This retrospective observational study included 60 patients diagnosed with HCM (diagnosis confirmed by CMR) and 60 HTN patients recruited from our outpatient department. We excluded patients with obstructive HCM, poor acoustic window, AF identified in the basal electrocardiogram, moderate or severe valvular disease, ischemic heart disease, or pulmonary hypertension defined as pulmonary artery systolic pressure (PASP) >45 mmHg. Patients were diagnosed with HTN about 4.2±2.3 years before. As controls, we included 34 healthy individuals without HTN, AF, or valvular disease, age-matched to HCM and HTN patients.

We analyzed clinical and echocardiographic data of participants divided into the HCM group, HTN group, and control group. Data from CMR of HCM patients at the time of diagnosis were also assessed. Echocardiographic images were collected 43±18 days after HCM diagnosis was made by CMR. Echocardiographers were blinded to CMR results. The study was approved by the scientific and bioethics committees of Coimbra Hospital and University Center (Coimbra, Portugal) and was performed in accordance with the Declaration of Helsinki.

A complete two-dimensional echocardiographic investigation was performed in all participants, including LV- and LA-STE with global longitudinal strain (GLS) analysis. We used a Vivid 7 (GE Healthcare, Horten, Norway) cardiovascular ultrasound device, with a 1.7/3.4-MHz tissue harmonic transducer. Standard echocardiographic views were obtained with frame-rate optimization (60–80 fps in 2D imaging). We performed an offline analysis of echocardiographic data using a specific software (EchoPAC 16.0; GE Healthcare).

Assessment of LV size and systolic function, including measurement of LV ejection fraction (LVEF), LV end-diastolic diameter (LVDD), and LV end-systolic diameter (LVSD), followed the current recommendations.¹⁵ STE-derived LV-GLS was obtained using a 16-segment model of the LV.¹⁶ Diastolic function including mitral E velocity, mitral A velocity, and mean E/e’ ratio, was also evaluated.

STE-based analysis of LA mechanics was performed as previously recommended;^{17 , 18} with offline analysis of the automatically averaged longitudinal strain curves for each atrial segment by specific software^{17 , 18} ( Figure 1 ). For processing, the initial frame was chosen as the frame reflecting the P-wave onset. LA strain and strain rate during systole (LASr and LASRr, respectively), early diastole (LAScd and LASRcd), and late diastole (LASct and LASRct, respectively) were measured as indicators of the LA reservoir, conduit, and contractile functions, respectively.^{14 , 18}

Figure 1

For analysis of inter-observer reproducibility, the 2D-STE strain and strain ratio measurements from 37 randomly selected HCM patients were made by a second investigator (JAF) and compared with those of the first observer (PMA).

The first observer repeated the measurements in the same 37 participants, and the intra-observer reproducibility was then assessed. The observers evaluated different regions of interest of the LA and were blinded to previous measurements.

All 60 HCM patients underwent CMR, performed with 1.5 T scanners (Philips, Best, the Netherlands) using standard protocols as suggested previously.⁴ LGE images were acquired 10-20 min after intravenous administration of gadolinium as recommended.²

Quantification of LGE was performed by manual adjustment of gray scale threshold, to define areas of visually identified LGE in short-axis planes and measured in centimeters (cm) of extension.

Normality of the distribution of continuous variables was assessed by histogram analysis and the Kolmogorov–Smirnov test. Continuous variables were expressed as mean ± standard deviation, and categorical variables were expressed as frequency (percentage). Between-group differences were evaluated using one-way ANOVA. After rejecting the null hypothesis, the Bonferroni multiple comparison test was conducted. For each variable with non-normal distribution, the homogeneity of variance was assessed using the Levene test. For categorical variables, the chi-square test or the Fisher’s exact test was used, as appropriate. Linear regression was used to correlate several continuous parameters. Assumptions for linear regression were checked beforehand. Namely, a linear relationship between data was visually assessed using scatter plots; no outliers were detected; autocorrelation was excluded using the Durbin-Watson test; homogeneity of variance of the residuals (homoscedasticity) was also checked visually by plotting residuals versus fitted values. Analysis of receiver operating characteristic (ROC) curves was performed to compute the discriminative power of LA mechanics parameters in HCM versus HTN. The curves were compared using the Delong method. We used the Bland–Altman method, intraclass correlation coefficient, and coefficient of variation to assess the inter- and intra-observer variability of LA 2D-STE strain and SR measurements. Statistical significance was set at p-<0.05. Stata IC for Windows (version 13; StataCorp, Lakeway Drive, TX, USA) and MedCalc for Windows (version 14.8.1; MedCalc Software, Ostend, Belgium) were used for the statistical analyses.

