European Journal of Cardiovascular Medicine

Prehypertension (PreHTN) was defined as systolic blood pressure of 120- 129 mm Hg and diastolic blood pressure of <80mm Hg, and prediabetes (PreDM) was defined as fasting blood sugar of 100-125 mg/dl (Impaired fasting glucose) or two hour postprandial glucose during 75g of OGTT(Oral Glucose Tolerance Test)140-199mg/dl or HbA1C level between 5.7 to <6.5%. Prevalence of PreDM, PreHTN, and coexisting PreDM and PreHTN in disease-free healthy adults were on the rise. One in every four disease-free adults has PreDM, one in three disease-free adults had PreHTN, and one in 10disease- free adults has to coexist PreHTN and PreDM.^1,2 Recognition of the enhanced risk for untoward events and the modification and reversal of risk is the goal that all physician scan aspire to.

The perceived potential for cardiovascular disease (CVD) risk enhancement by the clinical precursors: prehypertension (PreHTN) and prediabetes (PreDM), in healthy adults, however, remains unsubstantiated. The probable CVD risk enhancement with PreHTN and PreDM, in some measure, is dependent upon the high risk for conversion from PreHTN to hypertension and from PreDM to diabetes. A high proportion of men and women with blood pressure at the high end of the normal range in the Framingham cohort (JNC 6 criteria: blood pressure¼130– 139/85–89 mm Hg) developed hypertension four years. A similar proportion of disease- free adults (38%) with PreHTN (JNC 7 criteria: blood pressure¼120–139/80–89 mm Hg) in the Strong Heart Study progressed to hypertension within four years. A varying proportion of men and women(6–29%) with PreDM (American Diabetes Association criteria: impaired glucose tolerance indicated by two hourse rum glucose between 140– 199 mg/dl after a 75 g oral glucose load) convert to diabetes mellitus within four years.³

PreHTN and PreDM, however, also increase CVD risk because of their association with increased waist circumference (WC), high triglycerides (TGs), below-normal high-density lipoprotein cholesterol (HDL-C) and either elevated blood pressure (PreHTN) or fasting blood glucose (Pre DM). Each of these five risk factors, increased Waist Circumference (>90cm in men and >80 cm in women), elevated TG (>150mg/dl), low HDL-C (<40mg /dl in men and<50 mg/dl in women), increased blood pressure (blood pressure>130/85mmHg) and elevated fasting blood glucose (100– 125 mg/dl), is individually associated with increased adverse cardiovascular events. These factors increase CVD risk even more when any three (or more) of these five are used to diagnose the metabolic syndrome.^4-7

PROTEINURIA: It refers to the excessive excretion of protein in the urine. In normal conditions, urinary excretion of all proteins combined is <150mg/dl. The most abundant protein in normal urine is Tamm-Horsfall Protein an alpha 2 globulin synthesized by the renal tubules in the loop of Henle. Proteinuria results from 3 mechanisms: 1) glomerular injury; 2) tubular injury resulting in excessive production & excretion of tubular proteins; 3) over filtration of plasma proteins due to high plasma concentration (multiple myeloma). Various disease states can cause excessive excretion of protein in the urine, including glomerular and tubular diseases.

MICROALBUMINURIA: Under normal conditions, daily albumin excretion is in the range of 5–10 mg and the urine albumin: creatinine ratio is in the range of 0–29 mg albumin/g creatinine. Forty years ago, technology for measuring small amounts of urine albumin was described to determine abnormal amounts of albumin excretion or albuminuria.

Microalbuminuria is defined as an abnormal increase in albumin excretion rate within the specific range of 30–300 mg albumin/g of creatinine. The term was coined in the 1980s when technological advances made it possible to identify small but abnormal increases in albumin in the urine of patients with diabetes-hence the term “microalbuminuria.”^8-9 The National Kidney Foundation (NKF), the American Diabetes Association(ADA), and NIH recommend the measurement of albumin in urine using the albumin technique: creatinine ratio.

Table1. The salient features to differentiate microalbuminuria and proteinuria.

MACROALBUMINURIA: Macroalbuminuria was defined as an abnormal increase in albumin excretion rate ≥ of 300 mg albumin/g creatinine. Macroalbuminuria in diabetic and non diabetic subjects is a marker of accelerated decline in glomerular filtration rate (GFR).¹⁰ Macroalbuminuria indicates intrinsic renal disease and increased cardiovascular morbidity and mortality

Table2. Definition and significance of abnormal albumin excretion

Background

Definition of Pre DM:

• American Diabetes Association diagnostic criteria:
• FBS more than 100mg/dL, but less than 126mg/dL(Impaired fasting glucose)
• 2hoursPPBSaftera75gof OGTT between 140-199mg/dl(Impaired glucose tolerance)
• HbA1C-5.7 to<6.5%

Diagnosis of Pre HTN:

The 8^th Report of the Joint National Committee on Prevention, Detection and Treatment of High Blood Pressure (JNC8) states PreHTN as systolic blood pressure of 120–129 mm Hg and diastolic blood pressure of <80mm.

