The D‐HCM score, a new diagnostic tool for distinguishing hypertrophic cardiomyopathy from hypertensive cardiopathy

Abstract

Aim

The diagnosis of hypertrophic cardiomyopathy (HCM) with moderate hypertrophy is challenging. Hypertensive heart disease (HHD) is the most common differential diagnosis that mimics the LVH of HCM. The aim of this study was to compare the QRS duration in HCM and HHD to create a novel diagnostic tool to identify primary HCM.

Methods and results

We conducted an international retrospective multicentre study enrolling patients with true HCM and HHD. A total of 547 individuals with HCM and 139 with HHD were included. The median QRS duration was significantly shorter in HCM than in HHD (88 ms [80–94] vs. 98 ms [88–108]; P < 0.01). Multivariable logistic regression identified for the novel diagnostic HCM (D‐HCM) score: absence of antihypertensive drugs (+2); family history of unexplained sudden death (+2); QRS duration [<95 ms] = +1; maximum wall thickness (mm) [≥17] = +1. A cumulative QRS‐HCM score ≥2 supports the diagnostic certainty of true HCM with a sensitivity of 79%, specificity of 99%, negative predictive value (NPV) of 55%, and positive predictive value (PPV) of 99%.

Conclusion

The QRS duration in patient with HCM is significantly shorter compared with patients with HHD‐related LVH. QRS duration can be used as a diagnosis marker to distinguish between HCM and HHD. The D‐HCM score is a novel, simple, and accurate diagnosis tool for HCM patients with mild to moderate phenotypes.

Introduction

Sarcomeric hypertrophic cardiomyopathy (HCM) is one of the most common hereditary cardiomyopathies with an estimated prevalence of 1:500.¹ Hallmark of HCM is asymmetric left ventricular hypertrophy (LVH).² Diagnosis criteria for HCM rely on LVH features that share considerable overlap with other cardiac conditions that may result in LVH.^3–7 Hypertensive heart disease (HHD) is the most common condition resulting in concentric LVH affecting at least 30% of hypertensive patients.⁸ Subclinical forms and incomplete penetrance of HCM are common rendering the distinction from HHD challenging. Although genetic testing is highly specific for HCM, the diagnostic yield in sporadic, non-familial forms of HCM remains low.^9–11

HCM should be investigated because of frequent adverse events such as death, hospitalization for heart failure, admission for embolic stroke, and sustained ventricular tachycardia.¹²

While QRS increase has been reported in HHD-related LVH, recent data suggest that HCM could be associated with narrower than normal QRS expected.^13–17

We hypothesized that the QRS duration of the resting ECG may be a useful marker to discriminate the underlying LVH aetiology. The aim of this study was to compare the QRS duration in HCM and HHD to create a novel diagnostic tool to identify primary HCM.

Methods

Study population

We conducted an international retrospective multicentre study enrolling patients from the prospective HCM registries of three tertiary centres (Institut universitaire de cardiologie et pneumologie de Québec [Canada], Rangueil University Hospital of Toulouse and Haut-Lévêque University Hospital of Bordeaux [France]).

The study was approved by the ethics and review board of each participating centre and was in accordance with the Declaration of Helsinki.

Definitions

Genetic HCM was diagnosed according to current guidelines and defined as LV wall thickness >15 mm in one or more segments measured by either transthoracic echocardiography or cardiac magnetic resonance imaging not explained by abnormal loading conditions and unrelated to metabolic disorders, mitochondrial cardiomyopathy, infiltrative disorders, neuromuscular disease or malformation syndromes.^1,2 Individuals with long-term (≥5 years) uncontrolled hypertension (systolic blood pressure ≥160 mmHg) were excluded from the HCM cohort. Diagnostic certainty of primary HCM was assumed in the presence of the following findings: Unexplained left ventricular wall thickness of ≥15 mm (without abnormal loading conditions resulting in such LVH) ± ratio of end-diastolic septal/lateral wall thickness of ≥1.5 (in the case of septal forms of HCM) AND at least one of the following: (1) Pathogenic or likely pathogenic variant in a recognized gene that has been shown to be linked to primary sarcomeric HCM, (2) unexplained left ventricular aneurysm independent of size, (3) Specific histological findings including disarray of cardiomyocytes or (4) family history of primary HCM in at least 1 first-degree relative meeting the same diagnostic criteria as outlined.

