European Journal of Cardiovascular Medicine

Cardiovascular disease accounts for approximately 17.9 million deaths each year and remains the single largest contributor to global mortality, with a disproportionate and rising burden in low- and middle-income countries including India.1 Despite advances in pharmacotherapy, revascularisation, and device therapy, a substantial proportion of patients continue to experience symptom progression, arrhythmia, and premature death — often without a corresponding decline in the parameters used to monitor them.

Two limitations of conventional evaluation are relevant here. First, left ventricular ejection fraction (LVEF), the dominant imaging metric in clinical cardiology, is load-dependent and geometrically derived; it can remain within the normal range despite meaningful contractile impairment in early ischaemic disease, hypertensive heart disease, diabetic cardiomyopathy, and heart failure with preserved ejection fraction.15,16 Two-dimensional speckle tracking echocardiography (STE) addresses this by quantifying myocardial deformation directly. Global longitudinal strain (GLS) reflects the function of subendocardial longitudinal fibres, which are the earliest to be affected in most disease states, and has been validated against sonomicrometry and tagged magnetic resonance imaging.17,18 Strain rate, the temporal derivative of strain, additionally reflects the velocity of fibre shortening and is a comparatively load-independent index of contractility.21,22

Second, the neural regulation of the heart is rarely assessed at all. Cardiovascular disease is accompanied by a characteristic shift toward sympathetic predominance with parasympathetic withdrawal, and this autonomic imbalance is not merely epiphenomenal: it promotes adverse remodelling, arrhythmogenesis, and progressive functional decline.2,8 Heart rate variability (HRV) quantifies autonomic modulation of the sinoatrial node non-invasively from a short electrocardiographic recording, and reduced HRV predicts mortality after myocardial infarction and in chronic heart failure.2,4,5,6 Baroreflex sensitivity (BRS) captures the reflex arm of the same system, and impaired BRS independently predicts arrhythmic death.3,11 Both are inexpensive, require no contrast or radiation, and are feasible in outpatient settings — yet remain largely confined to research use.12

These two domains are usually studied in isolation. Mechanistically, however, there is reason to expect them to be linked. Sustained sympathetic activation increases myocardial oxygen demand, impairs subendocardial perfusion, promotes interstitial fibrosis, and disturbs calcium handling — all of which would preferentially compromise the longitudinal subendocardial fibres that GLS measures.8,23,24 If this neuro-mechanical coupling hypothesis holds, autonomic indices should track deformation indices within the same patient, and the relationship should be visible before LVEF declines.

Data testing this proposition directly are limited, particularly outside high-income settings and particularly across a mixed cardiac population rather than a single diagnosis. We therefore assessed cardiac autonomic tone and myocardial deformation concurrently in a prospectively enrolled Indian cohort with established heart disease, with two objectives: to characterise the magnitude of autonomic and deformation abnormality in a group whose mean LVEF was preserved, and to quantify the relationship between them.

Study design and setting

This was a prospective, observational, cross-sectional study conducted in the Department of Cardiology of a tertiary care teaching hospital in India, in collaboration with the Departments of Physiology and Radiology, over 18 months. Patients were recruited from the cardiology outpatient department and inpatient wards. The protocol was approved by the Institutional Ethics Committee and conducted in accordance with the Declaration of Helsinki (2013 revision) and Indian Council of Medical Research guidelines. Written informed consent was obtained from all participants in English or the local vernacular.

Participants

Eligible patients were aged 18–75 years with an established diagnosis of one or more of: ischaemic heart disease (stable angina or prior myocardial infarction with documented coronary disease); heart failure with reduced, mildly reduced, or preserved ejection fraction (the latter with echocardiographic evidence of diastolic dysfunction); or valvular heart disease of at least moderate severity. Patients were required to be medically stable, defined as no acute decompensation, cardiac hospitalisation, or change in cardiac medication within the preceding two weeks, and physically able to complete all study assessments.