Table3. Blood Pressure guidelines (AHA)

ALBUMIN:

The most abundant human protein available in the blood is human albumin. Its primary source of production is from the liver and constitutes more than one-half of total blood protein. T1/2= 20 days approximately. It is supposed to have a molecular mass of about 66.5kDa. The gene coding for albumin is found in chromosome 4. Any mutation in this gene may lead to the formation of abnormal proteins. Preproalbumin is converted to proalbumin in the liver's endoplasmic reticulum, cleaved to albumin in the Golgi apparatus and secreted out.

Albumin helps transport various hormones and other substances, buffers pH, and maintain oncotic pressure. In healthy persons, albumin is not excreted through kidneys because of its size and negative electric charge.

Figure1. Physiological effects of exogenous albumin

MICROALBUMINURIA:

In 1963 Keen and Chloverakis developed sensitive and specific radioimmunoassay for detecting human albumin in low concentration, i.e. microalbuminuria, which indicates the earliest stage of diabetic renal disease. Later various other methods were developed for the detection of microalbuminuria.⁹

DEFINITION AND PATHOPHYSIOLOGY:

Microalbuminuria means a significant increase in albumin excretion rate (AER). Albumin excretion in healthy subjects 1.5-20µg/min with geometric mean in the range of 6.5µg/min, these have been termed normoal buminuria.

Microalbuminuria thus defines the substantial wide range of albumin hyperexcretion ranging between 20-200µg/min (30-300mg/day).¹⁰ Normal persons excrete less than 30mg/day. Reagent sticks do not detect microalbuminuria for urinary protein, which generally becomes positive only when proteinuria is greater than 550mg/day. This degree of leakage is termed Macroproteinuria.

In 1963 Keen and Chloverakis developed a sensitive, specific radioimmunoassay for detecting human albumin in low urine concentration to study the sub clinical increase in urine albumin excretion rate (AER) might be the earliest pointer to the development of the diabetic renal disease.

Table 4. Definition of microalbuminuria and clinical nephropathy:

The Kidney Disease Improving Global Outcomes (KDIGO) 2012 Clinical Practice Guideline discourages the use of the term microalbuminuria. 'Recent classification is:

• Normal to mildly increased (instead of normoal buminuria) (<30mg/day)
• Moderately increased (instead of microalbuminuria) (30 to 300mg/day) and
• Severely increased (instead of macroalbuminuria or proteinuria) (>300 mg/day).

Microalbuminuria has been equated with incipient nephropathy and a risk factor for cardiovascular disease (CVD) in people with and without diabetes. No test distinguishes microalbuminuria linked to CVD and renal disease. A moderate increase in albumin excretion is also present in other conditions, like obesity, posture, exercise, diet, smoking, gender, puberty, infection, and inflammation. Hence, they are always not linked to renal disease.

TRANSIENT ALBUMINURIA:

Conditions associated with transient albuminuria were decompensated heart failure, vigorous exercise, fever, UTI, postural changes, or sleep apnea. Hence, confirmation of persistent microalbuminuria within three months of initial detection is recommended by the ADA and the National Kidney Foundation.

MICROALBUMINURIA AND CLINICAL SIGNIFICANCE:

Microalbuminuria is the identified marker of endothelial dysfunction associated with cardiovascular risk factors and inflammation markers. The presence of microalbuminuria significantly increases the risk for cardiovascular morbidity and mortality. Cross-sectional studies to indicate that microalbuminuria in hypertensive non-diabetics was associated with an increase in all-cause mortality. Most of the studies in nondiabetic hypertensives indicate a2to4 fold Increase in cardiovascular risk.

ECGCOMPLEXES

P-Wave: The deflection produced by atrial depolarization.

QRS Complex: Results from depolarization of right and left ventricles.

QRS Interval: From the beginning of Q-wave to the end of S-wave, the normal range is

0.08 to 0.12 second

T-Wave: The deflection produced by ventricular repolarization.