HHD, defined as increased concentric LV wall thickness ≥ 12 mm in individuals with chronic essential hypertension.^3,8 Chronic hypertension was defined as systolic BP ≥ 140 mmHg and/or diastolic BP ≥ 90 mmHg that required antihypertensive treatment for >1 year.⁸ The HHD patients were selected from a left ventricular hypertrophy registry of the Toulouse University Hospital. We only included patients with concentric LVH with a wall thickness of ≥15 mm to adjust to the diagnostic criteria of primary HCM. Patients did not undergo genetic testing. We excluded apical or asymmetric forms of LVH, patients with systolic anterior motion of the mitral valve (SAM), late gadolinium enhancement (LGE) on MRI, family history of primary HCM to rule out diagnostic bias. Patients with LVH associated with valvular aortic stenosis or coarctation were excluded.

All patients had undergone comprehensive clinical assessment including clinical examination, family tree, genetic investigation, resting 12-lead ECGs, ambulatory rhythm monitoring, transthoracic echocardiography (TTE) and CMR. Cardiac amyloidosis was excluded using echocardiographic global longitudinal strain assessment, standard laboratory testing and nuclear imaging (99mTc-pyrophosphate myocardial scintigraphy) according to current guidelines.^2,3

Cardiac imaging

Transthoracic echocardiography (TTE)

TTE was performed using GE Vivid S70N™ (GE Healthcare, USA) and Philips EPIQ CVx (Philips Healthcare, Netherlands). All measurements were in accordance with the American Society of Echocardiography guidelines.¹⁸ All echo analysis were performed by an experienced single reader blinded to the clinical data and diagnostic classification.

Cardiac magnetic resonance (CMR)

All patients in this study had at least one CMR which was required to be eligible for this study. Cardiac magnetic resonance imaging was performed using GE Signa 1.5 Tesla (GE Healthcare, USA), Siemens Magnetom 3 Tesla (Siemens Healthineers, Deutschland) or Philips Achieva 3 Tesla (Philips Healthcare, Netherlands) systems. Left ventricular ejection fraction (LVEF), septal, left posterior and maximal wall thickness end-diastolic LV diameter (EDLVD) and volume (EDLVV) were collected. Presence of LGE on MRI was noted. We set limits for myocardial fibrosis at ≥6 SD from the normal myocardium in accordance with published criteria for the assessment of myocardial fibrosis in hypertrophic cardiomyopathy.^19,20 The Maron HCM classification was defined based on the CMR morphology²¹ and left ventricular mass (LVM) was also measured. Manual measurements were done by internal and external contouring of the myocardium and post-treatment via the Argus post-treatment console. Automated measurements were also performed using a post-processing server containing CMR 42 (Circle Cardiovascular imaging) software.²² LVM was indexed to the body surface.

ECG analysis

Digital resting 12-lead ECGs were obtained using standard recording systems (Nihon Kohden, Cardiofax S model™, Nihon Kohden, Japan or General Electrics MAC™, Chicago, United States) and settings (25 mm/s speed, 10 mV/mm, 0.5–80 Hz filtering, sampling rate 8000/s, 50 Hz AC filter). QRS duration was calculated from the automated measurements of a standard 12-lead digital surface ECG to overcome inter-operator variability. The automatic QRS duration calculation uses a ‘median QRS’, represented by the 12-lead QRS superposition, which correlates very well with the manual measurements.¹⁵ All available ECGs of each individual were analysed, and the QRS duration values used for the final analyses were the mean of a minimum of three automatic measurements obtained on three ECGs performed at different times. To explore the possibility of QRS variability over time, five ECGs spanning the longest possible follow-up period of 176 randomly selected participants was analysed. Patients with branch blocks were included to estimate their prevalence in our cohort but were subsequently excluded from analysis.

