Characteristic of study-subjects and groups
After excluding subjects with previous coronary artery disease, myocardial or valvular heart disease, the final study sample included 1707 out of 2207 participants, of which 852 were defined as subjects with normal heart structure and function. As shown in Table 1, the groups of hypertensive and normotensive individuals were of approximately equal size. Among hypertensive patients, the majority had moderately increased BP (140–159 mmHg) during the visit. BP during the visit was significantly higher in men than in women, and more women received antihypertensive medication. Participants with moderately increased systolic BP and with systolic BP > 160 mmHg were largely from the KYH study (56% and 65%, respectively). Normal subjects were the youngest, and their BP values increased with age. All groups with hypertension had significantly higher BMI, higher prevalence of diabetes, and higher creatinine and NT-proBNP levels, indicating the presence of subclinical heart failure.
LV geometrical and functional parameters
Table 2 shows the LV geometrical and functional parameters comparing groups A-D. Adjustments of the mean values using multiple linear regression for factors known to affect cardiac function created only minor differences between the unadjusted and adjusted mean values. The unadjusted mean values with their respective standard deviations (SD) are displayed in the supplemental material (Table S1-S3). In general, there may be a gradual change in most of the parameters from normal subjects over the hypertensives with normalized, moderate and high BPs. Thus, individuals with the highest BP displayed the lowest ejection fractions and LV stroke volumes; and the highest LV masses, LV ES diameters, and heart rates. Compared with the normal control group, all hypertensive patients had higher LV ED and ES volumes and septal thickness, without significant differences between the hypertensive groups.
As shown in Table 3, all diastolic functional parameters were significantly different from those of the normotensive controls, with a gradual change towards the group with the highest BP. Reduced septal and lateral systolic (TD s´) and septal early diastolic tissue Doppler (TD e’), lower E-velocity, lower E/A ratio, higher A velocity, longer MV E DT, and increasing LA size indicate gradually decreasing relaxation properties in parallel with higher BP. Indicators of increased filling pressures, such as an E/A ratio >1.5 or low MV DT, were not higher in the hypertensive groups.
Table 4 demonstrates the effect of hypertension on myocardial functional strain and SR parameters. With increasing BP, the global strain of all layers, SR S, and SR E gradually decreased. Interestingly, hypertension had no significant effect on the percentage of segments with post systolic strain.
Figure 2 shows significant basal-to-apical strain gradients in all layers and hypertensive groups. In the presence of hypertension, the strain was significantly reduced in all basal septal and medial segments and had little effect on the apical segments. This renders a slightly higher basal-apical gradient for all segmental layer strains. Figure 3 demonstrates the apico-basal gradients for systolic and diastolic SR comparing the different hypertensive groups. Interestingly, systolic SR did not seem to be significantly affected by hypertension, while SR E decreased in all segments as a sign of reduced relaxation properties. While the reduction of systolic strain and SR only affects basal and medial segments, SR E was the only parameter that showed a significant difference between normal and hypertensive apical segments. SR A, an indicator of LV compliance, increases in parallel with increasing blood pressure, and SR A was the only S/SR parameter without a basal-to-apical gradient. As BP has a significant effect on global and segmental S/SR values, we generated global and segmental reference values for the S/SR parameter in individuals with elevated BP, as shown in Table 5.
DISCUSSION
Main findings:
To our knowledge, this is the largest study to describe the influence of treated or untreated hypertension on global and segmental S/SR, and the first study describing segmental SR E and SR A in hypertensive patients.
The main findings of the study are:
  1. Segmental basal-to-apical and endo- to epicardial gradients of S/SR are similar in normal individuals and individuals with hypertension.
  2. All segmental systolic S/SR and SR E were reduced in hypertension compared to individuals with normal blood pressure. The reduction of systolic S/SR only affected the medial and basal segments, while SR E was also significantly reduced in the apical segments.
  3. We demonstrated the dependency of S/SR values on increasing blood pressure, while individuals with normal BP on antihypertensive medication displayed a significant but less pronounced reduction.
  4. SR A was the only segmental parameter without basal-to-apical gradients. SR A increased with antihypertensive treatment and increasing BP.
LV geometry, systolic and diastolic function
The combination of lowered longitudinal systolic contraction and abnormal diastolic LV filling may play a key role in the development of acute and chronic heart failure in hypertensive patients.
LV systolic function is commonly considered normal in the presence of a normal EF and fractional shortening, despite the fact that neither index reflects all aspects of LV contractile function (13). However, numerous population studies have demonstrated the detrimental impact of a chronically increased afterload in hypertension on both LV global and segmental function (14-18). In accordance with previous studies, the present results showed increasing septal hypertrophy and ventricular mass in participants with hypertension, both in those well-controlled with antihypertensive treatment and more so in the uncontrolled group with increased blood pressure. Similar to previous reports (18), the ventricular cavity was slightly enlarged, and the EF was slightly but significantly reduced. Thus, the extreme form of hypertensive remodeling with a smaller LV cavity does not seem to constitute the majority of hypertension.
Changes in the diastolic properties of hypertensive individuals are well known, and several mechanisms have been discussed. First, impaired relaxation is caused by prolonged systolic contractions followed by delayed relaxation (19). Micro-scarring may also cause weakened or delayed relaxation (19). Second, diastolic LV filling pressures might increase due to low ventricular compliance with stiffened scarred myocardium or a small ventricular cavity.
