Echocardiographic and Impedance Cardiography Analysis of Left Ventricular Diastolic Function in Acromegaly Patients

Introduction

Acromegaly (AC) is a rare endocrine disease characterized by the excessive secretion of growth hormone (GH). The most common cause is a pituitary neuroendocrine tumor derived from somatotropic cells, which arise from a somatic point mutation of the α-subunit of the Gs protein. This results in the manifestation of symptoms indicative of the continuous activation of the growth hormone-releasing hormone (GHRH) receptor, coupled with an increased proliferation of somatotropic cells [1–3]. The disease has a prevalence of approximately 4600 cases per million population, with an estimated 116.9 new cases per million population diagnosed annually [4]. The diagnosis of acromegaly (AC) is based on the presence of characteristic clinical symptoms, elevated levels of growth hormone (GH) and insulin-like growth factor 1 (IGF-1) hormones, and magnetic resonance imaging of the pituitary gland [3,5]. The long-term effects of elevated GH and IGF-1 levels on the cardiovascular system are significant, resulting in hemodynamic dysfunction of the heart and blood vessels [1,6,7]. Consequently, patients with AC may develop acromegalic cardiomyopathy. The initial stage is typified by a hyperkinetic heart, whereas the intermediate stage is defined by cardiac biventricular hypertrophy, which involves the proliferation of myocardial fibrous tissue. This results in progressive interstitial remodeling and a decline in the heart’s diastolic and systolic function. The final stage is characterized by significant cardiac enlargement, severe systolic and diastolic dysfunction, and elevated peripheral vascular resistance, which ultimately result in congestive heart failure [7,8].

At an early stage of active AC, patients may develop left ventricular diastolic dysfunction (LVDD) and the associated arterial stiffness, which can lead to hemodynamic disorders and progressive deterioration of left ventricular (LV) function [6,9–12]. Establishing the diagnosis of asymptomatic LV dysfunction in patients with AC is crucial for reducing adverse cardiovascular events [7]. Long-term exposure to excessive levels of both the anabolic GH and IGF-1 and to autonomic nervous system activity leads to progressive impairment of vascular compliance [3,13,14]. This has adverse effects on LV hemodynamic function, resulting in impaired ventricular-arterial coupling and a gradual deterioration of LV pumping capacity [15–17]. At the time of their diagnosis, most patients with AC have a normal LV ejection fraction (LVEF) assessed on routine echocardiography [11,18]. However, a thorough echocardiographic assessment of LV diastolic function parameters may reveal subclinical LVDD already at an early stage of AC [10,6,12,19,20]. Progression of asymptomatic LVDD to symptomatic diastolic heart failure is often detected with a delay, which is associated with a poorer prognosis [9,21].

Identifying patients with AC and a high cardiovascular risk poses a considerable clinical challenge [7,13]. The pathophysiology of LVDD and the associated arterial stiffness in patients with AC is complex [6,10]. A better understanding of LVDD-associated hemodynamic disorders may cast more light on the pathophysiology of cardiovascular complications in patients with AC, which would mean more effective prevention measures and earlier treatment. Introduction of more personalized treatment may be facilitated by searching for noninvasive diagnostic tools that would be a simple way of obtaining valuable data of therapeutic relevance at an early stage of the disease. Impedance cardiography (ICG) as a noninvasive method of assessing the hemodynamic profile seems to be capable of providing valuable information on LV functional capacity and arterial compliance, which was already demonstrated in earlier studies in patients with and without cardiovascular disease [22–24]. Preliminary data also demonstrated the effectiveness of ICG in clinical assessments of patients with active AC [14,17].

Therefore, this study aimed to evaluate the echocardiographic parameters of left ventricular diastolic function and impedance cardiography parameters of cardiovascular hemodynamics in 33 patients with AC.

Material and Methods

STUDY POPULATION:

After being approved by the ethics committee of the Military Institute of Medicine (Approval No. 76/WIM/2016), the study was conducted in accordance with the principles of Good Clinical Practice (GCP) and the Declaration of Helsinki. All subjects signed an informed consent form.

In this paper we present secondary analysis of the study.

In this observational cohort study, conducted at the Military Institute of Medicine – National Research Institute in Warsaw, we prospectively enrolled 33 adult patients of both sexes who had not undergone endocrinological or neurosurgical treatment, newly diagnosed with active AC (18 males; mean age 47 years; male to female ratio: 1.2, controlled hypertension in 54.5% of patients, mean blood pressure [BP] of 121/77 mmHg), with no clinically significant comorbidities. Table 1 shows study population characteristics.