Genetic testing

All patients in HCM cohort had undergone genetic testing using targeted next-generation sequencing (NGS). DNA sequencing targeted all coding exons, all exon–intron boundaries, and some potential mutation sites located outside the coding regions of the target genes. Deletion/duplication analysis was performed for most samples. The number of targets genes extended over the past 5 years and increased from initially 19 to more recently 92 genes including systematic sequencing of the 37 genes of mitochondrial DNA: ABCC9, ACAD9, ACADVL, ACTA1, ACTC1, ACTN2, AGK, AGL, ALPK3, APOA1, BAG3, BRAF, CBL, COX15, CSRP3, ELAC2, EPG5, FBXL4, FHL1, FHOD3, FLNC, FXN, GAA, GLA, GSK3B, HRAS, JPH2, KLHL24, LAMP2, MIPEP, MT-ATP6, MT-ATP8, MT-CO1, MT-CO2, MT-CO3, MT-CYB, MT-ND1, MTND2, MT-ND3, MT-ND4, MTND4L, MT-ND5, MT-ND6, MT-RNR1, MT-RNR2, MT-TA, MT-TC, MT-TD, MT-TE, MT-TF, MT-TG, MT-TH, MT-TI, MT-TK, MT-TL1, MT-TL2, MT-TM, MT-TN, MT-TP, MT-TQ, MT-TR, MT-TS1, MT-TS2, MT-TT, MT-TV, MT-TW. MT-TY, MYBPC3, MYH7, MYL2, MYL3, NDUFAF2, PLN, PRKAG2, PTPN11, RAF1, RIT1, SLC25A4, SOS1, TNNC1, TNNI3, TNNT2, TPM1, and TTR. Variant classification was conducted according to current guidelines.¹

Statistical analysis

Continuous data were expressed as mean and standard derivation (SD) or median and interquartile range (p25, p75) where appropriate. Qualitative variables were presented as percentages and compared between groups using χ² test or Fisher's exact test. Pearson or Spearman's correlation was used to compare QRS measurements over time. Comparison of continuous variables between different groups was performed using ANOVA or Kruskal–Wallis testing where appropriate. All statistical tests were two-sided. A P value < 0.05 was considered to be significant. Statistical analysis was performed using the ‘R Studio’™ (RStudio, Inc. 2019 version 1.2.5001, Boston, MA, USA).

To develop the novel diagnostic HCM (D-HCM) score, we first performed univariate analysis using logistic regression including all variables expected to be associated with the diagnosis of HCM (age, sex, absence of antihypertensive drugs, family history of sudden death, QRS duration, septal and maximal wall thickness, LVM, and presence of late gadolinium enhancement). Patients with QRS widening related to bundle branch blocks, intraventricular conduction delays or paced QRS were excluded from the analysis. Multivariate analysis was performed including variables from the univariate analysis with a P-value threshold of <0.2. The odds ratio obtained from the final model were used to assign coefficients to the score variables. The optimal threshold value for HCM diagnosis was calculated for each quantitative variable included in the score. The D-HCM score was then calculated for each patient, and the study population was divided into two categories: low risk of HCM compared with the entire analysed cohort (risk score < 2), high risk compared with the entire analysed cohort (risk score ≥ 2). The diagnostic cutoff was chosen to provide optimal accuracy and predictive values. The discriminatory ability of the logistic regression model and the risk score was assessed using a ROC curve.

Results

Baseline characteristics

A total of 686 patients were enrolled including 547 individuals with HCM and 139 with HHD (Figure 1). Baseline characteristics of the study population are displayed in Table 1. A positive family history of sudden cardiac death was found in 23% of HCM patients.

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Table 1 Baseline characteristics.

