Krishna Prasad

Human gene for physical performance

A specific genetic factor that strongly influences human physical performance has not so far been reported, but here we show that a polymorphism in the gene encoding angiotensin-converting enzyme does just that. An ‘insertion’ allele of the gene is associated with elite endurance performance among high-altitude mountaineers. Also, after physical training, repetitive weight-lifting is improved eleven-fold in individuals homozygous for the ‘insertion’ allele compared with those homozygous for the ‘deletion’ allele.

Increased central pulse pressure and augmentation index in subjects with hypercholesterolemia

OBJECTIVES The goal of this study was to investigate the relation between serum cholesterol, arterial stiffness and central blood pressure. BACKGROUND Arterial stiffness and pulse pressure are important determinants of cardiovascular risk. However, the effect of hypercholesterolemia on arterial stiffness is controversial, and central pulse pressure has not been previously investigated. METHODS Pressure waveforms were recorded from the radial artery in 68 subjects with hypercholesterolemia and 68 controls, and corresponding central waveforms were generated using pulse wave analysis. Central pressure, augmentation index (AIx) (a measure of systemic stiffness) and aortic pulse wave velocity were determined. RESULTS There was no significant difference in peripheral blood pressure between the two groups, but central pulse pressure was significantly higher in the group with hypercholesterolemia (37 +/- 11 mm Hg vs. 33 +/- 10 mm Hg [means +/- SD]; p = 0.028). Augmentation index was also significantly higher in the patients with hypercholesterolemia group (24.8 +/- 11.3% vs. 15.6 +/- 12.1%; p < 0.001), as was the estimated aortic pulse wave velocity. In a multiple regression model, age, short stature, peripheral mean arterial pressure, smoking and low-density lipoprotein cholesterol correlated positively with AIx, and there was an inverse correlation with heart rate and male gender. CONCLUSIONS Patients with hypercholesterolemia have a higher central pulse pressure and stiffer blood vessels than matched controls, despite similar peripheral blood pressures. These hemodynamic changes may contribute to the increased risk of cardiovascular disease associated with hypercholesterolemia, and assessment may improve risk stratification.

Association of Angiotensin-Converting Enzyme Gene I/D Polymorphism With Change in Left Ventricular Mass in Response to Physical Training

BACKGROUND The absence (deletion allele [D]) of a 287-base pair marker in the ACE gene is associated with higher ACE levels than its presence (insertion allele [I]). If renin-angiotensin systems regulate left ventricular (LV) growth, then individuals of DD genotype might show a greater hypertrophic response than those of II genotype. We tested this hypothesis by studying exercise-induced LV hypertrophy. METHODS AND RESULTS Echocardiographically determined LV dimensions and mass (n=140), electrocardiographically determined LV mass and frequency of LV hypertrophy (LVH) (n=121), and plasma brain natriuretic peptide (BNP) levels (n=49) were compared at the start and end of a 10-week physical training period in male Caucasian military recruits. Septal and posterior wall thicknesses increased with training, and LV mass increased by 18% (all P<.0001). Response magnitude was strongly associated with ACE genotype: mean LV mass altered by +2.0, +38.5, and +42.3 g in II, ID and DD, respectively (P<.0001). The prevalence of electrocardiographically defined LVH rose significantly only among those of DD genotype (from 6 of 24 before training to 11 of 24 after training, P<.01). Plasma brain natriuretic peptide levels rose by 56.0 and 11.5 pg/mL for DD and II, respectively (P<.001). CONCLUSIONS Exercise-induced LV growth in young males is strongly associated with the ACE I/D polymorphism.