Regarding sample size, we planned a study of a continuous response variable in independent control and experimental subjects, with 0.5 control(s) per experimental subject. In LA mechanics analysis (LA strain in reservoir and contractile phases), the desirable response within each subject group is normally distributed with a standard deviation of five.^{7 , 10} If the true difference between experimental and control subject means is four, we would need 51 experimental subjects and 26 control subjects to be able to reject the null hypothesis that the population means of the experimental and control groups are equal with a probability (power) of 0.9. The type I error probability associated with this test of this null hypothesis is 0.05. We could further include 60 HCM patients and 60 HTN patients to further improve the statistical power of the study.

The clinical features of the study population are summarized in Table 1 . The mean age of HCM patients was 55±18 years, and 57% of patients were male. This did not vary significantly from HTN patients and controls. HTN patients had more diabetes mellitus , dyslipidemia, and obesity.

Table 1

Characteristic	Controls (n=34)	HCM group (n=60)	HTN group (n=60)	p-value
Age, years (±SD)	56±10	55±18	61±12	0.081*
Male sex (%)	20 (55)	34 (57)	34 (57)	0.124#
Diabetes mellitus (%)	0	15 (25)	35 (58)	0.022#
Dyslipidemia (%)	0	24 (40)	43 (72)	0.014#
Obesity (%)	0	12 (20)	28 (47)	0.031#
Antihypertensive drugs
Diuretics use (%)	0	15 (25)	32 (53)	0.018#
Beta-blocker use	0	45 (75)	37 (62)	0.068#
ACEI/ARB use	0	41 (68)	45 (75)	0.072#
CCB use	0	27 (45)	42 (70)	0.032#
Other anti-HTN use	0	12 (20)	20 (34)	0.056#

Data are given as mean ± standard deviation or as frequency (percentage). ACEI/ARB: angiotensin converting enzyme inhibitor/angiotensin receptor blockers; CCB: calcium channel blocker; HCM: hypertrophic cardiomyopathy; HTN: arterial hypertension. * One-Way ANOVA.^#Chi-square test.

In the HCM group, there was a higher use of beta-blocker therapy, while in the HTN group, a higher prescription of angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) was found.

The echocardiographic characteristics of participants are summarized in Table 2 . The mean LVEF were not different between the groups. LVDD was higher in the HTN group than in the HCM group. PASP was not different between the HCM and HTN groups and was significantly reduced in the control group.

Table 2

Parameters	Controls	HTN group	HCM group	Global P-value	p value: controls vs HTN	p value: HCM vs HTN
LVEF, %	62.9±4.3	62.9±4.9	66.5±10.1	0.083	0.969	0.055
LVDD, mm	48.3±5.2	51.9±0.8	49.4±1.0	0.108	0.019	0.083
LVSD, mm	30.3±3.2	32.3±0.7	30.7±0.9	0.369	0.119	0.225
IVS, mm	10.2±2.8	14.3±3.6	16.5±5.4	0.028	<0.001	0.032
LV-GLS, %	-20.6±1.1	-17.5±0.7	-12.7±0.5	<0.001	0.192	0.008
PASP, mmHg	22.1±4.7	26.3±0.2	28.6±1.3	0.021	0.009	0.245
LAVi, mL/m2	23.5±4.2	31.1±1.3	33.5±2.5	<0.001	0.001	0.067
Mitral E velocity, m/s	0.8±0.1	0.7±0.2	0.8±0.2	0.156	0.068	0.182
Mitral A velocity, m/s	0.5±0.1	0.8±0.2	0.7±0.3	0.005	<0.001	0.151
E/e’ ratio	7.0±1.65	13.2±1.2	16±1.0	<0.001	<0.001	0.035
LASr, %	36.9±10.8	24.4±8.2	17.2±9.0	<0.001	<0.001	<0.001
LAScd, %	25.9±13.3	19.9±8.7	15.4±9.1	<0.001	0.067	0.022
LASct, %	10.9±6.2	5.1±0.9	1.9±0.3	<0.001	0.003	<0.001
LASRr, %	1.9±0.5	1.2±0.1	0.8±0.1	<0.001	<0.001	<0.001
LASRcd, %	-2.1±0.6	-1.8±0.1	-0.6±0.1	<0.001	0.082	<0.001
LASRct, %	-1.9±0.7	-1.7±0.1	-0.9±0.1	<0.001	0.344	<0.001