	HHD (n = 139)	HCM (n = 547)	P-value
Age (years)	66 (54–76)	59 (49–69)	<0.01
Male	101 (73%)	367 (67%)	0.2
Weight (kg)	77 (67–89)	76 (67–88)	0.6
Height (m)	170 (162–177)	170 (162–176)	0.6
BMI (kg/m2)	27 (24–30)	27 (24–30)	0.9
Positive genetic testing	0	170 (31%)	<0.01
HBP	139 (100%)	250 (46%)	<0.01
Diabetes	47 (34%)	69 (13%)	<0.01
Dyslipidaemia	42 (30%)	191 (35%)	0.3
Coronary artery disease	23 (16%)	60 (11%)	0.1
Family history of sudden death	0	124 (23%)	<0.01
Antiarrhythmic medications	14 (10%)	181 (33%)	<0.01
Antihypertensive drugs	130 (100%)	265 (48%)	<0.01
Beta-blockers	92 (66%)	313 (62%)	0.5
QRS duration (ms)	98 (88–108)	88 (80–92)	<0.01
LVEF (%)	60 (55–65)	62 (60–70)	<0.01
Septal wall thickness (mm)	15 (15–15)	18 (16–21)	<0.01
Maximal wall thickness (mm)	15 (15–15)	18 (16–21)	<0.01
Indexed LVM (g/m2)	82 (68–104)	91 (74–107)	0.02
LGE	50 (36%)	402 (73%)	<0.01

Patients with bundle branch block or other forms of QRS widening were excluded from the analysis.

Median septal and maximal segmental wall thickness (TTE measurement) were significant lower in HHD than HCM (15 mm [15–15] vs. 18 mm [16–21], P < 0.01). The median indexed LVM (CMR measurement) was significantly higher in HCM compared with HHD (91 g/m2 [74–107] vs. 82 g/m² [68–104]; P = 0.02).

Genetic testing was performed in all patients of the HCM cohort. A pathogenic or likely pathogenic variant was identified in 170 HCM patients (31%). Mutations in MYBPC3 and MYH7 represented the most common variants (Figure 2).

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QRS analysis

The median QRS duration was significant shorter in HCM compared with HHD (88 ms [80–94] vs. 98 ms ([88–108]; P < 0.01) (Figure 3). A sensitivity analysis was performed for different HCM subgroups. The QRS duration showed no difference between the centers, between genetically positive and genetically negative HCM patients (Figure 4A,B). There was no difference between apical and septal forms of HCM, and in the absence or presence of superimposed antihypertensive drugs over time (Figure 4C,D).

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To demonstrate the QRS stability over time in HCM patients (supplementary files 1), we analysed consecutive ECGs in a subgroup of 176 randomly selected HCM patients over the maximal-available follow-up period. A median of 5 consecutive ECGs per HCM individual were analysed spanning a median follow-up of 27 months (7–56). The QRS duration in HCM patients remained stable over time (P = 0.68) (supplementary files).

Novel D-HCM score

Univariate analyses among all 686 patients demonstrated that age, sex, absence of antihypertensive drugs, a family history of sudden unexplained cardiac death, QRS duration, septal wall thickness, maximal wall thickness, LVM, indexed LVM and LGE on MRI were significantly associated with a diagnosis of HCM (Figure 5; Table 2). All variables met the selection criterion (P ≤ 0.2) and were entered into the multivariate model. In the multivariable analysis (Table 2), absence of antihypertensive drugs, family history of sudden unexplained death, QRS duration, maximal wall thickness and LGE remained independent significant predictors of HCM diagnosis (P < 0.05). We considered this model with 5 predictors as the full prediction model.

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Table 2 Univariate and multivariate analysis of parameters predicting HCM.

	Univariate analysis	Multivariate analysis
	OR 95% CI	P-value	OR 95% CI	P-value
Age (years)	0.97 [0.96–0.98)	<0.01	0.99 [0.96–1.01]	0.3
Male	0.77 [0.51–1.16]	0.2	0.9 [0.4–2.03]	0.8
Antihypertensive drugs	0 [0-inf]	<0.01	0 [0-inf]	<0.01
Family history of SD	>100 [0-inf]	<0.01	>100 [0-inf]	<0.01
QRS duration (ms)	0.91 [0.89–0.93]	<0.01	0.88 [0.85–0.92]	<0.01
Septal wall thickness (mm)	1.49 [1.37–1.62]	<0.01	0.85 [0.56–1.29]	0.4
Maximal wall thickness (mm)	1.96 [1.72–2.22]	<0.01	2.47 [1.59–3.85]	<0.01
LVM (g)	1.01 [1–1.01]	0.02	1.01 [1–1.01]	0.8
Indexed LVM (g/m2)	1.01 [1–1.01]	0.03	0.99 [0.97–1.02]	0.8
LGE	4.93 [3.32–7.33]	<0.01	2.72 [1.35,5.48]	<0.01

The optimal threshold value of QRS duration to identify HCM were 95 ms (sensitivity 62%, specificity 81% and AUC 0.77) and 17 mm (sensitivity 81%, specificity 77% and AUC 0.84) for maximal wall thickness (supplementary files 2).