Prospective Prognostic Assessment of Blood Pressure Response During Exercise in Patients With Hypertrophic Cardiomyopathy

BACKGROUND Previous studies revealed that an abnormal blood pressure response (ABPR) during exercise was common in young hypertrophic cardiomyopathy (HCM) patients and was associated with a family history of premature sudden cardiac death (SCD). This study was performed prospectively to assess the prognostic significance of blood pressure response during exercise in young patients with HCM. METHODS AND RESULTS Maximum symptom-limited treadmill exercise testing with continuous blood pressure monitoring was performed in 161 consecutive patients 8 to 40 years old (27+/-9). A normal blood pressure response, defined as an increase in the systolic pressure of at least 20 mm Hg from rest to peak exercise in the absence of a fall of >20 mm Hg from peak pressure, was seen in 101 (63%). In 60 (37%), the blood pressure response was abnormal. There was no significant difference in patients with normal blood pressure response and ABPR in terms of age, sex, follow-up, or recognized risk factors for SCD. During the follow-up period (mean, 44+/-20 months), SCD occurred in 12 patients: 3 (3%) in the normal blood pressure response group versus 9 (15%) in the ABPR group (P<.009). ABPR had a sensitivity of 75%, a specificity of 66%, a negative predictive value of 97%, and a positive predictive value of 15% for the prediction of SCD. There was no significant difference in the incidence of other recognized risk factors between patients with SCD and the survivors. CONCLUSIONS A normal exercise blood pressure response identifies low-risk young patients with HCM. An ABPR identifies the high-risk cohort; the low positive predictive accuracy, however, indicates that further risk stratification is warranted.

Angiotensin-converting-enzyme gene insertion/deletion polymorphism and response to physical training.

BACKGROUND The function of local renin-angiotensin systems in skeletal muscle and adipose tissue remains largely unknown. A polymorphism of the human angiotensin converting enzyme (ACE) gene has been identified in which the insertion (I) rather than deletion (D) allele is associated with lower ACE activity in body tissues and increased response to some aspects of physical training. We studied the association between the ACE gene insertion or deletion polymorphism and changes in body composition related to an intensive exercise programme, to investigate the metabolic effects of local human renin-angiotensin systems. METHODS We used three independent methods (bioimpedance, multiple skinfold-thickness assessment of whole-body composition, magnetic resonance imaging of the mid-thigh) to study changes in body composition in young male army recruits over 10 weeks of intensive physical training. FINDINGS Participants with the II genotype had a greater anabolic response than those with one or more D alleles for fat mass (0.55 vs -0.20 kg, p=0.04 by bioimpedance) and non-fat mass (1.31 vs -0.15 kg, p=0.01 by bioimpedance). Changes in body morphology with training measured by the other methods were also dependent on genotype. INTERPRETATION II genotype, as a marker of low ACE activity in body tissues, may conserve a positive energy balance during rigorous training, which suggests enhanced metabolic efficiency. This finding may explain some of the survival and functional benefits of therapy with ACE inhibitors.

Cardiac fatigue following prolonged endurance exercise of differing distances.

PURPOSE Recent echocardiographic studies have reported cardiac dysfunction following ultra-endurance exercise in trained individuals. The duration of exercise required to elicit cardiac dysfunction and the mechanisms underlying this phenomenon have not been fully elucidated. The aim of the present study was to examine the presence of cardiac dysfunction following a half-Ironman and Ironman triathlon in trained individuals. METHODS 14 male triathletes (age: 32 +/- 5 yr; height: 180 +/- 8 cm; body mass: 75 +/- 9 kg) completed a half-Ironman triathlon. Following a 4-wk period, 10 of the original 14 triathletes completed an Ironman triathlon. All triathletes were assessed using ECG, echocardiography, and blood analysis pre-, immediately post-, and 48 h postrace for both distances. RESULTS Echocardiographic results indicated diastolic and systolic left ventricular dysfunction, for both race distances, which were associated with altered relaxation characteristics and a reduced inotropic contractility, respectively. Following 48-h recovery, all echocardiographic measures were similar to resting values. Creatine kinase MB (CKMB) was significantly elevated immediately postrace for both distances; however, it accounted for less than 5% of the total CK value and in the presence of an elevated total CK and CKMM implied that the elevated CKMB was noncardiac in origin. Troponin-T, however, was significantly elevated immediately postrace for both distances and returned to normal following 48-h recovery indicating myocardial damage. CONCLUSIONS Ironman and half-Ironman competition resulted in reversible abnormalities in resting left ventricular diastolic and systolic function. Results suggest that myocardial damage may be, in part, responsible for cardiac dysfunction, although the mechanisms responsible for this cardiac damage remain to be fully elucidated.