In the hypertensive population of our present study, the predominant diastolic dysfunction was impaired relaxation, which gradually increased with BP. Thus, hypertensives showed prolonged MV E DT and reduced MV E velocity and septal and lateral e´. In 10% of all hypertensives, NT-proBNP levels were pathologically elevated, indicating increased filling pressures, while remaining normal in all healthy controls. This observation is congruent with the close connection between heart failure, preserved EF, and hypertensive hearts (20). However, echocardiographic parameters for elevated filling pressures such as MV E-velocity, E/A ratio, and shortened DT were lower in the hypertensive group. As Prinzen et al. showed, delayed relaxation is an acute response to prolonged contractions at elevated blood pressure (20). We assume that impaired relaxation was a response to elevated blood pressure and hypertrophy was present in the majority of hypertensive patients, while higher filling pressures (indicated by increased NT-proBNP) were only present in 10% of the hypertensive population.
Strain and Strain Rate
Global systolic longitudinal S/SR showed lower values depending on higher BP, while no significant S/SR difference was registered between normal BP without antihypertensive treatment and controlled BP with treatment. These findings are in line with a recent population study reporting a significant reduction in global GLS/SR among “ineffectively treated” hypertensives but not in those with BP control (21). It is known, that decreased GLS occurs before LV hypertrophy in hypertensive patients (22, 23). Moreover, it was shown that GLS remained reduced in hypertensives compared to normotensives, even after the reduction of myocardial mass (21).
However, SR E was the only parameter that showed significant functional differences between all groups (A-D). Thus, early relaxation, measured as longitudinal SR E, appears to be the most sensitive parameter for subtle functional changes in the hypertensive population. Impaired relaxation as a key to the early detection of hypertensive heart disease has been previously described by the use of TDI e´ (24), and GLS has been suggested as a marker for early myocardial dysfunction in hypertensive heart disease (25), while SR E has not been previously described in a hypertensive population.
Strain-rate imaging provides new information regarding segmental systolic and diastolic function. Smaller studies on hypertensive hearts have suggested decreasing apico-basal gradients as pathognomonic of hypertension (19, 26). However, the present data suggest that normotensive controls and hypertensives in the investigated age group (40–70 years old) have similar apico-basal gradients, while apical, mid, and basal segmental S/SR values in hypertensive hearts are equally reduced. Kuznetsova et al. described two segmental groups with basal-mid strain at –20.7 ± 1.98% vs. –20.0 ±2.35% and apical strain at –24.3 ±3.41 vs –23.2 ±2.61% in hypertensive and normotensive individuals, respectively. These results are similar to the present findings, although the division into four segmental groups in the present study delivers even more distinct basal septal to apical gradients.
To the best of our knowledge, this study is the first to compare segmental SR E and SR A in hypertensive and normotensive populations. Segmental SR E is not implemented in commercialized bulls-eye plots, and only a few studies have focused on SR E as a possible clinical marker (27). However, our results suggest that SR E might be the most sensitive S/SR marker for subclinical functional deterioration, and that differences between the three BP groups, especially in the apical segments, were best shown by this specific marker.
Higher BP was accompanied by a higher SR A, indicating reduced relaxation but normal end-diastolic filling pressure (28). Thus, a ventricle with poor filling after the relaxation phase is compensated for by atrial contraction when ventricular compliance is preserved. SR A showed no intersegmental gradient between segment groups. This can be explained by atrial contraction towards a fully relaxed ventricle in a state of uniform segmental compliance.
Study limitations
This study used conventional echocardiographic measurements by different readers from the three study locations. Inter-investigator variabilities of these measurements have been performed and showed a significant bias for all M-mode-based dimensional measurements. We applied linear regression analysis by integrating possible confounders, which were corrected for reader-specific differences. This problem did not affect the strain measurements, because they were performed by a single reader. Doppler and volume measurements are robust to inter-observer variability and are not affected by inter-reader variability (29). Furthermore, BP measurements were not taken at the same time as echocardiograms. Therefore, the influence of BP on myocardial function may be underestimated.
Clinical applications
The assessment of segmental LV longitudinal S/SR provides new insights into the myocardial function in hypertension. Kuznetsova et al. demonstrated a higher risk of cardiovascular events in individuals with low longitudinal strain and number of abnormal conventional echocardiographic measures (18). According to the present results, segmental SR E seems to be the most promising S/SR parameter, which should be investigated in future risk-stratification studies.
In hypertensive hearts, assessment of increased filling pressure is challenging. The combination of impaired relaxation with high filling pressures results in mitral flow patterns known as “pseudonormalization,” which typically hampers accurate estimation of diastolic filling pressures.
We also showed that basal-to-apical gradients are present in the normal population and should not be interpreted as an indicator of hypertensive heart disease. Typically, hypertension is characterized by reduced segmental systolic S/SR values and SR E values with a preserved basal to apical gradient. Elevated BP results in different S/SR values, without overt myocardial disease. To accurately identify myocardial pathology in the presence of high BP, we defined segmental S/SR in hypertensive individuals without features of structural cardiac disease.
Conclusion
This study describes in detail the influence of hypertension on global and segmental systolic function. Although all longitudinal functional parameters are reduced in hypertensive hearts, impaired relaxation appears to be the predominant cause of cardiac dysfunction in these patients. Accordingly, of all systolic and diastolic LV functional parameters, global and segmental SR E as a measure of LV relaxation is potentially the best indicator of reduced LV function in chronic and acutely elevated BP.
Contributorship
MK: data collection, strain analysis, statistical analysis, and writing of the manuscript; HAC: artifact analysis, strain analysis for inter-observer-variability; AVK: critical revision of the manuscript for important intellectual content; SM and AR funding and conduction of the data collection in Russia; critical revision of the manuscript for important intellectual content; HS: design funding and conduction of the Tromsø7 study and critical revision of the manuscript; AR: study design, funding of the PhD project, statistical analyses, and writing
Acknowledgement
We acknowledge the contributions of KYH and Tromsø7 study participants. Further, we would also like to thank Editage (www.editage.com) for the English language editing.
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