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Video Presentation | DOI: https://doi.org/10.31579/2641-0419/044
1Faculty of Medicine, Tetovo Republic of North Macedonia.
2Department of Internal Medicine Faculty of Medicine, Tetovo Republic of North Macedonia.
3Department of Cardiology Faculty of Medicine"Ss Kiril and Metodij" University Skopje Republic of North Macedonia. 4Department of Cardiology Faculty of Medicine M. Teresa Tirana Republic of Albania.
5Department of Internal Medicine Faculty of Medicine, Tetovo Republic of North Macedonia.
6,7Department of Cardiology Medical Center Dures Republic of Albania.
8Private Health Institute of family medicine "Florenc "Tetovo Republic of North Macedonija.
9Department of Internal Medicine-General Hospital"DR Ferit Murat" Gostivar Republic of North Macedonia.
10Private Health Institute”Rostusha”Debar Republic of North Macedonia.
11Faculty of Medicine, Tetovo Republic of North Macedonia.
*Corresponding Author: Ylber Jani, Faculty of Medicine,Tetovo Republic of North Macedonia.
Citation: Jani Y., Rexhepi A., Pocesta B., Kamberi A., Ferati F., et al. (2020) Role of inflammation on the control of the arterial hypertension among patients with metabolic syndrome. J. Clinical Cardiology and Cardiovascular Interventions, 3(3); Doi:10.31579/2641-0419/044
Copyright: © 2020 Ylber Jani, This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Received: 21 January 2020 | Accepted: 03 February 2020 | Published: 07 February 2020
Keywords: cardioplegic arrest; postoperative case
Following the introduction of intracardiac repair of tetralogy of Fallot, early mortality in 1950s was as high as 25%. However, by the mid-1980s, this has reduced to 2% and currently ~ 0% even in neonates and young infants [1-11] despite the risk of reoperations, a large number of studies have documented satisfactory long-term survival rates in repaired tetralogy of Fallot, with a 30-year survival rate ranging from 86% to 91.7%. [8-22]
MetS – Metabolic Syndrome
CRP – C-reactive protein
BW – Body weight
BMI – Body mass index
BP – Blood pressure
SBP – Systolic blood pressure
DBP – Diastolic blood pressure
T2DM – Diabetes Mellitus type 2
WCi – Waist circumference
HDL-C – High density lipoproteins cholesterol
TG – serum triglycerides
ESC/ESH -- Europian society of Cardiology /Europian society of Hypetension
Despite enhanced screening and therapeutic management, hypertension remains the most prevalent chronic disease worldwide and the leading cause of heart disease, chronic kidney disease, and stroke in both men and women1. In recent years, a vast body of evidence has accumulated indicating the role of the immune system in the regulation of blood pressure and modulation of hypertensive pathology. It is widely accepted that hypertension is a pro-inflammatory disease and that the immune system plays a vital role in mediating hypertensive outcomes and end organ damages [2].
Metabolic syndrome (MetS), is a clouster of metabolic risk factors that includes high blood pressure, hyperglicemija, dyslipidemija and abdominal obesity, has been an increasing health problem worldwide for the last three decades, is associated with advers cardiac events [3]. Patient with MetS usually present increased levels of C-reaktive protein (CRP) wich is a prototypic marker of inflamation4, however the influence of icresed levels of CRP on control of aterial hypertension in patient with MetS, data are scarce.
We set out to determine the influence of inflammation (assessed by icresed levels of CRP) on control of aterial hypertension in patients with MetS. We set out to teste hypothesis: Patients with MetS and high level of CRP have higher prevalence of uncontrolled arterial hypertension than patients with MetS and lower level of CRP. These findings might lend further insight into inflammation-immune reactivity in arterial hypertension strategies for the controll of arterial hypertension in patients with MetS.
Objective: We sought to determine the influence icresed levels of CRP on control of aterial hypertension in patients with MetS.
Study design.
We conducted a multicenter observational cross-sectional study. The study population was recruited from our outpatient clinic between juni 2018 and juni 2019. Subjects who fulfilled the criteria for MetS according to the results of recent laboratory tests were prospectively evaluated.
The population consisted of 420 patients with MetS aged ≥ 18 years, divided in two groups: 211 participans (100 females and 111 males) with level of CRP>3mg/l, and 209 participans (104 females and 105 males) with level of CRP<3mg/l).