Statistical analysis: one-way ANOVA with Bonferroni test for multiple comparisons. HCM: hypertrophic cardiomyopathy; HTN: hypertension; IVS: interventricular septum; LASr: left atrial systolic strain (reservoir function); LAScd: left atrial early diastolic strain (conduit function); LASct: left atrial late diastolic strain (contractile function); LASRr: left atrial systolic strain rate (reservoir function); LASRcd: left atrial early diastolic strain rate (conduit function); LASRct: left atrial late diastolic strain (contractile function); LAVi: left atrial volume indexed; LVDD: left ventricular end-diastolic diameter; LVSD: left ventricular end-systolic diameter; LVEF: left ventricular ejection fraction; LV-GLS: left ventricular global longitudinal strain; PASP: pulmonary artery systolic pressure.

Regarding LV diastolic function, mitral E velocity did not vary among groups, and mitral A velocity was higher lower in the HTN group than in the control group. E/e’ ratio was significantly impaired in the HCM group and preserved in the control group.

Compared to controls, HCM and HTN patients had significantly larger LA volume indexed to the body surface area (LAVi) ( Table 2 ). LA deformation parameters were globally decreased in both HTN and HCM groups, in relation to the control group. In the HTN group, reservoir function was preserved, although significantly reduced compared to that in the control group; the conduit phase was not different from the control group, and strain in contractile phase (but not LASRct) was significantly impaired in HTN patients ( Table 2 , Figure 2 ).

Figure 2

All LA deformation phases were significantly reduced in the HCM group than in the HTN group ( Table 2 , Figure 2 ). Of all LA mechanics parameters, LASRr and LASRct were the best discriminators of HCM (versus HTN), followed by LASr. LASRr and LASRct had high specificity and positive predictive value (PPV) ( Table 3 ). Despite the discriminative power, LAScd had the highest specificity (94%) and LASct the highest sensitivity (95%) ( Table 3 ).

Table 3

	AUC	95% CI	p-value	Sensitivity (%)	Specificity (%)	Criterion	PPV (%)	NPV (%)
LASr(%)	0.76	0.66-0.84	<0.001	80	71	21.8	73	78
LAScd (%)	0.65	0.54-0.74	0.012	32	94	9.9	84	58
LASct(%)	0.65	0.54-0.75	0.016	95	34	5.1	59	87
LASRr (%)	0.80	0.71-0.88	<0.001	65	89	0.8	86	72
LASRcd (%)	0.69	0.59-0.79	<0.001	54	87	-0.8	81	65
LASRct (%)	0.80	0.71-0.88	<0.001	64	91	-0.9	88	72
IVS (mm)	0.62	0.51-0.70	0.012	55	74	15.2	68	63
LV-GLS (%)	0.74	0.64-0.83	<0.001	57	84	-13.5	78	66
E/e’ ratio	0.67	0.55-0.78	0.009	67	71	13	70	68

AUC: area under the curve; HTN: arterial hypertension; HCM: hypertrophic cardiomyopathy; IVS: interventricular septum; LASr: left atrial systolic strain (reservoir function); LAScd: left atrial early diastolic strain (conduit function); LASct: left atrial late diastolic strain (contractile function); LASRr: left atrial systolic strain rate (reservoir function); LASRcd: left atrial early diastolic strain rate (conduit function); LASRct: left atrial late diastolic strain (contractile function); LV-GLS: left ventricular global longitudinal strain; NPV: negative predictive value; PPV: positive predictive value.