STUDY DESIGN:

The diagnosis of AC was established based on the clinical presentation, blood hormone levels, and imaging study findings, as specified in the current guidelines of the European Society of Endocrinology (ESE) [25,26]. The clinical assessment focused on typical somatic manifestations of AC and their duration. The laboratory tests focused on typical abnormalities detected in AC, such as elevated GH and IGF-1 levels and a lack of GH suppression 2 hours after a 75 g oral glucose tolerance test (2h OGTT). The blood samples were analyzed for GH and IGF-1 by chemiluminescence immunoassay using the COBAS 6000 E601 analyzer (Roche Diagnostics, Switzerland). Concentrations of growth hormone (GH) and insulin-like growth factor 1 (IGF-1) exceeding the reference range for sex and age were deemed to be abnormal. A lack of inhibition of GH secretion after 2 hours in a 75 g oral glucose tolerance test was deemed to be abnormal if the GH concentrations determined by immunochemistry did not fall below 46 pmol/l (1.0 μg/l), with a final adjustment for sex, body mass index (BMI), and use of oral hormonal contraception.

The patients underwent a comprehensive functional assessment of the pituitary gland, which included adrenocorticotropic hormone (ACTH), thyroid-stimulating hormone (TSH), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) assessments. Additional diagnostic investigations included magnetic resonance imaging (MRI) of the pituitary gland, which revealed a pituitary neuroendocrine tumor in each patient [25,26].

Study exclusion criteria included conditions that adversely affect LV hemodynamic function, such as: 1) heart failure with mid-range or reduced ejection fraction (LVEF <50%); 2) clinically significant valvular disease; 3) a history of acute or chronic coronary syndrome; 4) a history of pulmonary embolism; 5) a history of a stroke or transient ischemic attack; 6) acute kidney injury or chronic kidney disease (estimated glomerular filtration rate of less than 60 mL/min 1.73 m²); 7) peripheral vascular disease; 8) chronic obstructive pulmonary disease; 9) acute or chronic respiratory failure; 10) pregnancy; 11) lack of an informed consent; 12) age under 18 years; and 13) a poor acoustic window on echocardiography.

CLINICAL DATA AND BLOOD CHEMISTRY:

Clinical data included a history of cardiovascular symptoms, concomitant diseases, family history positive for cardiovascular disease, and smoking status. The following parameters were measured/calculated: body mass index (BMI), heart rate (HR), and a standard office (BP) measurement based on European Society of Cardiology (ESC) guidelines, including systolic and diastolic BP (SBP and DBP) with the use of an automated sphygmomanometer (Omron M4 Plus, Japan) [27]. Body mass index (BMI) was calculated according to the formula weight (kg) divided by height squared (m2). Hypertension was defined as a systolic blood pressure of 140 mmHg or greater and/or a diastolic blood pressure of 90 mmHg or greater, or the receipt of treatment for previously diagnosed hypertension [27].

Laboratory tests included assessments of renal function (estimated glomerular filtration rate based on the MDRD formula), carbohydrate metabolism disorders (impaired fasting glucose; impaired glucose tolerance; type 2 diabetes mellitus [T2DM]), and lipid metabolism disorders (total cholesterol, low-density lipoprotein [LDL] cholesterol, high-density lipoprotein [HDL] cholesterol, and triglyceride levels). Laboratory tests were conducted in the morning following a 12-hour fast. The blood samples were analyzed using the COBAS 6000 C 501 I E 601 analyzer (Roche Diagnostics, Switzerland). The Friedewald formula was employed to calculate the subject’s low-density lipoprotein cholesterol.

The evaluated patients with AC were not on any medications that could affect the hypothalamus–pituitary–adrenal axis or the associated hemodynamic profile parameters.

IMPEDANCE CARDIOGRAPHY:

Impedance cardiography is a contemporary, noninvasive methodology founded upon the principle of impedance (resistance) variation of body segments in relation to blood flow in major arterial vessels. The analysis of the electrical resistance of the chest enables the monitoring of hemodynamic parameters. During the examination, changes in voltage are analyzed in relation to changes in blood volume and velocity in large vessels during systole and diastole. A notable benefit of this approach is the capacity to calculate parameters such as stroke volume and cardiac output, which can be valuable in the diagnostic process [28]. This method is clinically useful for the assessment of cardiac hemodynamics, arterial compliance, and chest fluid content in patients with hypertension, coronary heart disease, and heart failure [22–24]. Furthermore, ICG has been demonstrated to be a valuable tool in evaluation of patients with newly diagnosed active AC [14,17].

