Cardiovascular diseases are the major cause of death worldwide, and from these coronary heart disease is the most important cause of sudden death. The risk associated with cardiovascular disease can in many ways be estimated from electrocardiogram (ECG). The electrocardiographic variables prolonged QT interval, increased magnitude of T wave alternans (TWA) and higher heart rate (HR) are all associated with increased risk of unfavourable cardiac events.
Prolonged QT interval, and also increased TWA, can be a consequence of genetic variation in cardiac ion channels or other proteins affecting intracellular ion balance. The association of genetic variation with cardiac repolarization, measured as QT interval, has been widely studied, but most of the studies have focused on variables in ECG measured at rest, while systematic studies concerning these associations during exercise or recovery are largely missing. The genetic background of TWA has not been systematically studied.
Previous population based studies have repeatedly shown that higher resting HR is associated with less favourable prognosis in subjects with and without previous history of cardiovascular disease. Higher HR is also related with faster pulse wave velocity, an acknowledged marker of arterial stiffness. However, there is also a clear association of higher HR with decreased augmentation index, i.e. reduced central pressure wave reflection, which is considered to be haemodynamically beneficial.
The aim of the present thesis was to study the genetic and haemodynamic background of the ECG risk markers, QT interval, TWA, and HR at rest during physical challenge. The associations between genetic variants with cardiac repolarization during exercise testing were examined because the present knowledge in this context is limited, and also the reasons why higher HR is associated with less favourable prognosis are not well understood.
A total 2212 Finnish Cardiovascular Study (FINCAVAS) participants were genotyped using TaqMan assays, and their maximal TWA values and QT intervals were measured from continuous ECG recordings during clinical exercise test at rest, exercise and recovery. The examined nucleotide polymorphisms were located in the cardiac ion channel genes KCNH2 (rs1805123), SCN5A (rs1805124), KCNE1 (rs727957 and rs1805127) and in nitric oxide synthase gene, NOS1AP (rs10494366), all of which have been previously found to be functionally relevant.
The DYNAMIC study subjects (n=522, 261 men, aged 20-72 years, without medication directly affecting HR) were examined in order to gain information about the association between higher HR and the less favourable prognosis observed in population studies. The relationship of resting HR with the principal haemodynamic variables peripheral and central blood pressure, stroke volume, cardiac output, systemic vascular resistance, and markers of left cardiac work, cardiac oxygen demand, arterial stiffness and central wave reflection were examined. The haemodynamic variables were noninvasively recorded in supine and upright position by the use of whole body impedance cardiography and radial applanation tonometry.
In the FINCAVAS study the polymorphism rs1805123 of KCNH2 was associated with QT interval within women only at rest, but this polymorphism was not associated with TWA. From the studied polymorphisms the rs1805127 of KCNE1 was associated with TWA in the whole study population, but the relationship was most significant within women. The polymorphisms rs727957 and rs1805124 were not related with TWA. In addition, rs10494366 of NOS1AP was associated with TWA during exercise testing in a sex-specific manner.
In the DYNAMIC study population higher resting HR was significantly associated with lower stroke volume but also with higher cardiac output, reflecting increased cardiac work. Higher HR was also associated with increased arterial stiffness. Moreover, higher HR showed a relatively weak but significant association with elevated blood pressure. All relations remained remarkably similar during supine and upright positions. In conclusion, this thesis studied the background of ECG risk markers. From the studied genetic variants the polymorphisms rs1805123, rs1805127 and rs727957 were associated with cardiac repolarization, measured as QT interval or TWA during clinical exercise testing. In addition, the basic and easily available ECG variable, HR, was associated with increased cardiac work and arterial stiffness, and to a lesser extent with elevated blood pressure, in both supine and upright position. Knowledge of these ECG-related characteristics may provide useful additional information for the risk stratification of cardiovascular diseases in the future.