Patients were excluded for acute coronary syndrome or decompensated heart failure within two weeks; arrhythmias precluding reliable HRV analysis (persistent or permanent atrial fibrillation, atrial flutter, ventricular ectopy exceeding 10% of recorded beats, complete heart block); any implanted pacemaker, defibrillator, or resynchronisation device; significant non-cardiac comorbidity independently affecting autonomic function or exercise performance (chronic obstructive pulmonary disease or asthma with FEV1/FVC < 70%, haemoglobin < 10 g/dL, uncontrolled thyroid disease, eGFR < 15 mL/min/1.73 m2); known primary autonomic neuropathy with documented orthostatic hypotension; inadequate echocardiographic image quality despite optimisation; and pregnancy or lactation.

Sample size

Sample size was estimated for the detection of a Pearson correlation coefficient of r = 0.30 — a conservative estimate drawn from prior literature — with two-sided α = 0.05 and 80% power, using Fisher’s Z transformation, yielding n = 85. Allowing for 15–20% loss due to incomplete investigations, poor acoustic windows, or withdrawal, and to preserve power for subgroup comparison and multivariable modelling with up to four predictors, the target was set at 130 patients.

Assessment protocol

All assessments were completed within a 48-hour window under standardised conditions. Patients abstained from caffeine, nicotine, and strenuous activity for at least 12 hours beforehand, and all testing was performed between 08:00 and 12:00 to limit circadian variation in autonomic tone.

Cardiac autonomic function testing

Heart rate variability. After a minimum 10 minutes of supine rest in a quiet room at 22–24°C, a 12-lead electrocardiogram was recorded digitally at a sampling rate of at least 1000 Hz. A 5-minute artefact-free segment was selected for analysis. R-R interval series were visually inspected and manually edited to remove ectopic beats and artefact. Time-domain indices (SDNN, RMSSD, pNN50) and frequency-domain indices (low-frequency [LF] power 0.04–0.15 Hz, high-frequency [HF] power 0.15–0.40 Hz, LF/HF ratio, total power) were derived using validated software with Fast Fourier Transform, following the Task Force standards of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology.1 LF and HF are reported in normalised units (nu).

Baroreflex sensitivity. BRS was assessed by two complementary methods to improve reliability. In the sequence method, continuous beat-to-beat blood pressure was recorded by validated finger plethysmography; spontaneous sequences of three or more consecutive beats with concordant change in systolic pressure (≥ 1 mmHg/beat) and R-R interval (≥ 6 ms/beat) were identified automatically, and BRS was expressed as the regression slope of ΔR-R against ΔSBP in ms/mmHg.10 In the Valsalva method, patients maintained an expiratory pressure of 40 mmHg for 15 seconds, and BRS was derived from the phase IV overshoot. Patients with severe aortic stenosis or active ischaemia did not undergo the Valsalva manoeuvre. The mean of available methods was used for analysis; BRS < 3 ms/mmHg was regarded as severely impaired.

Echocardiography and deformation imaging

Transthoracic echocardiography was performed by a single trained operator using a commercially available system with a 3.5–5 MHz phased-array transducer, with patients in the left lateral decubitus position. Apical four-chamber, two-chamber, and long-axis views were acquired at 50–90 frames per second, with depth and sector width minimised to maximise frame rate; three consecutive cardiac cycles were stored during breath-hold. Studies in which fewer than 14 of 16 segments were trackable were excluded.

Offline analysis was performed with vendor-independent software by an independent analyst blinded to clinical and autonomic data, on de-identified loops. GLS was calculated as the average peak systolic longitudinal strain across 16 left ventricular segments from the three apical views; values less negative than −16% were regarded as impaired.15 Global longitudinal strain rate (GLSR), global circumferential and radial strain, and left atrial strain were also derived. LVEF was measured by the biplane method of discs, and conventional diastolic indices (E/A, E/e′, deceleration time, TAPSE) were recorded per contemporary recommendations.26

Reproducibility was assessed in 20 randomly selected studies, re-analysed by the same observer after a four-week washout and independently by a second blinded observer, with agreement expressed as intraclass correlation coefficients, coefficients of variation, and Bland–Altman limits of agreement.

Statistical analysis

Analyses were performed in IBM SPSS Statistics v26.0 and R v4.2.0, with two-tailed p < 0.05 considered significant. Normality was assessed by Shapiro–Wilk and Kolmogorov–Smirnov tests with visual inspection of histograms and Q–Q plots. Continuous variables are reported as mean ± SD or median (IQR) as appropriate, and categorical variables as counts and percentages.