All participants underwent a comprehensive medical history and physical examination. Resting ECG, anthropometrics, measuring of blood pressure according to standard protocol (obtained after 10 min of rest in the sitting position, expressed as the average of 3 consecutive measurements), the mean systolic and diastolic blood pressure recording during the study period, were calculated. Hypertension was defined be current ESC/ESH guidelines for the management of arterial hypertension as office systolic blood pressure (SBP) values ≥140 mmHg, and/or diastolic blood pressure (DBP) values ≥90 mmHg and/or current anti-hypertensive therapy [6]. Uncontroled BP, was defined defined be current ESC/ESH guidelines for the management of arterial hypertension [5]. The blood pressure was considered to be controlled if the calculated mean systolic and diastolic blood pressure recording during the study period was found to be less than 140/90mmHg. Among adults younger than 60 years and less than 150/90mmHg.in general population aged ≥60 years. Diabetes mellitus was defined as a fasting serum glucose level ≥126 mg/dL and/ or current medical therapy with an oral hypoglycemic agent and/or insulin6.Body mass index (BMI) was calculated as weight (kg) divided by the square of the height (m2).Weight was measured with weight balance scales, and height with stadiometer. Waist circumference WCi, was reported in cm.
An overnight fasting blood sample, was drawn from each patient to determine: blood glucose, lipid profile tests total serum cholesterol (TC), serum High density lipoproteins cholesterol (HDL-C), serum triglycerides (TG).The sample analysis was performed using standard biochemical analytical methods. Plasma CRP levels was measured using latex particle-enhanced immunoassay with the mephelometry (Roche Swiss). Consistent with recommendations from Centers for Disease Control and Prevention [7] (a CRP cutpoint of 3.0mg/L), was used to differentiate high-risk and low-risk group.
Exclusion criteria, included a diagnosis of dementia senilis, secondary hypertension, serum creatinine level >2mg/dl, age under 18 years and over 79 years.
MetS was defined according to the harmonized definition of the International Diabetes Federation and other organizations [8], that three or more out of five following criteria are considered as MetS: (1) central adiposity {Waist circumference (WCi)} >102 cm in men and >88cm in women [9]); (2) serum HDL-C < 50 mg/dL in women or < 40 mg/dL in men; (3) serum triglyceride levels > 150 mg/dL; (4) SBP ≥ 140mmHg or DBP ≥ 90mmHg or use of antihypertensive drugs;(5) the presence of diabetes mellitus(DM) or use of anti-diabetic drugs. A standardized case report form was used to collect data from medical record and was send to the central data management unit.
The study is in compliance with the Declaration of Helsinki. All patient that participated in this study were written informed, consent was obtained from all participating patients before they were enrolled into the study.
Statistical Analysis
Results are expressed as mean and ±SD, or as percentage. A simple descriptive analysis was performed for the general characterization of the sample and distribution of variables. The distribution of variables was tested for normality using the Kolmogorov-Smirnov test, and the heterogeneity of variances was evaluated by Levene's test. To compare baseline characteristics and echocardiographic findings between groups, we used Student,s unpaired t test for continuous data, Mann-Whithey U -test for continuous data with abnormal distribution, and X2-test for categorical data. The association between variables were analyzed using logistic regression. Odds ration (OR) and 95% confidence interval (CI) were estimated by logistic regression. A, p value <0.05 was considered statistically significant for a confidence interval of 95%.Data were coded, entered and analysed using SPSS software package (SPSS 19.0).
A total of 420 subjects with MetS enrolled in our study, stratified in two groups:209 participans (47.5% females and 50.2% males) with level of CRP < 3mg/l, and 211 participans (47% females and 53% males) with level of CRP > 3mg/l, completed the survey and had data for 1-year medical record review. A mean of 3.4 BP recordings were obtained for each participans.
Baseline demographic, anthropometric and laboratory, characteristics by group are displayed in (Table 1)
No significant differences in: age, gender. Diastolic BP, were observed between groups. Participans with level of CRP >3mg/l had significantly higher means: SBP (140.7 ±14.5 vs. 132.3±18.5 p= 0.000), BMI( 31.1 ±4.7 vs. 25.6±4.2 p=0. 000), WCi (102.3 ±3.8 vs. 95.8 ±7.8 p=0.00); uncontrolled glycemia(6.8±0.6 vs. 6.4±0.8 p=0.003) and number of risk factors for MetS {frequency of presence five risk factor for MetS was higher among participans with level of CRP > 3mg/l (18 % vs. 6.7%; p= 0.000)}.
(Table 2), presens the frequency of controlled BP in participans with MetS and different level of CRP. Among those with level of CRP > 3mg/l (N=211) controlled BP according to evidence and current guidelines, was achieved in 23.6% of participans,whereas among those with level of CRP< 3mg/l(N=209) controlled BP was achived in 48.3%; p=0.000).The diference was found to be statistically significant.
