Fragmented Ventricular Complexes and Blood Pressure Variability Assessed by Ambulatory Blood Pressure Monitoring in Patients With Metabolic Syndrome

Introduction Hypertension is a leading risk factor for the development of cardiovascular and metabolic derangements. In patients with metabolic syndrome (MetS), hypertension is one of the cornerstones showing high variability which is detected in ambulatory blood pressure monitoring. Fragmented ventricular complexes on ECG are seen as hypertensives and are a viable and easy measure of myocardial fibrosis even in the absence of obvious hypertrophy. Aim The present study was undertaken to study the blood pressure variability in patients of MetS with fragmented QRS (fQRS) versus normal ventricular complexes (QRS). Results Out of 100 patients, 22 (22%) had fQRS complexes. Hypertension and diabetes were the most prevalent associated in both groups but a difference was seen with coronary artery disease, which was significantly associated in the fQRS group (8.97% vs 95.45%, p<0.001) as compared to the non-fQRS group. Significant differences were observed in waist circumference (p=0.019), triglyceride (p=0.006) and left ventricular ejection fraction (p<0.001) between the two groups. There was a marked difference (p<0.05) between heart rate variability during day and night time between normal and fQRS sub-groups, being higher in the latter. A similar pattern of change was observed for systolic and diastolic blood pressures and associated dipping. Conclusion Significant differences exist between heart rate and blood pressure changes in patients with fQRS of MetS, thus making fQRS a potent indicator of cardiovascular status.


Introduction
Blood pressure (BP) is characterised by marked short-term fluctuations such as beat-to-beat, minute-tominute, hour-to-hour, and day-to-night changes.Twenty-four-hour ambulatory BP monitoring (ABPM) is the most widely available tool to assess short-term BP variability (BPV), its patterns, underlying mechanisms and clinical implications [1].A large and increasing number of studies support the evidence that BPV represents a strong and independent risk factor for cardiovascular diseases (CVDs) [2,3], as well as for hypertension-related morbidity and mortality [4].
Metabolic syndrome (MetS) is a cluster of disorders that puts an individual at risk of developing serious health issues.MetS has been defined by multiple criteria.The two widely used criteria for identifying MetS are the National Cholesterol Education Programme (NCEP) Adult Treatment Panel (ATP-III) and the International Diabetic Federation (IDF).NCEP-AT III criteria recognise the presence of any three of the conditions as MetS, while IDF emphasises the presence of central obesity with any two other conditions as MetS [5,6].Various studies have indicated that among individuals with MetS, of the five risk factor components, hypertension was observed most frequently in both genders (up to as high as 85%) [7,8]. is no longer accepted.Repeat measurements are needed to ensure the accuracy of these measurements.Circadian variability affects BP and heart rate changes [9], thereby cementing it as one of the markers of hypertension as well as influencing endocrine disorders [10], renal disorders [11], headache and neuropathic pain [12], behavioural patterns [13] and most importantly in metabolic and cardiovascular disorders [14,15].Twenty-four-hour ABPM is the most widely available tool to assess short-term BPV and its wide use in the practice and research of hypertension allows meaningful insight into BPV's patterns, clinical significance, and underlying mechanisms.It is well-accepted that short-term (within 24 hours) variations are affected by sympathetic activation, peripheral resistance (caused by arterial elastic properties) [16], blood viscosity, vasoconstrictors effects, and emotional and behavioural factors.
Fragmented QRS (fQRS) was defined by an additional R wave (R') or notching within the QRS complex.fQRS on 12-lead electrocardiography (ECG) was originally defined as narrow QRS complex duration (<120 ms) and improved identification of prior myocardial infarction in patients who are being evaluated for coronary artery disease (CAD) [17].A narrow fQRS complex as a ventricular conduction abnormality is a sign of myocardial fibrosis and is associated with adverse outcomes in various CVDs [18,19].Therefore, the presence of fQRS on ECG, as an indicator of myocardial fibrosis, may be a sign of increased BP even in the absence of left ventricular (LV) hypertrophy.
The present study aimed to study the BPV in patients of MetS with fQRS and normal QRS.