U-wave: The deflection (usually positive) is seen following T-wave. The exact cause of this deflection is unknown. It is currently thought to be due to the ventricular (Purkinje) conductive system's slow repolarization. U-wave is positive in leads in which the QRS complex is positive. The abnormal U-wave is either exaggeration of average U-wave voltage, U-wave appearance. It is not usually seen, or inversion of U-wave occurs in ischemic heart disease hypokalemia and various cerebrovascular accidents. PR interval: beginning of the P-wave to the beginning of Q- wave, the average duration is 0.12 to 0.20 sec. QT interval: From the beginning of the Q wave to the end of the T wave., the average duration is 390-450 ms in men and 390-460 ms in women.

ECHOCARDIOGRAM:

Echocardiography is one of the most versatile non-invasive imaging techniques in clinical cardiology. Because it does not utilize ionizing radiation, itis free of known risk and can be used safely throughout pregnancy. Transthoracic imaging with the transducer applied to the chest wall is usually satisfactory. Better quality information is obtained by the transoesophageal approach, in which the transducer is mounted on a probe and positioned in the esophagus directly behind the heart. It provides better quality images because noribsare intervening, and a probeisc losel applied to the heart. It is particularly useful for imaging the left atrium, aorta, prosthetic heart valves.

Principles:

A transducer containing a piezoelectric element converts electrical energy into an ultrasound beam directed towards the heart. The beam is reflected when it strikes an interface between different density tissues. The reflected ultrasound, or echo, is converted back to electrical energy by the piezoelectric element, which permits the construction of an image using two basic information units.

• The echoes' intensity defines the density difference at tissue interfaces within the heart
• The time taken for echoes to arrive back at the transducer defines the distance of the cardiac structures from the transducer.

Density differences within the heart are greatest between the blood-filled chambers and the myocardial and valvular tissues, all of which are visible on the echocardiogram. Thus, real-time imaging throughout the cardiac cycle provides a Dynamic cardiac function record.

M-mode Echocardiogram:

This provides a unidimensional 'ice-pick' view through the heart. Continuous recording on photographic paper provides an additional time dimension, there by permitting the dynamic component of the cardiac image. Thus, on the transthoracic M-mode echocardiogram, anteriorly located (right-sided) structures lie above the posteriorly located (left-sided) structures, but on the transesophageal echocardiogram, the display is reversed.

MATERIALS AND METHODS

SOURCEOF DATA: The data was collected from the Department of General Medicine, Sri Aurobindo Medical College & PG Institute-Indore (M.P.)

Type of study: Prospective observational study

Duration: October 2022 to October 2024

Inclusion criteria: Age above 20 Years and

• Subjects with Systolic Blood pressure in the range of 120 to 129 and diastolic blood pressure in the range of <80 mm of Hg.
• Subjects with fasting blood glucose range from 100to125mg/dl after8 hours overnight fast and 2-hour postprandial blood sugar after 75g of OGTT between 140-199 mg/dl.
• Spot A Murinealbumin/ creatinine ratio of 30 to 300mg/gm or 24 hr urine protein count between 30 to 300 mg/day or Urinary dipstick estimation, BMI in the range of 19 to 25 kg/m2, normal kidneys on renal ultrasound and normal blood urea and serum creatinine levels, no clinical history Suggestive of CKD.

Exclusion criteria:

Subjects with febrile illness, diabetes, hypertension, Heart failure and stroke, UTI, chronic kidney disease, smokers and athletes, and subjects are taking analgesics and diuretics.

Method of Collection of Data Group1 Isolated prediabetics. Group2 Isolated prehypertensives.

Group 3 subjects with both prediabetes and prehypertension.

All the patients underwent a clinical examination in the form of physical, demographics, vitals pulse rate, respiratory rate, Blood pressure, temperature, systemic examinations, etc

Relevant examinations like Fasting & Random blood sugar, 2 hr postprandial sugar, ECG, 2D ECHO, USG scan Abdomen were performed.

• Complete blood count
• Erythrocyte sedimentation rate
• Renal function test
• Serum electrolytes
• Serum Lipid profile

ECG-CRITERIA

• A heart rate of less than 60/ min is regarded as bradycardia, and a heart rate is exceeding 100/ min as tachycardia.
• ST-segment depression, which is 0.5mm or the elevation of more than1 mm, was taken as abnormal.
• If there is an inversion of T-waves in lead so ther than aVRandV1itis taken as abnormal.
• QT cif it more than 0.44m-secondsis taken as prolonged
• U-wave was considered significant when exaggerating U-wave voltage was noted when appeared in more than 2-leads.(>25% of T wave ) and inverted when T waves are upright.