In a logistic regression (Table. 3), there was independent association of CRP levels >3mg/l with uncontrolled BP (OR=3.1, 95%CI 2.06 - 4.75). There were signi-fiacant association of uncontrolled BP with: uncontrolled glycemia (OR =1.4,95%CI 0.97-1.84); increased BMI (OR=4.4; 95%CI 3.02-4.05) and five risk factors for MetS. (OR=2.3, 95%CI 1.93-2.81).
Table 3. Logistic Rgresion Model: Association of uncontrolled BP with: CRP levels (>3.0mg/L), uncontrolled glycemia, increased BMI and five risk factor for MetS.
In this study we found that patients with MetS and higher levels of CRP had significantly higher prevalence of uncontrolled BP than did those with MetS and lower levels of CRP. Results that confirmed our hypothesis. Low-grade inflammation is now a recognized hallmark of hypertension, and ther is an expanding literature regarding the role of inflammation and inflammatory cells in hypertension, in particular T lynphocites are now thought to have a central role in the development of hypertension and related organ injury [10] Based on the cenral role played by the cytokine milieu in determining lymphocyte differentiation and activation, differences of cytokines levels likely contribute to observed difference on the prevalence of uncontrolled BP in present study, and will impact the overall physiological outcome of an inflammatory response. The CoLaus Study reported that serum CRP, interleukin-6 and THF-α levels were positively associated with BP [11,12] Also, Grundy SM et all, suggests a significant association among inflammation, hypertension, and the metabolic syndrome [13]. Nevertheless, despite an association between high CRP levels and hypertension, a causal relationship has not been demonstrated. In fact, Smith et al. used a Mendelian randomization approach to examine a possible causal relationship analyzing the association of the 1059G/C polymorphism in the human CRP gene with hypertension, the work failed to confirm a causal relationship between CRP and blood pressure [14].
In our study, BP was controlled at 38% patient only. This result is consistent with previous findings that patients with hypertension and MS have an elevated prevalence of uncontrolled BP [15,16]. The study results allow evaluating the effetivity of hypertension treatment as for drug choise, decrease of sBP and dBP associated with a certain drug, a drug combination, and therapeutic inertia in these patients.
We also found that BP control was worse among patients with MetS and higher CRP levels in the presence of more MetS risk factors. It appears that there is an interaction between hypertension and metabolic disorder factors, although the mechanisms that are involved in this interaction remain unclear. Results in present study are consistent with previous findings [17]. It has been suggested that metabolic disorder factors have additive effects on BP control and cardiovascular disease. Arcucci et al. have reported that BP control worsens in the presence of more metabolic disorder factors [17] These data sugest that presence of more metabolic disorder factors, decrease the probability of BP control. We found association of number of risk factors of MetS and higher levels of CRP. However, it is unknown whether the number of MetS risk factors can influence the levels of CRP. Previeous study demonstrated that number of risk factors did not influence the levels of CRP in patients with MetS [18]. Also in present study we found association of highe levels of CRP in patient with uncontrolled BP and elevated levels of triglycerides, low HDL levels, obesity and uncontrolled glycemia. Results in present study are consistent with previous findings [19-21].
Study limitations
The study employed a cross-sectional design, and as such, the results could show only factors associated with uncontrolled hypertension. Study design limited to make causal inferences regarding increased CRP levels and control of arterial hypertension in patient with MetS. A larger sample would certainly increase the statistical power of the study, and probably some differences would therefore become more expressive. Despite some methodological limitations, this study clearly demonstrated a relationship between increased CRP levels and control of BP in patient with MetS.
Clinical Implications
These data provide further evidence that poor BP control is common in patients with MetS, and further investigations on the immune reactivitiy in hypetension may result in the identification of new strategies for the treatment of the disease. Therapeutic interventions to reduce activity of immunity may prove beneficial in reducing consequences of hypertension including: myocardial infarction, heart failure, renal failure and stroke.
We think, we brought some good evidence, in our present study, that patients with MetS and higher CRP level have a higher prevalence of unconrolled BP. These results indicate that presence of an subclinical inflammatory process in the natural history of MetS, through presence of high CRP levels, negatively affect BP control in patients with MetS. Measurement of this inflammatory protein may help to determine individuals cardiovascular risk and activity of immune system, it might be a novel therapeutic target for the treatment of high blood pressure in these individuals.
