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:
- Segmental basal-to-apical and endo- to epicardial gradients of S/SR
are similar in normal individuals and individuals with hypertension.
- 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.
- 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.
- 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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