From the multivariable model, we developed a point-based score. The number of points for each item is equal to the coefficient of the multivariate prediction model with the outcome variable ‘diagnostic certainty of primary HCM’. The following variables and their corresponding points were incorporated in the D-HCM model: Absence of antihypertensive drugs = +2; Family history of unexplained SD = +2; QRS duration [< 95 ms] = +1; maximal wall thickness (mm) [≥17] = +1 (Figure 5). The score suggests HCM for a score ≥ 2 points with a sensitivity of 79%, a specificity of 99%, a NPV of 55%, a PPV of 99%, AUC of 0.94 and Youden'J index of 0.78 (supplementary files 3).

Figure 6 shows the performance of the D-HCM score in the HCM and HHD cohorts. Among HHD patients, 138 individuals (99%) had an D-HCM score of less than 2 points. Only 1 individual (0.01%) had a score of 2 and would have been falsely diagnosed with HCM. Among HCM patients, 435 individuals (80%) had a score ≥ 2 points and would have been correctly classified, whereas 112 HCM patient had a score of < 2 points and would have been misclassified (supplementary files 3). Receiver operating curve analysis showing the corresponding cutoff values for logistic regression model and D-HCM score are shown in Figure 7, with a regression AUC of 0.97 95%CI [0.95–0.98] and a score AUC of 0.94 [0.93–0.96].

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Discussion

Key findings of the present study include the following observations: (1) The QRS duration in true sarcomeric HCM is significantly shorter compared with HHD for the same degree of LVH. (2) The QRS duration in primary HCM remains stable over time. (3) The D-HCM score is a new HCM diagnostic tool with a very high specificity and PPV (99%).

With an estimated prevalence of 1:250–1:500,¹ HCM represents one of the most common hereditary cardiomyopathies and a frequent cause of referral to specialized cardiogenetic clinics. Given the potential impact for longitudinal follow-up of probands and the need for family screening, an accurate diagnosis of true primary HCM has significant implications for individual patients but also for the burden on health care systems. The addition of an intrinsic QRS duration < 95 ms adds a simple and reproducible diagnostic parameter that may be useful to distinguish true HCM from HHD resulting in significant LVH.

Current diagnostic criteria for primary HCM rely on a purely descriptive echocardiographic LVH pattern and have significant limitations. The lack of specificity may increase the risk of false positive diagnosis.⁵ This may be further enhanced by changing demographics of the referral population (at least in North America) to specialized cardiogenetic clinics over the past two decades.⁶ A recent study illustrated the growing proportion of older patients with mild–moderate HCM phenotypes.⁶ Maximal wall thickness in this HCM subgroup is significantly lower (average age 56 ± 15 years, wall thickness 17.5 ± 3.5 mm) compared with historical HCM cohorts (average age 44 ± 17 years, wall thickness 20.4 ± 5.7 mm).⁶ Moreover, the increased prevalence of arterial hypertension in this aging population represents an additional confounder and frequently results in HHD.²³ All this contributes to the struggle of diagnostic certainty and differentiation of true HCM from HHD is particularly challenging in these individuals who represent an important proportion of referred patient and who might particularly benefit from our proposed diagnostic score.

Our data demonstrate the presence of a significant difference in the QRS duration between primary HCM and LVH related to HHD. Patients with true HCM present with significantly shorter QRS durations that are stable over time. We also observed that the cumulative incidence of true bundle branch block or nonspecific intraventricular conduction delay was significantly more frequent in patients with HHD.

Incorporating the QRS duration with a cutoff value of ≤95 ms into our proposed multivariable D-HCM score identified primary HCM patients with a sensitivity of 79% and a specificity of 99%.

