Beat-to-Beat Blood Pressure Variability as a Predictive Tool for Identifying Cardiovascular Events in Anemic Women

ABSTRACT IMAGE

INTRODUCTION

Anemia is associated with decreased oxygen capacity of blood and can lead to cardiovascular disease (CVD) by decreased oxygen delivery to myocardium and systemic tissues. These changes are associated with a compensatory increase in cardiac function (stroke volume or heart rate) to maintain adequate oxygen supply. A 1g/dL hemoglobin (Hb) decrease is associated with increased risk of cardiovascular associated death particularly in those who suffer myocardial infarction.^[1] Atherosclerosis risk in communities study has shown that in apparently healthy men and women, with anemia, there was a 40% increased risk of CVD during a 6 year follow-up.^[2] Anemia increases preload, reduced afterload resulting in increase in cardiac output. This eventually leads to left ventricular hypertrophy, a maladaptive condition of heart that is a well-recognized risk factor for CVD and mortality.^[3-5] Viscosity of blood is determined by the amount of Hb that affects blood pressure (BP) and causes arterial stiffness.^[6] One substance that is cardioprotective is nitric oxide (NO) whose production is altered in anemia. Normally, NO is activated by cofactors present in erythrocytes such as tetrahydrobiopterin and calmodulin and intracellular Hb is a circulating reservoir of NO.^[7] Hence, a reduction in red blood cell and Hb can lead to deficient NO supply to the tissues affecting the fundamental physiologic process of vasodilatation causing cardiovascular disturbances with impaired endothelial function. This can leads to drastic changes in BP, including, short- and long-term variability in BP which have been recognized recently as important risk factors for development and progression of vascular events.^[8] BP variability (BPV) has emerged as a reliable hemodynamic marker with widespread clinical and research utility. Higher BPV may cause remodeling of arterial walls with vascular smooth muscle proliferation, extracellular matrix deposition, and increased shear stress of endothelium. These structural and functional changes of vessel wall lead to arterial stiffness and hypertension.^[9] Continuous BPV captures the intricacies of BP dynamics which are not otherwise collected by intermittent BP monitoring. It is however defined as a progression of variation with time, and hence, the variability is measured over 5 min and can be associated with other markers such as Hb and anemia status. There is no specific description or cut off for the gender-based BPV but previous cross-sectional studies have shown BPV to be more evident in women than men.^[10] Recent studies have shown that the quantification of BPV along with the gold standard measurement of average BP is of both pathophysiologic and prognostic importance.^[11,12] It is assessed using non-invasive finger cuffs and tracks BP using infrared photoplethysmography.^[13] Research on beat-to-beat BPV remains a relatively new field with a potential early diagnostic value for premature changes before overt symptomatic manifestations.^[14] Beat-to-beat fluctuations in BP are referred to as very short term BPV. Studies on BPV related to anemia are limited. As anemia is a common condition in women in India, analyzing its association with BPV will possibly provide some new insights related to cardiovascular health. Hence, the present study aims to assess role of beat-to-beat BPV as a cardiovascular risk factor reflecting underlying vascular pathology in anemic women. The aim of the present was to see the effect of anemia on autonomic functions with the objective to assess beat-to-beat BPV in women with low Hb levels.

MATERIAL AND METHODS

After obtaining Institute Ethics Committee approval, a total of 52 women in the age group of 26–60 years were recruited in the study of which 26 were defined as cases whose Hb levels were <12 g/dL as per the World Health Organization criteria. Controls were those who were apparently healthy women whose Hb was above 12 g/dL. All participants were subjected to autonomic function testing that mainly included assessment of heart rate variability, beat-to-beat BPV, and galvanic skin response (GSR). AD instruments, power lab 8/35, human non-invasive blood pressure nano system, and lab chart software were used. Hemodynamic parameters such as BP curve, systolic, diastolic and mean pressures, heart rate, and interbeat interval were measured. The system has the nano wrist unit connected to the fingers with non-invasive dual finger cuffs that provide beat-to-beat BP monitoring and a height correction unit to compensate for hand movements relative to the heart during autonomic testing and calibration module. Electrocardiogram (ECG) leads are connected to measure the heart rate variability in Lead II. The GSR amplifier measures the electrodermal activity indicating sweat gland activity on skin, showing physiological or psychological arousal. The GSR unit has bipolar finger electrodes that are contoured around the fingers with use of a suitable conductance electrode paste to improve skin contact and quality of recording. Women with any other comorbid conditions including history of any pre-existing heart disease, hypertension, diabetes, hyperlipidemia, and renal disease were excluded from the study to remove the effects of confounding factors on BP.

RESULTS

The mean age of women with anemia was 31.12 ± 7.13 years and those without anemia were 29.73 ± 5.28 years. The Hb levels in cases were 9.26 ± 0.84 g/dL and in controls was 12.98 ± 0.59 g/dL. This difference in Hb was found to be significant with P = 0.00001.