Materials And Methods
The present research was carried out as a prospective observational study in a tertiary care North Indian hospital over a span of 24 months from 2021 to 2023.Outdoor and hospitalized patients with MetS who met the inclusion and exclusion criteria were enrolled in the study.

Inclusion and exclusion criteria
All patients above the age of 18 years, of either gender, after informed consent diagnosed with MetS by NCEP ATP-III criteria [5] were included in the study.Patients not meeting the inclusion criteria with either bundle branch block, non-sinus rhythm/arrhythmia, stable angina pectoris or acute coronary syndrome, valvular heart disease and those with malignancy on radiotherapy were excluded.

Sample size
The sample size of the study was 100 patients.

Methodology
All the diagnosed cases of MetS fulfilling the inclusion criteria were first clinically examined.During the examination, personal details, duration of MetS, family history, and details of co-morbidities were collected.Patients were referred for ECG and 2D ECHO, and on the basis of the findings of the above tests; patients were divided into two groups: fQRS and non-fQRS (normal QRS).Blood samples were collected and BP monitoring was done on ABPM machines.

Procedure for ABPM
ABPM was performed using a mobil-o-graph r (IEM, Aachen, Germany), and the results were analysed using an HMS Client-Sever-4.0system (Hypertension Management Software, IEM, Stolberg, Germany).The BP and heart rate were monitored for one whole day: every 30 min during the day (0700 to 2200 hours) and every 60 min during the night (2200 to 0700 hours).More than 90% of the readings were valid.

Observed parameters
The observed parameters for ABPM included peak day-time heart rate, peak night-time heart rate, average night-time heart rate, average day-time heart rate, minimum day-time heart rate, minimum night-time heart rate, diastolic and systolic BP, average BPV and BP circadian rhythm.

Statistical analysis
The statistical analysis was done using Statistical Package for the Social Sciences (IBM SPSS Statistics for Windows, IBM Corp., Version 21, Armonk, NY).The values were represented in number (%) and mean±SD.Chi-square and student 't' tests were used and a p-value of <0.05 was deemed significant.

Results
Of the total 100 patients of MetS, 22 patients (22%) have fQRS complex.The mean age in patients with a normal QRS complex was 58.51±9.19 years whereas that with fQRS had a mean age of 51.55±8.58years which was statistically significant (p-value 0.002) (Table 1).