2D ECHO CRITERIA:

Echocardiographic variables were calculated according to American society of echocardiography (ASE) guidelines

• LV systolic function was identified by LV ejection fraction. Doppler indices (A>E across the mitral valve) were used for the LV diastolic dysfunction.
• Mitral valve opening by planimetry was used to see the mitral stenosis apart from the valve thickening, and doming of AML and paradoxical motion of PML were used.
• Flow across the aortic valveis used to look at the aortic stenosis.
• Color imaging and Doppler are used for any regurgitation.
• 2D imaging is used to rule out left atrial thrombus.

Left ventricular internal dimensions at systole and diastole (LVIDs and LVIDd), interventricular septal dimension (IVSd) and posterior wall thickness (PWT) were measured.

Estimation of Microalbuminuria by Micral test: All patients with overt macroalbuminuria detected by albustix (Combur test) were excluded from the study. Micral test, an immunological rapid dip stick semi qualitative technique for detecting microalbuminuria, was used to estimate microalbuminuria.

Micral test components: The test strip contains monoclonal antibodies against human albumin (immunoglobin G) labelled with colloid Gold.

Gender: The total Number of subjects studied was 50, and the studied population's age varied from 20 to 65 years.

The mean age of the study population was 44.3±9.6.

There were 28 males, and 22 female subjects were recorded.

The male subjects' mean age was 43.9±10.2, and that of female subjects was 44.7± 8.8 years. 64% of the studied population was in the age group of 30 to 50 years.

Table 6. Age & gender distribution of the study population.

Chisquaretest; ns: not significant, Chi-square value= 2.56

Figure 4: Age & gender distribution of the study population BMI The mean body mass index of the study population was 23.84±0.85Kg/m2.

Table 8. Hyperlipidemiain Pre-hypertensive, prediabetic, and Pre- hypertensive and prediabetic subjects

In the present study, hyperlipidemia in 2% of Prediabetic, 4% in Prehypertensive, and 8% in Both Pre-hypertensive and Prediabetic subjects observed with statistical significant difference between normal and hyperlipidemia in three groups.

Table 9. SBP and DBP in male & female subjects

Prevalence of pre-hypertension and prediabetics: Of the total 50 subjects, 12 had isolated prehypertension, 15 subjects had isolated prediabetic, and 23 had both prediabetic and prehypertensive.

Table 12. Association of three groups with Microalbuminuria positive and Microalbuminuria negative

When all the major study subgroups were examined for their association with Microalbuminuria statistically significant associations were seen with all the study sub groups p=0.001 for preDM, p=0.001 for pre HTN and p=0.001 for both prediabetes and prehypertension.

Table15. Incidence of Pre-hypertensive and Prediabetic subjects in the studied population.

ECG & 2D ECHO Changes ECG changes were assessed using Minnesota codes 4-1e4-2 for ST segment depression and 5- 1e5-3 for T wave changes. Echocardiographic variables were calculated according to American society of echocardiography (ASE) guidelines.

Table 16: ECG changes in Microalbuminuria positive and Micro albuminuria negative patients

Cardiac involvement as manifested by ST and T wave changes was seen in 9 cases of Microalbuminuria positive. In the present study, it is evident from the above table, ECG abnormalities among Microalbuminuria group, ST and T wave changes (18%) were the most common abnormalities followed by tachycardia (4%), and Arrhythmias (2%). In cases of Normoal buminuria group, ST-segment depression (2%), Arrhythmias (2%), T-Wave inversions (1%), and Tachycardia (2%).

Table17. 2D Echo changes in Microalbuminuria positive and Microalbuminuria negative patients

Increased left ventricular mass index were observed in11 cases of Microalbuminuria positive.

Among the Microalbuminuria group, the 2Decho abnormalities, LV dysfunction (22%) was most common, followed by aortic valve (2%) abnormality.

Incases of Normo albuminuria subjects, LV dysfunction (4%) was the abnormality.

Table21: Relationship between Microalbuminuria and 2 DEcho changes

Chisquare value =11.125, PValue <0.001(high Sig.)

2D ECHO abnormalities are statistically significant in patients with Microalbuminuria (22%) than Normo albuminuria (26). Binary logistic regression analysis found to be significant predictor for ST and T wave changes p<0.001 for prediabetes and prediabetes and both prediabetes and prehypertension were found to be significant predictors of increased LVMI p=0.05 for prediabetes and p=0.05 for both prediabetes and prehypertension.

The current study examined the prevalence of Microalbuminuria in prediabetes, prehypertension, coexistent prediabetes, and prehypertension. The total number of subjects studied was 50, and the studied population's age varied from 20 to 65 years. Estimating urinary microalbumin was done for all patients using a micral strip test with early morning urine samples. Micral test has got comparable sensitivity of 88% and specificity of 99%.