Although highly specific, genetic testing for known Mendelian HCM substrates is limited by its low sensitivity in unselected patient populations with suspected or confirmed HCM diagnosis. In these patient populations, the diagnostic yield of genetic testing for non-familial forms of HCM is only about 21–35%.^1,8–10

With the Mayo and Toronto scores, there are two well-validated models to predict the probability of a positive genotype in patients with HCM^24,25 However, both models are not designed to distinguish primary HCM from HHD in individuals with mild to moderate phenotypes. As shown in our study, the D-HCM score is independent from the underlying HCM genotype and thus may apply to all HCM subgroups.

In the absence of a positive genetic substrate, specific histopathological features on cardiac biopsy may point to primary HCM diagnosis. Hallmark of primary HCM is the disorganization of the myocardial histoarchitecture resulting in myocardial disarray which is characterized by misalignment of hypertrophied myocytes (perpendicularly or obliquely instead of parallel alignment) around central cores of collagen a pinwheel-like configuration.²⁶

On the cellular level, cardiomyocytes also show a disorganized myofibrillary architecture.²⁷ However, systematic endomyocardial biopsies in patients with suspected HCM are not clinically acceptable, as they are associated with significant risks.

Cardiac MRI should be part of the diagnostic workup in all patients with suspected or confirmed HCM adding important diagnostic and prognostic information for individual patient management.⁶ Interstitial myocardial fibrosis can be found in hypertensive heart disease and is sometimes difficult to distinguish from HCM.²⁸ Although the majority of primary HCM cases present with asymmetric LVH, its absence does not exclude the diagnosis. Diffuse and symmetric forms HCM phenotypes may account for up to 42% of cases.²⁹ On the other hand, asymmetric LVH patterns have also been described in HHD.³⁰ Despite its well-established role, the use of CMR for HCM is still suboptimal in many industrialized countries.¹⁰

Additional features on cardiac imaging such as systolic anterior motion of the mitral valve (SAM) are common but not specific to HCM^31,32 Emerging imaging features such as echocardiographic strain analysis or T1 mapping on CMR are promising tools but still require more validation to assess their role as additional diagnostic parameters,^5,7,33

The proposed D-HCM score is a novel, simple, and accurate diagnostic tool that may be particularly useful for HCM patients with mild–moderate phenotypes. The D-HCM score is easy to use and can be quickly performed in any office where an automatic ECG analysis is available. The strength of the score is that it is highly specific, with a very high positive predictive value (99%). Therefore, when it indicates HCM (≥2), there is a very high probability that this is true.

The mechanistic and electrophysiological properties underlying the narrower QRS in HCM compared with the wider QRS in HHD remain unknown and are subject of many hypotheses at this point.^15,34 So far, there are no functional cellular models that could convincingly explain the electrocardiographic observations.

Limitations

Our study has several limitations. First, this is a retrospective study with limitations inherent to any retrospective study design. However, all patients were prospectively enrolled and major efforts were performed including deep phenotyping to obtain optimal diagnostic certainty. All study centres are tertiary university centres, and our study population may have been affected by referral bias. The D-HCM score is not applicable to patients with paced rhythm or underlying bundle branch block.

At this point, the D-HCM score has not been externally validated in other HCM-HHD cohorts which might strengthen the robustness of our observations.

Although the presence and distribution pattern of myocardial fibrosis was reported for each patient with CMR, there was no systematic quantification of the left ventricular late gadolinium enhancement. This information could have also been useful to discriminate between primary HCM and HHD. Because of the large number of exams without fibrosis quantification, we only included the presence or absence of LGE into the final analysis.

We developed the D-HCM score to increase diagnostic specificity in patients who most likely present true primary HCM. The score sensitivity is about 80% meaning that there is a 20% risk of a false negative diagnosis in individuals with LVH. It is therefore important to integrate the results of this score within the global clinical context.

Conclusion

The QRS duration in patients with primary HCM is significantly shorter compared with patients with HHD-related LVH and remains stable over time. QRS duration can be used as an additional diagnostic marker to distinguish between HCM and HHD. We developed the D-HCM score, a novel, simple, and accurate diagnostic tool that may be particularly useful for gene negative HCM patients with mild to moderate phenotypes.

Funding

None.

Conflict of interest

None declared.

Data availability statement

Data are available on request from the authors.

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