Discussion
Individuals having metabolic derangements are at high cardiovascular risk (CVR) and the presence of multiple metabolic disorders increases this risk further.The presence of a cluster of these metabolic disorders namely obesity along with insulin resistance (diabetes), hypertension and dyslipidemia is termed as MetS.MetS is found to be associated with deterioration of the LV systolic and diastolic functions.One of the factors for this impairment is myocardial fibrosis.fQRS complexes are found to be associated with myocardial fibrosis [20].Since treatment for myocardial fibrosis centres around addressing the underlying disease, it is important to treat MetS which can limit the worsening go cardiac functions.Hypertension is present in almost 80% of patients with MetS and pressure overload, induced by hypertension, results in extensive cardiac fibrosis; therefore, hypertension by BPV and fQRS is important to be studied from both preventive as well as early management points of view [21].
BPV as a confounding factor in CVD occurrence, severity and complication in the backdrop of metabolic disease has been extensively studied [22,23].Considering fQRS as an indicator of complicated MetS with an increased risk of cardiac events, it is essential that the role of BPV in MetS patients should be interpreted in context with fQRS status which was the basis of our research.In our study amongst MetS inductees, fQRS was observed in 22% of patients while the remaining 78% had normal QRS, which is similar to a study by Oner [20] et al. that reported MetS prevalence of fQRS to be 26.1%.They also reported a higher prevalence of diabetes and hypertension along with higher glycemic levels, obesity parameters and hemodynamic parameters in MetS, a similar pattern seen in our study.
In our study, fQRS patients were significantly associated with T2DM and CAD.The prevalence of hypertension was also higher among fQRS.The relationship between hypertension and T2DM in MetS does not require much elaboration as they are component factors of MetS and should not be viewed as a comorbid condition.However, the presence of both factors has been associated with CVR factors of their own.
Kanga [26] compared the heart rate variability (HRV) of 121 males with MetS and 131 male controls, 58 females with MetS and 191 control females.They observed men and women with MetS had lower total power and high-frequency (HF) power of HRV than controls whether supine or upright while men and women with MetS had lower upright low-frequency power of HRV than controls.After adjustment for age, smoking habits, alcohol intake, height, HR and breathing frequency, only the differences in upright total power and HF power of HRV between women with MetS and control women remained significant.
In the present study, fQRS MetS patients had significantly higher HRs (Peak Daytime, Av.Daytime and Av.Night time value).Systolic BP (Peak Day and Night, Av.Day and Night and Min.Night time values) and Diastolic BP (Peak, Av. and Min.values both day and night time).The association of fQRS with a diurnal variation of MAP was not found to be significant.The majority of fQRS MetS patients had been found to be extreme dippers (64.7%) while the majority of normal QRS MetS patients were found to be dippers.Reverse dippers were also higher among fQRS MetS as compared to MetS normal QR patients (5.9% vs. 4.3%).There are limited studies reporting any distinction in the BPV pattern of MetS patients.Ukkola et al. [27] who had enrolled 1770 non-diabetic untreated patients had reported non-dipping to be significantly associated with MetS.Felisbino-Mendes et al. [28] had reported pulse pressure (PP) (daytime, night time, av.24h) was significantly elevated in cases of hypertriglyceridemia, dyslipidemia, overweight, and obese.
Age-adjusted MS was associated with higher CVR (OR = 4.5 and 3.6), 24-h PP (OR = 2.3 and 4.7), and daytime PP (OR = 2.2 and 4.6).They concluded that MS was highly prevalent and correlated with altered 24-hour BP parameters.
Taghia et al. [29] analysed the complete data on ABPM in patients with diabetes.They reported that approximately 54.2% of participants had non-dipping nocturnal patterns and 28.6% were risers.Nondipping nocturnal BP was associated with CVD, neuropathy, and retinopathy.
Marcus et al. [1] established an association between MetS and BPV in a longitudinal study; they found that a one-year intervention resulted in weight reduction as well as a reduction in BPV.These findings establish that modulation of CVR through appropriate interventions has a direct impact on the BPV.In the present study, we could not carry out a longitudinal study but a cross-sectional study found that patients with higher CVR (fQRS) have a significantly different BPV pattern as compared to those without fQRS.
The findings of the present study showed that in an otherwise matched MetS population having no significant difference with respect to traditional biochemical markers (fasting blood sugar, postprandial blood sugar, Hb1c, serum lipids, serum creatinine) that are differentiated only by QRS fragmentation vis-àvis ejection fraction and 2D Echo abnormalities.BPV can be a useful, easy and non-invasive measure to determine the risk of cardiac events.

Limitations
The present study included 100 patients of MetS in whom ABPM was done and subsequently correlated with fQRS.Although results are promising a larger sample size would go a long way to increase the power of the study.The presence of fQRS is more sensitive than Q wave on ECG to identify myocardial scar, yet it is less specific.A combination of fQRS with Q wave in a 12-lead ECG shows a 74% sensitivity and 92% specificity [30].Thus, a combined assessment with both entities would have further increased the weight of the study.Also, the patients could have been followed up, to assess if the fQRS changes/resolution occurred with control of BP and lifestyle modifications.

Conclusions
Ambulatory blood pressure is a useful, easy and non-invasive measure to determine the difference in BPV pattern in patients of MetS with high CVR (fQRS) as compared to those with normal QRS.fQRS is an important indicator of deteriorating cardiac patients and can be used to screen potential patients of cardiovascular insult who otherwise do not comply with 24-hour monitoring.Thus, early suspicion and tailored assessment would go a long way in reducing the financial burden, resources and extensive testing thereby reducing overall morbidity and mortality.