In our present study, the prevalence of Microalbuminuria was 40% in the overall study population, with a prevalence rate of 24% in total male subjects and 16% of total female subjects. The results were comparable with other studies.

Sriharibabu et al. (2014) in their study, Microalbuminuria was seen in 40% of the total study population. The prevalence of Microalbuminuria in males was 50%, and in females, it was 30%.

In our study, the prevalence of Microalbuminuria was 10% of isolated prediabetics, 10% of isolated pre- hypertensives and 20%of subjects with prehypertension and prediabetes.

The study by Sriharibabu et al. (2014) showed that microalbuminuria was observed in 22.2% of prediabetics, 25% of prehypertensives and 58% of patients with both prehypertension and prediabetes.38

The majority of the study subjects with Microalbuminuria were in the age group of 41 to 60 years with 32%, followed by 20 to 40 years, with 22% prevalence in our study. Even in the study subgroups, microalbuminuria prevalence rates were higher in males than in female patients.

A study conducted by Sharan et al.57 showed the prevalence of microalbuminuria to be 63%. In a study by Bohm et al. in 2007, the prevalence of microalbuminuria was found to be 58.4%, in which males were affected more than female patients. 39

A study by Hitha et al. in the year 2008 in South India showed the prevalence of microalbuminuria to be 26.6%.41

A study by Sriharibabu et al. reported that most of the study subjects with Microalbuminuria were in 30 to 50 years, with a progressive increase from 3rd to 5th decades. Even in the study subgroups, microalbuminuria prevalence rates were higher in male subjects than female subjects.

Various other studies were conducted and reported that advancing the age and male gender are associated with higher prevalence rates of Microalbuminuria. The observations made in this study are in accordance with those studies.

The other observations made in this study were that prehypertension is more commonly seen in males at a younger age than females, and prediabetes is more common after 40 years in both males and females. These observations have implications while screening populations for prediabetes and prehypertension.As both prediabetes and prehypertension ultimately progress to diabetes and hypertension in the majority, their prevalence rates decreased with advancing age.

ATTICA study, Strong Heart Study and other studies were confirmed that prehypertension and prediabetes conditions could increase the risk of developing cardiovascular disease.57,58

In our study, 26% of Microalbuminuria subjects were showing ECG changes in the form of ST-segment and T wave changes, and 22% of subjects of Microalbuminuria positive were showing 2DECHO changes in the form of increased LVMI in the total study populations.

Yu-Qing Huang et al., the study also suggested that prehypertension is associated with an increased risk for cardiovascular and all-cause mortality compared with diabetes,but not for prehypertension alone.

Where as study by Srihari babu et al. demonstrated that cardiac involvement in 32.5% of subjects in the form of ST-segment and T wave changes and 25% subjects in the form of increased LVMI in the total study population.

In our study of ECG abnormalities, ST and T wave changes were observed in subjects of 40-60 age groups; the increased

LVMI in 2DECHO was observed predominantly in the 40 to 60 years age group. Increased LVMI was observed higher in males than in females.

A study by Sriharibabu et al. demonstrated that ST and T wave changes were seen in subjects of all age groups where increased LVMI was observed predominantly in the 30 to 50 years age group.

In our study, cardiac involvement was more commonly observed in prehypertensives and prehypertension and prediabetes than isolated prediabetes in the total study population.

Cardiac changes were significantly higher in Microalbuminuria positive subjects than Microalbuminuria negative subjects p<0.001 for ST and T wave changes in ECG and p<0.001 for increased LVMI in 2DECHO. Future cardiovascular clinical trials involving drugs that target albuminuria more specifically are needed to resolve whether specific lowering of albuminuria results in cardiovascular protection and whether this is a cost- effective health care approach.

This study's limitations were the low sample size for assessing the cardiovascular risk associated with Microalbuminuria. This study's results cannot be extrapolated, as there were differences in the studied populations and selection criteria.

• In our study, 26% of Microalbuminuria subjects showed ECG changes in the form of ST-segment and T wave changes, and 22% of Microalbuminuria subjects were showing 2DECHO changes in the form of increased LVMI in the total study populations.
• Microalbuminuria may be an ideal target for early primary prevention using Cardiovascular protective therapy regimens. Microalbuminuria may prove a biomeasure for individualizing treatment regimens in subjects with CVD risk.
• Lifestyle modifications like healthier diet (high fiber, whole grain, fruit and vegetable-rich, calorie deficit), increased physical activity (at least 150 minper week) and weight loss (7% of current weight) in these otherwise healthy adults with coexisting PreHTN and PreDM could prevent conversion to hypertension, diabetes mellitus, or both. This is the first step in the primary prevention of CVD.

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