Analysis of variance for repeated measures shows both systolic and diastolic beat-to-beat BPV in cases which were found to be highly significant from supine to immediate standing to 5 min thereafter with P = 0.00001. The coefficient of variation (CV) from supine to immediate standing was highest in systolic BP in women with anemia, showing the association of Hb levels and BPV [Table 1]. The changes were more prominent in cases and in systolic than diastolic BP variation [Table 2]. Further, to avoid any interference by specific stressors or factors, average real variability (ARV) was also evaluated. It is the mean value of the absolute difference of consecutive measurements. ARV was found to be higher in those with anemia compared to controls [Table 3].

Analysis of heart rate variability has shown a significant difference in total power (P = 0.0014) between cases and controls with higher total power in cases. VLF power was lower in in those with anemia than controls but the difference was not significant (P = 0.382). HF power between the two groups was found to be significantly lower in cases than controls (P = 0.012). RMSSD was found to be significantly lower in those with anemia compared to those without (P = 0.023). Higher SDRR was measured in controls than cases [Table 4].

While the GSR was not found to be significant in controls from baseline to after stimulation phase, in cases, there was a significant difference with P = 0.001 [Table 5].

A negative but weak correlation was established between Hb levels in cases and beat-to-beat BPV.

DISCUSSION

One of the major causes for anemia especially in India is iron deficiency. Most susceptible to anemia are children and women in general which increases during pregnancy. It can lead to cardiomyopathy and high output heart failure due to inadequate oxygen delivery to tissues which in heart leads to myocyte dysfunction. A compensatory increase in cardiac output to maintain the demands leads to a hyperdynamic state. While the heart has the capacity to withstand such adverse effects of anemia during resting conditions, activity aggravates the condition leading to morbidity and mortality.^[15] It has also been reported that high output heart failure is driven by an ongoing increased sympathetic activity that can be assessed by autonomic testing and beat-to-beat BP changes.^[16] Arterial baroreflex sensitivity, endothelial dysfunction, arterial stiffness, and other such factors regulate BPV modulation in a complex mechanism^[17] Very short-term beat-to-beat BPV measurements provide detailed information about cardiac autonomic functions which were observed in studies earlier.^[18-20] The CV from supine to immediate standing was highest in systolic BP in women with anemia, showing the association of Hb levels and BPV. Fluctuations in BP cause repeated contractions and expansions in blood vessels and heart which over a period of time impairs vascular functions further expanding the range of fluctuations.^[21] Increase in the BPV range can lead to arteriosclerotic changes, coronary and peripheral artery disease and stroke which are associated with poor prognosis.^[22-24] Analysis of average real variation (ARV) helps in understanding the true variability in the beat-to-beat BP monitoring and removes any specific effect of stressors providing a more authentic evaluation.^[25] In the present study, higher ARV in cases shows that anemia is an independent factor affecting BPV hence can be relied on to predict any future cardiovascular events.

Heart rate variability parameters included total power, VLF, LF, HF, RMSSD, and SDRR. These parameters are based on time and frequency domain analysis with spectral analysis components. Low heart rate variability was found in anemic women who indicated sympathovagal imbalance associated with higher cardiac risk. Total power reflects the body’s capability to adapt to stressful conditions which were reduced in women with anemia. RMSSD which reflects the integrity of vagus nerve mediated autonomic control of the heart focusing on the rapid fluctuations in the heart and showing beat-to-beat variability was significantly reduced in cases compared to controls. It measures the time difference between each heart beat in real time and characterizes short-term rapid changes in heart rate which usually occurs under the influence of parasympathetic NS hence indicating vagus-mediated control of heart. Lowered RMSSD levels can have a negative consequence during a medical emergency. Good activity of vagus nerve decreases heart rate, increases blood flow to the heart, and stabilizes myocardium to prevent ventricular fibrillations. Higher number of standard deviation of NN intervals indicates the coping ability of the body in stressful conditions. Impaired autonomic activity can trigger inflammation and arrhythmias in the heart, disturbing the BP and flow dynamics increasing the risk of CVD. The sympathovagal imbalance brought about by lowered Hb levels in women also reflects on the GSRs. It measures the electrical response of the skin to sweat gland activity. In our study, changes were more prominent in anemic women than controls further providing evidence of altered autonomic behavior.

CONCLUSION

Correcting anemia early can reverse heart conditions like cardiomyopathy. Patients with anemia can benefit from regular evaluation of BPV to predict future cardiac disease. Anemia may be an important surrogate marker for evaluating prognosis in heart failure patients, which is reflected in changes in BPV. Assessing beat-to-beat variability in BP in anemic women will serve as strong predictor of CV events like stroke. Detecting changes in beat-to-beat BPV can also help understand the mechanism of action of antihypertensive drugs, selecting suitable drugs and as a useful diagnostic tool for detecting CVD.