On admission, all subjects newly diagnosed with AC that were included in this study underwent an ICG examination with a Niccomo device (Medis, Ilmenau, Germany) after 10 minutes of resting in a supine position. The examination was conducted by a qualified nurse with expertise in impedance cardiography. The data recorded during the 10-minute assessment were exported into Niccomo software. ICG is a useful, repeatable, and – most importantly – noninvasive diagnostic technique for patients with heart failure and hypertension. Moreover, according to recent reports, ICG may be also useful in patients with pituitary neuroendocrine tumors. Based on the data obtained via ICG, we analyzed HR, SBP, and DBP measurements; we also analyzed the hemodynamic profile of each patient: 1) parameters of the heart’s function as a pump: stroke volume (SV [ml]) and stroke volume index (SI [ml/m2]); cardiac output (CO [ml/min]) and CO index (CI [ml×m−2×min−1]); velocity index (VI [1000×Z0×s−1]: VI=1000×dZmax×Z0−1), which reflects the maximum LV outflow velocity; acceleration index (ACI [100×Z0×s2]: ACI=100×dZmax×dt−1), which reflects the maximum acceleration of blood flow in the aorta; Heather index (HI [Ohm×s2]: HI=dZmax×TRC), which reflects the maximum LV contraction force; 2) LV afterload parameters: systemic vascular resistance (SVR [dyn×s×cm−5], SVR index (SVRI [dyn×s×cm−5×m2]), and total arterial compliance index (TACI); and 3) preload parameters: thoracic fluid content (TFC). Considering the PREDICT study findings, we stratified the high-risk patients based on the cutoff values of SI <35 ml/m2 and TFC >35 1·kΩ-1 [29–31].

ECHOCARDIOGRAPHIC EXAMINATION:

On admission, all subjects newly diagnosed with AC underwent a two-dimensional echocardiographic examination with standard substernal and apical views, in accordance with American Society of Echocardiography and European Association of Cardiovascular Imaging (EACVI) guidelines, with a 4.6 MHz transducer (VIVID E 95 GE Medical System, Wauwatosa, WI, USA) [32]. The imaging measurements were obtained by a highly qualified cardiologist in the echocardiography laboratory, which has the highest C reference level in Poland. The following parameters were assessed: the LV end-diastolic diameter (LVDd) and right ventricular end-diastolic diameter (RVDd) measured in the parasternal long axis (PLAX), left atrial (LA) end-diastolic diameter measured in the parasternal long axis (PLAX), LA volume (LAV) measured in the 4-chamber axis, LAV index (LAVI) assessed using the biplane disk summation technique from apical 4-chamber and 2-chamber views, LV wall thickness in a parasternal long-axis view, left ventricular mass (LVM), and LVM indexed to body surface area (LVMI). To determine LV hypertrophy, LVM was indexed to body surface area (BSA) calculated using the DuBois formula. The thickness of the interventricular septal and inferolateral walls was obtained from the PLAX. To quantitatively assess LV function, we measured LV end-diastolic diameter measured in the PLAX and LV ejection fraction (LVEF) calculated using Simpson’s biplane method in the apical 2- and 4-chamber views [32].

The following mitral blood flow parameters were measured in the apical 4-chamber view by positioning the pulsed-wave Doppler gate in the left ventricle between the mitral leaflet tips: the E wave, which is the peak early diastolic velocity; the A wave, which is the peak velocity of blood flow generated by atrial contraction; and the E/A ratio (E/A). Tissue Doppler in the apical 4-chamber view was used to measure mitral annular early diastolic velocity by placing the Doppler gate at the level of septal (e‘sep) and lateral (e‘lat) parts of the mitral annulus. Based on these measured parameters, we obtained the averaged (septal and lateral) value (e‘ avg) and estimated the E/e’ ratio. In accordance with current ASE/EACVI recommendations for assessing LV diastolic function, we used E, A, e‘sep, e‘lat, LAVI, and peak velocity of tricuspid regurgitation (TRVmax), depending on LVEF [33].

STATISTICAL ANALYSIS:

Statistical analysis and electronic archiving were done with MS Office and Statistica 12.0 (StatSoft Inc., Tulsa, USA). The data were carefully checked by visual inspection to identify any errors and extreme values. The distribution of continuous variables was assessed visually and with the Shapiro-Wilk test. The results are presented as means±standard deviation (SD), medians, and interquartile ranges for continuous variables, and as absolute values (n) and percentages (%) for qualitative variables. Pearson’s correlation coefficient and Spearman’s rank correlation coefficient (depending on variable distribution) were used to analyze the relationship between selected parameters of cardiovascular structure and function. Heart rate, blood pressure, and ICG-derived hemodynamic parameters (ACI, CI, HI, SI, VI, SVRI, TACI, TFC) were correlated with echocardiographic indices related to left ventricular diastolic function (E/A, E/e’, e‘ avg, e‘ lat, e‘sept) and with echocardiographic indices of left atrial (LAa, LAVI). The level of statistical significance was P<0.05.

Results

BASELINE CHARACTERISTICS:

The demographic, clinical, and laboratory data of the study population are presented in Table 1, whereas detailed echocardiographic and hemodynamic parameters assessed via ICG in patients with AC are presented in Table 2 and in our previous papers (Figures 1, 2) [14,17,34].