QT dispersion and risk factors for sudden cardiac death in patients with hypertrophic cardiomyopathy

This study examines the relation of QT dispersion (QTd) on a surface electrocardiogram (ECG) to clinical features and established risk factors of sudden cardiac death (SCD) in patients with hypertrophic cardiomyopathy (HC). One hundred fifty-six consecutive patients with HC (91 men, mean age 41+/-15 years, range 7 to 79) and 72 normal subjects (41 men, mean age 39+/-9 years, range 20 to 60) were studied. Standard 12-lead ECGs were recorded from each subject using a MAC VU electrocardiograph. Patients with nonsinus rhythm, atrioventricular conduction block, QRS duration > 120 ms, age < 15 years, and low amplitude T waves were excluded from the analysis (n=51). Another 22 patients who were receiving amiodarone and/or sotalol therapy were also excluded. QT interval and QTd were measured using automated analysis in the remaining 83 patients (46 men, age 40+/-14 years, range 16 to 76). QT interval (406+/-38 ms), QTc interval (432+/-27 ms), and QTd (43+/-25 ms) were significantly greater in patients with HC than in normal controls (386+/-31 ms, 404+/-16 ms, 26+/-16 ms, respectively) (p <0.0001). QTd was significantly greater in patients with HC with chest pain compared with asymptomatic or mildly symptomatic patients (50+/-28 ms vs 37+/-20 ms, p=0.02). Increased QTd was found in patients with dyspnea New York Heart Association functional classes II/III than in those with dyspnea New York Heart Association functional class I (50+/-27 ms vs 38+/-22 ms, p=0.04). QTd was weakly correlated with maximum left ventricular wall thickness (r=0.228, p=0.038). No significant association was found between QTd and any risk factors for SCD. Thus, patients with HC have increased QTd. The QTd correlates with symptomatic status. Assessment of QTd might provide complementary clinical characterization of patients with HC but its relation to SCD remains uncertain.

Is there increased sympathetic activity in patients with hypertrophic cardiomyopathy

OBJECTIVES This study aimed to assess autonomic nervous system activity in patients with hypertrophic cardiomyopathy. BACKGROUND Patients with hypertrophic cardiomyopathy are traditionally thought to have increased sympathetic activity. However, convincing evidence is lacking. METHODS Heart rate variability was assessed from 24-h ambulatory electrocardiographic (Holter) recordings in 31 patients with hypertrophic cardiomyopathy and 31 age- and gender-matched normal control subjects in a drug-free state. Spectral heart rate variability was calculated as total (0.01 to 1.00 Hz), low (0.04 to 0.15 Hz) and high (0.15 to 0.40 Hz) frequency components using fast Fourier transformation analysis. RESULTS There was a nonsignificant decrease in the total frequency component of heart rate variability in patients with hypertrophic cardiomyopathy compared with that of normal subjects (mean +/- SD 7.24 +/- 0.88 versus 7.59 +/- 0.57 ln[ms2], p = 0.072). Although there was no significant difference in the high frequency component (5.31 +/- 1.14 versus 5.40 +/- 0.91 ln[ms2], p = 0.730), the low frequency component was significantly lower in patients than in normal subjects (6.25 +/- 1.00 versus 6.72 +/- 0.61 ln[ms2], p = 0.026). After normalization (i.e., division by the total frequency component values), the low frequency component was significantly decreased (38 +/- 8% versus 43 +/- 8%, p = 0.018) and the high frequency component significantly increased (16 +/- 6% versus 12 +/- 6%, p = 0.030) in patients with hypertrophic cardiomyopathy. The low/high frequency component ratio was significantly lower in these patients (0.94 +/- 0.64 versus 1.33 +/- 0.55, p = 0.013). In patients with hypertrophic cardiomyopathy, heart rate variability was significantly related to left ventricular end-systolic dimension and left atrial dimension but not to maximal left ventricular wall thickness. No significant difference in heart rate variability was found between 14 victims of sudden cardiac death and 10 age- and gender-matched low risk patients. CONCLUSIONS Our observations suggest that during normal daily activities, patients with hypertrophic cardiomyopathy experience a significant autonomic alteration with decreased sympathetic tone.