Agim Zeqiri;Dali Lala, Fatmir Ferati;Arben Mirto;Data collection/pro-cessing-Sotiraq Xhunga;Artur Serani;Ylber Jani; Analysis/interpretation-Ylber Jani;Ahmet Kamberi;Atila Rexhepi; Bekim Pocesta;Literature Search- Ylber Jani;Agin Zeqiri;Dali Lala; Fatmir Ferati;Artur Serani. Critical Reviews-Ahmet Kamberi.
All authors read and approved the final manuscript.
The authors reported no conflict of interest and no funding has been received on this work.
Following the introduction of intracardiac repair of tetralogy of Fallot, early mortality in 1950s was as high as 25%. However, by the mid-1980s, this has reduced to 2% and currently ~ 0% even in neonates and young infants [1-11] despite the risk of reoperations, a large number of studies have documented satisfactory long-term survival rates in repaired tetralogy of Fallot, with a 30-year survival rate ranging from 86% to 91.7%. [8-22]
In general, the patient survival rate declines significantly 15 years after intracardiac repair with mortality rates increasing from 0.12% per year in the first 15 years to 0.39% per year after 15 years. [21] The reported freedom from reoperations after intracardiac repair of tetralogy of Fallot in the neonatal period at 1 month, 1 year and 5 years have been 100%, 93% and 63% respectively. The relatively high rate was influenced by the complex anatomy in symptomatic neonates with tetralogy of Fallot, a high incidence of non-confluent pulmonary arteries, branch pulmonary arteries and conduit insertion. [8-22]
The most common indications for reoperation following intracardiac repair of tetralogy of Fallot are the result of long-term complications related to right ventricular outflow tract such as severe pulmonary regurgitation, residual right ventricular outflow tract obstruction and conduit failure. [8-22] Reoperation for residual ventricular septal defect is indicated if the Qp: Qs exceeds 1.5. The most common location of residual ventricular septal defect is postero-inferior corner of ventricular septal defect because of superficial bites at primary surgery. Other reasons for reoperation include pulmonary valvular stenosis, left pulmonary artery stenosis, aortic valvular stenosis or insufficiency. The indication for reoperation in residual right ventricular outflow tract is controversial. Generally, surgery is indicated for right ventricular outflow tract gradient is more than 60 mmHg. [8-22]
The effect of transannular patch on long-term survival and re-intervention remains controversial. Lillehei and colleagues in a series of 106 patients with 25 years of follow-up after intracardiac repair of tetralogy of Fallot reported no pulmonary valve replacement or right ventricular failure.[1,2] Meijboom and colleagues reported no difference in long-term survival in a cohort of patients with repaired tetralogy of Fallot, 14.7 years after surgery, half of whom had a transannular patch. [23] Other investigators have implicated transannular patching as a risk factor for reintervention and reduced long-term survival. [9,19-22]
Although many surgeons try to minimize the long-term complications by focussing on the optimal timing for surgery and the technique of right ventricular outflow tract reconstruction, controversy continues to surround the design of the surgical procedure particularly with respect to right ventricular outflow tract reconstruction. [5,6,24] There is mounting concern that over the long-term, free pulmonary regurgitation may lead to progressive right-sided heart failure, reduced functional status, arrhythmias, reoperations and reduced life expectancy. [25-27] some centres have reported high rates of reoperation to replace the pulmonary valve in these patients. [24,28] On the other hand, residual right ventricular outflow tract obstruction is also known to result in a high incidence of reoperation and arrhythmias.[1-14]
Literature documents a lot of experimental work demonstrating the deleterious effects of chronic pulmonary regurgitation on right ventricular function, right ventricular volume and exercise performance. [28-30] Several large series of pulmonary valve replacement for correction of chronic pulmonary regurgitation have been published. [25,28,29] However, the indications have been ill-defined in most of the series. Influences are further complicated by the poor correlation between right ventricular function and exercise.