The mean age of the 33 subjects (including 18 males, male to female ratio: 1.2) was 47±13 years. Seventy-eight percent of subjects had abnormal body weight (the mean BMI was 27.8 kg/m²), with 9 obese patients (27.3%) and 17 overweight patients (51.5%). The mean BP was 121/77 mmHg (94% of patients had BP <140/90 mmHg). Eighteen (54.5%) of the patients with AC had been diagnosed with hypertension; however, in each case it was well controlled, usually with 1 or 2 antihypertensive medications. A small number of patients had been diagnosed with carbohydrate metabolism disorders (T2DM in 6 patients [18.2%], prediabetes in 10 patients [30.3%], and lipid metabolism disorders (dyslipidemia in 3 patients [9.1%]). No subjects had renal dysfunction (the mean creatinine level was 0.76±0.19 mg/dl). Eight patients had been diagnosed with TSH deficiency; however, this was well controlled with a stable dose of L-thyroxin. Thirty-one out of the 33 patients had a preserved anterior pituitary function. All patients with AC had a normal LVEF of 63%, assessed via Simpson’s method.

LEFT ATRIAL SIZE: A larger LA size in the study population was associated with lower VI (P=0.02), ACI (P=0.002), and HI (P=0.01). A larger LA area was associated with lower VI (P=0.04), ACI (P=0.004), and HI (P=0.003). There was no significant association between the LA area and LAVI (Table 3).

LV DIASTOLIC FUNCTION:

Fifteen patients (45%) were diagnosed with LVDD.

In the evaluated population of patients with AC: 1) a lower E/A ratio was associated with higher DBP (P=0.01), mean BP (MBP; P=0.03), and SVRI (P<0.001), and with lower SI (P<0.001), CI (P=0.007), VI (P=0.04), ACI (P=0.02), and TACI (P=0.004); 2) lower e‘sept was associated with lower SI (P=0.004), CI (P=0.03), and ACI (P=0.047) and with a higher SVRI (P=0.006); 3) lower e‘lat was associated with a lower SI (P=0.046); 4) a lower e‘avg was associated with lower SI (P=0.01) and CI (P=0.048) and with a higher SVRI (P=0.03); 5) a lower E/e’ ratio was associated with higher SBP (P=0.02) and TFC (P=0.03) (Table 4).

Discussion

CLINICAL IMPLICATIONS:

A hemodynamic balance between the left ventricle and the vascular system is of crucial clinical significance in patients with AC. Early detection of cardiovascular hemodynamic disorders in patients with AC may prevent symptomatic cardiac dysfunction. ICG can provide valuable, complementary data for therapeutic decision making in patients at an early stage of AC who are diagnosed with LVDD. Personalized treatment in patients with active AC can ensure better outcomes by improving the pumping function of the heart and reducing LV preload and afterload. The diagnostic potential of ICG in detecting subclinical abnormalities in the hemodynamic profile in patients with LVDD and in selecting appropriate medical treatment seems to be promising, although this requires further prospective studies.

STUDY LIMITATIONS:

One limitation of our study was its small sample size, which was due to the low prevalence of hormone-secreting pituitary tumors and the strict exclusion criteria, to obtain a population with no clinically significant comorbidities (ie, mostly young or middle-aged individuals with AC and no concomitant cardiovascular disease). For this reason, our findings should not be freely extrapolated onto the general population of patients with AC. Our study protocol did not include diagnostic assessments intended to exclude asymptomatic chronic coronary syndrome. Nonetheless, there was no evidence of myocardial ischemia in the evaluated group (no typical clinical manifestations, no impairment in LV wall contractility, normal electrocardiographic tracings).

It should be noted that this method also has certain limitations. The diagnostic value of impedance cardiography is questionable in the following clinical situations: tachycardia exceeding 250 beats per minute, significant arrhythmias, severe aortic regurgitation, extremely high blood pressure, intra-aortic counterpulsation, severe septic shock, post-sternotomy condition, very short or tall stature, severe obesity, and severe malnutrition. Furthermore, the quality of the measurement is contingent upon the quality of the skin preparation and the presence of movement artefacts.

Also, the normal values for some of the analyzed ICG parameters (ACI, VI, HI) were not definitively established and their interpretation was based on our previous analysis including controls [17]. Echocardiography is subject to a number of limitations, including the potential for variability between vendors, the dependence on operator experience, the necessity for optimal image quality, the impact of frame rate, loading conditions, and external mechanical factors such as chest wall structure.

Conclusions

Impaired LV diastolic function in AC is associated with impaired pumping function of the heart and higher afterload as assessed on ICG. ICG can be useful in detecting impaired LV function as a pump and assessing LVDD-related increase in arterial stiffness in young and middle-aged patients with AC.