All HCM patients underwent CMR (the gold standard method for diagnosis). The mean indexed end-diastolic volume (EDVi) was 96±32 mL/m² , the mean interventricular septum thickness (IVS) was 18.7±3.5 mm. Approximately 34% of the patients had systolic anterior movement of the mitral valve, and 12% of the patients had apical HCM. LGE was present in 52 (87%) HCM patients, and the mean area of extension was 2.8 cm.

Table 4 summarizes the results of the linear regression analysis between the extension of LGE (in cm) and several CMR and echocardiographic parameters in HCM patients. LV measures, EDVi (by CMR), LVDD and LVSD by echocardiography, LV-GLS or the E/E’ ratio did not predict LGE extension. IVS thickness measured by CMR, but not by echocardiography, predicted LGE. Both LASr and LASRcd predicted LGE extension. A decrease of 0.5% in LASr and of 2.79% in LASRcd predicted an increase of 1cm in LGE ( Figure 3 ).

Table 4

Late gadolinium enhancement	Adj R2	β	p-value
IVS by CMR	0.32	0.12	0.051
IVS by echocardiography	0.24	0.08	0.088
EDVi by CMR	0.01	0.01	0.843
LVDD	0.01	-0.02	0.795
E/E’ ratio	0.01	-0.04	0.802
LV-GLS	0.04	0.08	0.467
LASr	0.12	-0.02	0.085
LAScd	0.15	-0.01	0.092
LASct	0.35	-0.51	0.045
LASRr	0.12	-1.29	0.073
LASRcd	0.42	2.79	0.027
LASRct	0.21	0.33	0.066

CMR: cardiac magnetic resonance; EDVi: indexed end-diastolic volume; IVS: interventricular septum; LASr: left atrial systolic strain (reservoir function); LAScd: left atrial early diastolic strain (conduit function); LASct: left atrial late diastolic strain (contractile function); LASRr: left atrial systolic strain rate (reservoir function); LASRcd: left atrial early diastolic strain rate (conduit function); LASRct: left atrial late diastolic strain (contractile function); LGE: late gadolinium enhancement; LVDD: left ventricular end-diastolic diameter; LV-GLS: left ventricular global longitudinal strain.

Figure 3

The parameters of LA deformation showed intraclass correlation coefficient values of 0.64 to 0.94, indicating good to excellent reproducibility of such measurements (Supplemental Table). The Bland–Altman plots revealed very small inter-observer ( Figure 4 ) and intra-observer ( Figure 5 ) discrepancy in the measurements of LA strain and strain rate.

Figure 4

Figure 5

Our study has several limitations. First, the software used for strain analysis was dedicated to the analysis of the LV strain, and not to LA strain, which could distort our results to some extension.

Second, the heterogeneity of our study population in terms of different comorbidities can affect the obtained results. The fact that a higher proportion of HTN patients had diabetes and obesity could affect the analysis of LA mechanics, due to a worsening in the LV diastolic function. However, this is an intrinsic association that could not be excluded, as there are few patients with HTN as the only cardiovascular risk factor. Most patients were adequately treated with ACEI and ARB, which could counteract the diastolic dysfunction in these patients, by affecting LV remodeling. In contrast, beta-blockers in HCM does not directly affect LV remodeling, without necessary changes in LV diastolic function or LA mechanics. However, we could not evaluate if and to what extent this was true. Nevertheless, by directly comparing two heterogenous groups of real-world patients with HTN or HCM, we could detect differences in LA mechanics between these two groups as seen in everyday practice.

Third, it has been demonstrated that HCM patients with paroxysmal AF might have a greater degree of LA myopathy than patients without AF.²⁵ In our study, although we excluded patients with AF on basal electrocardiogram, there may still exist unidentified patients with paroxysmal FA, with a more severe cardiac phenotype, that were not entirely characterized in our analysis.

Fourth, we did not have external validation for the proposed cutoffs, so we could not properly suggest LA strain as an accurate discriminator.

Fifth, we did not include HTN patients in the variability analysis, which would be important to truly evaluate reproductivity of all parameters.

Finally, this was not an outcome-based study, so we could not draw any conclusions about the prognostic value of LA strain rate in this population. Nevertheless, this study attempted to clarify the LA deformation mechanics in LVH secondary to HCM and to HTN. Future studies with larger samples are warranted to clarify the prognostic value of LA strain rate in LVH.