In some study, the most common indications for reoperation is pulmonary regurgitation.[25,28-30] In contrast, some authors experienced residual or recurrent right ventricular outflow tract obstruction as the most common indication for re-intervention. Bacha and associates demonstrated no significant difference in need for re-intervention between patients with or without a transannular patch and use of a transannular patch did not reduce late survival. [32]
The need for a transannular patch reflects the severity of the right ventricular outflow tract obstruction at the annular level. Consequently patients in whom a transannular patch was used were at the more severe end of the morphologic spectrum. In the published literature, long-term survival of patients after transannular patch is equivalent to that of patients with annulus sparing repairs, implying that the use of a transannular patch resulted in neutralization of this risk factor. Bacha and colleagues also confirmed that the compensatory responses to chronic right ventricular overload are adequate for at least 25 years. [32]
Analysis of the published literature substantiates that other technical factors in addition to use of a transannular patch might influence late outcome.[4-22] These factors include the length of the ventriculotomy, width of the patch, number of coronary arteries divided, preservation of the moderator band and preservation of the tricuspid valve function through careful attention to the papillary muscles, chords and leaflets during patch placement on the ventricular septal defect. Distortion and stenosis of the pulmonary arteries as well as elevation of pulmonary vascular resistance by preliminary shunts are important additional factors when a 2-stage repair is undertaken.[8-22] Overall survival and functional status of reoperation are very good, a 10-year actuarial survival of 92%, with 93% of patients in New York Heart Association class I or II.[23,28]
We present here-in a 39 year-old woman with repaired tetralogy of Fallot and significant right ventricular outflow tract obstruction in New York Heart Association class III undergoing resection of right ventricular outflow tract obstruction under moderately hypothermic cardiopulmonary bypass and cardioplegic arrest. At 13 years of age, she underwent intracardiac repair of tetralogy of Fallot using transatrial, transpulmonary approach without transannular patch. Postoperative peak systolic right-to-left ventricular pressure ratio (Prv/Plv) at primary operation was 0.8. At the time of reoperation the peak systolic gradient between right ventricle and pulmonary artery was 104 mmHg with obstruction mainly at the level of mid right ventricular cavity. The pulmonary valves were normal and pulmonary arteries were confluent and non-restrictive. There was no residual ventricular septal defect or pulmonary arterial problems. Postoerative recovery was uneventful.
She was weaned off cardiopulmonary bypass on dopamine 5 µg/kg/min and dobutamine 5 µg/kg/min in stable hemodynamics. Postoperative peak systolic right-to-left ventricular pressure ratio (Prv/Plv) was 0.5. At 10 months follow-up she is asymptomatic in New York Heart Association functional class I.
Surgical Techniques
Following systemic heparinisation, elective right femoral arteriovenous cannulation was done using long femoral arterial and venous cannulae (Edwards Lifesciences LLC, One Edwards Way, Irvine, CA, USA).
Under cardiopulmonary bypass, secondary median sternotomy was performed with the heart decompressed on bypass. The pericardium overlying the aorta, right ventricular outflow tract and superior vena cava was dissected.
The superior caval vein was dissected and cannulated directly using an angled metal tipped venous cannula and drained directly into the oxygenator. The intrapericardial inferior caval vein was dissected and looped for later occlusion.
The main pulmonary artery was transversely opened in between stay sutures 0.5 cm above the pulmonary ring.
The ascending aorta was dissected free from the main pulmonary artery and right pulmonary artery for later selective aortic cross-clamp.
The aorta was cross-clamped using an atraumatic aortic vascular clamp. Myocardial protection was achieved by intermittent administration of St. Thomas (II) based cold blood cardioplegia (4: 1) and ice cold saline.
After snugging the inferior caval vein, the right atrium was directly incised in between stay sutures 1 cm parallel to the atrioventricular groove.
The right ventricular outflow tract obstruction was at the mid cavity level. The obstructing muscle core was excised by a combined trans right atrial and pulmonary artery approach. Adequacy of muscle excision was assessed by visual inspection and by inserting an appropriate sized Hegar’s dilator. The tricuspid valve was checked for competency by injection cold saline within the right ventricle.
The right atrium was closed in two layers using 5-0 polypropylene suture (Johnson and Johnson Ltd., Ethicon, LLC, San Lorenzo, USA) to achieve perfect hemostasis. The aortic cross-clamp was removed, thereby restoring myocardial perfusion. The three pulmonary cusps were examined for any iatrogenic injury and competence. The pulmonary artery was closed in two layers: horizontal mattress, and over and over continuous suture of 5-0 polypropylene.
The patient was weaned off cardiopulmonary bypass with stable hemodynamics on dopamine 7.5µg/kg/min and milrinone 50µg/kg/min over 20 minutes followed by 0.25µg/kg/min.
Despite advances in clinical care and decision-management, a subset of adult survivors with tetralogy of Fallot will require surgical intervention, regardless of underlying pathology. The tetralogy of Fallot subtype and presence of specific coexisting lesions determine the freedom from re-intervention. Proper myocardial preservation and complete relief of right ventricular outflow tract obstruction paying attention to all components of right ventricular outflow tract including the pulmonary arteries is mandatory for a successful outcome.
The author(s) declared no potential conflicts of interest with respect to the research, authorship and/or publication of the article.
The authors received no financial support for the research, authorship and/or publication of this article.
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