TABLE 1 : Age distribution between patients of metabolic syndrome with and with our fragmented QRS
both groups were comparable, whereas CHD was significantly more common in the fQRS ECG.Of the 78 patients, a total of 64 (82.05%) had angiotensin-converting enzyme/angiotensin receptor blockers (ACEI/ARB) usage in the normal ECG and 22 (100%) patients in the fQRS group.On the basis of ACEI/ARB, the two groups were comparable (Table2).

TABLE 2 : Comparison and summation of variables between normal and fragmented QRS ECGs
The mean BMI and waist circumference were 29.19±3.05and91.60±7.47 in normal and 29.29±2.33 and 87.39±6.73 in fQRS ECG, respectively.Although BMI was not significantly different but mean waist circumference was significantly different between the two groups.The mean haemoglobin (Hb), total leukocyte count (TLC) (x103) and platelet were 12.06±1.90,8.24±3.14 and 2.01±0.73 in normal and 12.86±1.78,7.90±2.19and2.12±0.77 in fQRS ECG, respectively.In addition, the mean Hb, TLC (x103) and platelet were not significantly different between normal and fQRS ECG.Blood sugars (both fasting and postprandial), glycated Hb and renal profile were only comparable.With respect to lipid profile, only serum triglycerides were significantly different between the two groups (Table3).

TABLE 3 : BMI and blood profile difference between the two study groups
BMI: body mass index; VLDL: very low-density lipoprotein; LDL: low-density lipoprotein; HDL: high-density lipoprotein; HbA1c: glycated haemoglobin

Table 4
shows the comparison of the mean heart rate (HR) between normal and fQRS ECG.The mean HR Peak DT (Day Time), HR Peak NT (Night Time), HR Av (Average) DT, HR Av NT, HR Min DT and HR Min NT were 94.15±20.27,88.96±17.76,83.17±17.47,80.01±16.00, 79.92±22.35and78.22±21.68 in the normal ECG group and 107.32±15.91,95.45±15.32,94.64±12.76,90.18±11.93,85.09±13.99 and 88.45±17.95 in the fQRS ECG.The mean HR Peak DT, HR Av DT, HR Av NT and HR Min (Minimum) NT were significantly higher in the fQRS ECG than in the normal ECG.The HR Peak NT and HR Min DT were also higher in fQRS, but not significantly different.

TABLE 5 : Comparison of mean systolic and diastolic blood pressure variability and their average during
daytime (DT) and night time (NT) between normal and fragmented QRS ECGSBP: systolic blood pressure; DBP: diastolic blood pressure; AV: average; DT: day time; NT: night time; Min: minimum

Table 6
shows the comparison of mean arterial pressure (MAP) between normal and fQRS ECG.The mean 2024 Mishra et al.Cureus 16(5): e59950.DOI 10.7759/cureus.599505 of 10 MAP (Max) and MAP (Min) were 119.78±12.35,74.37±13.59 in normal and 119.23±13.62 and 75.91±15.58 in fQRS ECG.In addition, the mean MAP (Max) and MAP (Min) did not differ significantly between normal and fQRS ECG.In addition, the mean diurnal variation (S) did not differ significantly between normal and fQRS ECG.

TABLE 6 : Comparison of mean MAP and mean heart rate between normal and fragmented QRS ECG
The percentages of normal dipping, extreme dipping, reverse dipping and non-dipping were 71.79%, 19.23%, 2.56%, and 6.41% in normal and 36.36%,59.09%,0.00%,and 4.55% in fQRS ECG, respectively.On the basis of dipping both groups were significantly different (Table7).

TABLE 9 : Linear regression analysis to assess the potential association between different parameters and fragmented QRS ECG
HR: heart rate; DT: day time; NT: night time; AV: average; min: minimum; SBP: systolic blood pressure; DBP: diastolic blood pressure; MAP: mean arterial pressure; BMI: body mass index; BS: blood sugar; HbA1c: glycated haemoglobin; VLDL: very low density lipoprotein; LDL: low density lipoprotein; HDL: high density lipoprotein