Echocardiographic pitfalls in the diagnosis of hypertrophic cardiomyopathy

The diagnosis of hypertrophic cardiomyopathy (HCM) can often be difficult. Traditionally, it has been a diagnosis of exclusion, requiring the demonstration of left ventricular hypertrophy (LVH) in the absence of other causes, such as systemic hypertension or aortic stenosis.1 2 Early reports focused on the presence of asymmetrical hypertrophy with an outflow tract gradient (hence the acronym HOCM) but it has become clear that this is not the most common appearance.3-7 Furthermore, recent reports of genotypically affected individuals without hypertrophy, who are nevertheless at risk of sudden death,8 further complicate the situation. Recently, McKenna and colleagues9 proposed modified criteria for the diagnosis of HCM, which overcome some of the problems associated with the conventional criteria (table 1). The new proposed criteria highlight the importance of a comprehensive family history and 12 lead electrocardiogram (ECG) over the echocardiogram in the diagnosis of HCM. Even then, extreme care must be taken because systematic family screening programmes have identified patients who are phenotypically normal but have affected siblings and offspring. These carriers can be missed and their progeny miscoded with less rigorous protocols. Diagnosis can only be 100% reliable when all the implicated gene loci have been identified. Until then the combination of ECG and echocardiography, in conjunction with other clinical information, remain the most useful tests for the diagnosis of patients with HCM. Here, we discuss some of the pitfalls encountered in the echocardiographic evaluation of HCM. View this table: Table 1 Echocardiographic pitfalls As a rule, patients with HCM have a considerably increased left ventricular wall thickness, an echocardiographic marker of ventricular hypertrophy, with a small non-compliant but apparently well contracting left ventricle. Early M mode echocardiographic studies defined the characteristic features as asymmetrical hypertrophy of the ventricular septum, with or without systolic anterior motion of the mitral valve, and premature closure …

T Wave Complexity in Patients with Hypertrophic Cardiomyopathy

The complexity of the T wave assessed by principal component analysis (PCA) has been proposed to reflect obnormal repolarization, which may be arrhythmogenic. To determine whether PCA can differentiate patients with hypertrophic cardiomyopathy (HCM) from normal subfects and whether PCA is of prognostic importance in HCM, 112 patients with HCM (41 ±14 years, 64 males) and 72 healthy subjects (39 ± 9 years, 41 males) were studied. Patients with sinus node dysfunction, AV conduction block, flat T waves, QRS > 140 ms, and those < 15 years were excluded from this study. Standard 12‐lead ECGs were recorded digitally using the MAC‐VU system (Marquette Medical Systems). PCA parameters were computed using the QT Guard software package by Marquette. PCA ratio was significantly greater in HCM patients than in normal controls (23.9%± 12.4% vs 16.1%± 7.6%, P < 0.0001) and was correlated with QT‐end dispersion (r = 0.24. P = 0.01) and QT peak (Q point to T peak) dispersion (r = 0.35, P < 0.0001). HCM patients with syncope (n = 23) had increased PCA ratios compared with those without syncope (29.1%± 11.5% vs 22.5%± 12.3%, P = 0.01). PCA ratio was similar in patients with and without nonsustained ventricular tachycardia on Holter (25.9%± 11.4% vs 22.7%± 12.1%, P = 0.2), as well as in patients treated with amiodarone or sotalol versus those not on therapy. In conclusion, assessment of the complexity of the T wave by PCA differentiates HCM patients from normal subjects. PCA ratio correlated with QT dispersion and an increased PCA ratio was associated with a history of syncope in HCM.