography was uniformly performed by an ultrasound device GE- Vingmed vivid 7system (GE-Vingmed Ultrasound AS, Horten, Norway), equipped with a 2-to 4-MHz transducer. The standard echocardiographic imaging protocol included measurements of LV end-diastolic and end-systolic diameters, wall thickness, LV mass (per European Association of Cardiovascular Imaging criteria), left atrial (LA) and LV volumes (using the biplane Simpson method for volume calculation), right ventricular basal and middle diameter. Complete pulsed-wave (PW) Doppler derived mitral inflow echocardiographic parameters of LV diastolic function included the early (E) and late (A) diastolic filling velocities at the tip of the mitral leaflets from the apical four-chamber view, DT of early filling velocity and isovolumetric relaxation time (IVRT), corresponding to the time from aortic valve closure to onset of mitral inflow. The ratio between peak systolic (S) and diastolic (D) flow velocity was obtained by PW Doppler interrogation of pulmonary venous flow from the apical four-chamber view. Furthermore, Doppler tissue imaging-based mitral annular relaxation velocity (e’) was assessed at the lateral mitral annulus using spectral Doppler techniques with LV filling pressure estimated using the E/e’ ratio. Tricuspid annular plane systolic excursion (TAPSE) was measured by pointing the motionmode (M-mode) cursor on the tricuspid lateral annulus in the apical 4-chamber view, as the height difference of the valve annulus excursion (in millimetres). The peak tricuspid regurgitation (TR) gradient was calculated by the simplified Bernoulli equation on the basis of the peak TR velocity, by using the continuous-wave Doppler of the TR trace in apical 4-chamber view. Right atrial pressure (RAP) was estimated by the basal diameter of inferior vena cava and its respiratory excursions. Systolic pulmonary artery pressure (sPAP) was calculated by adding the TR peak systolic gradient to the RAP estimate Finally Speckle tracking analysis was executed.

Speckled tracking echocardiography was performed on three consecutive cardiac cycles of two-dimensional LV images from the three standard apical views. Custom acoustic tracking software allowing semi-automated, two-dimensionally derived strain analysis (Echo PAC Advanced Analysis Technologies; GE Healthcare) was applied to two-dimensional grayscale images by tracking movements of “speckles” in myocardial tissue, frame by frame, throughout the cardiac cycle. The software automatically divides each image into six myocardial segments and accepts segments of good tracking quality while rejecting poorly tracked segments, allowing the observer to manually override its decision at the same time using visual assessment. The peak negative systolic longitudinal strain was assessed from six segments in apical long- axis, four-chamber, and two-chamber view. GLS was calculated by averaging each value of regional peak longitudinal strain obtained in each apical view before aortic valve closure, which was defined in the apical long-axis view. Longitudinal strain was calculated by average of six basal, six middle, and six apical LV segments.

Peak systolic dispersion (PSD) was estimated directly by the machine, by comparing the difference between the earliest systolic peak and the latest amongst all the segments. Less negative values reflect progressive impairment in GLS and therefore in LV systolic function.

Statistical analyses

Continuous variables distribution was checked for normality using the Shapiro- Wilkinson test, and reported accordingly as mean ± standard deviation or median (quartile 1 – quartile 3). Categorical variables were reported as count and percentage. Univariate association between global longitudinal strain and echocardiographic variables was tested using Spearman’s correlation. Two-tailed p values <0.05 were considered statistically significant. Statistical analysis was conducted using R (R Foundation for Statistical Computing).

Results

Between march and august 2022, twenty-six patients were enrolled. Table 1 summarizes the main baseline characteristics of the enrolled population. 73% were male and mean age was 43±11 years. Most patients were male (73%), smokers, with an average consumption of 1 (0.81-1.88) pack/die, and the totality were alcoholics. Among the patients, 12 (46%) were suffering from hypertension and all of them were on anti-hypertensive therapy, psychotropic drugs were assumed by almost 31%. Up to 1/3rd of patients were multi-drug users, with an average consumption of

1.50±0.91 drugs, in particular, half of the population took cocaine and marijuana, whereas roughly 12% used heroin, methadone or hashish.

Echocardiographic features are summarized in Table 2. Mean ejection fraction was 57% (53%–63%), with regional wall motion abnormalities being reported in only one patient, sent for further evaluations. Valvopathies were reported in a minority of individuals, of whom 11.5% had aortic regurgitation and 15.4% mitral regurgitation both trivial. Mean average global longitudinal strain value was -18.3% (-%17 – - 20,1%). Mean E/A was 1.1 (0.91.2) and mean e/e’ average 6.7 (6.2-7.2). Right ventricular function estimated by TAPSE ad S’ wave evaluation was preserved.

Scatter plots depicting the correlations between average global longitudinal strain and echocardiographic parameters are shown in the Figure 1(correlation between average GLS and E/A and e/e’, DTD, systolic PAP). In particular, we found a modest, yet significant correlation between average GLS and E/A (Spearman’s r = 0.43, p = 0.03), whereas other parameters did not correlate significantly with GLS.

Table 1: Baseline features.

Table 2: Echocardiographic features