Bivariate associations were assessed by Pearson’s r for normally distributed variables and Spearman’s ρ otherwise, interpreted as weak (< 0.3), moderate (0.3–0.5), strong (0.5–0.7), and very strong (> 0.7). To avoid ambiguity arising from the negative sign convention of longitudinal strain, correlation and regression analyses used the absolute magnitude of GLS; a positive coefficient therefore denotes an association between higher heart rate variability and greater (i.e. better) longitudinal deformation. Between-group comparisons used the independent-samples t-test or Mann–Whitney U test for two groups, and one-way ANOVA with Tukey’s HSD or Kruskal–Wallis with Dunn’s correction for three or more groups; categorical variables were compared by chi-square or Fisher’s exact test. Multivariable linear regression with hierarchical entry was used to identify independent correlates, including variables significant at p < 0.10 on univariate testing together with age, sex, LVEF, and NYHA class. Model assumptions were verified through residual plots, variance inflation factors (VIF < 5), and Cook’s distance.

Baseline characteristics

One hundred and thirty patients completed the protocol (Table 1). Mean age was 56.4 ± 11.2 years, with a male predominance (82 patients, 63.1%). Mean BMI was 27.8 ± 3.9 kg/m². Comorbidity burden was high: hypertension in 78 (60.0%), diabetes mellitus in 52 (40.0%), and dyslipidaemia in 61 (46.9%).

Most patients had moderate functional limitation, with 68 (52.3%) in NYHA class II and 42 (32.3%) in class III. Ischaemic heart disease was the commonest diagnosis (58 patients, 44.6%), followed by heart failure (47, 36.2%) and valvular heart disease (25, 19.2%).

Table 1. Baseline demographic and clinical characteristics (n = 130)

Cardiac autonomic function

Autonomic indices are shown in Table 2. Overall variability was reduced (SDNN 82.6 ± 24.3 ms), with a more marked reduction in the vagally mediated index RMSSD (21.4 ± 10.8 ms). Spectral analysis showed a shift toward sympathetic predominance, with LF 61.2 ± 12.5 nu, HF 29.6 ± 9.4 nu, and an LF/HF ratio of 2.3 ± 0.8.

Mean baroreflex sensitivity was 5.8 ± 2.1 ms/mmHg, below the range expected in healthy adults and approaching the threshold of severe impairment in a subset of patients.

Table 2. Heart rate variability and baroreflex sensitivity (n = 130)

Echocardiographic and deformation findings

Mean LVEF was 52.4 ± 8.1%, within the preserved range (Table 3). Despite this, GLS was impaired at −15.8 ± 3.2%, substantially below the normal reference of approximately −20% and less negative than the −16% threshold used to define impairment.¹⁵ Global longitudinal strain rate was −0.89 ± 0.21 s⁻¹, and left atrial strain was 21.4 ± 5.3%. The dissociation between a preserved mean ejection fraction and an impaired mean GLS was the central imaging observation of the cohort.

Table 3. Echocardiographic and deformation parameters (n = 130)

Relationship between autonomic tone and myocardial deformation

SDNN correlated moderately and significantly with the magnitude of GLS (r = 0.42, p < 0.001): patients with greater overall heart rate variability demonstrated better longitudinal deformation. The relationship persisted across the range of LVEF observed, including among patients whose ejection fraction was within normal limits, indicating that the association was not simply a reflection of overt systolic dysfunction.

Comparison across disease categories

Subgroup analysis showed a consistent gradient across diagnoses (Table 4). Patients with heart failure had the lowest SDNN (70.5 ms) and the most impaired GLS (−14.2%), whereas ischaemic (86.2 ms; −16.4%) and valvular (88.1 ms; −17.1%) subgroups were comparatively better preserved. Differences were significant for both SDNN (p = 0.004) and GLS (p = 0.001). Notably, the ordering of subgroups was identical for the neural and the mechanical index, with heart failure most affected on both.

Table 4. Autonomic and deformation parameters across disease categories

The principal finding of this study is that in a mixed cohort of patients with established heart disease, cardiac autonomic dysfunction and impaired left ventricular longitudinal deformation coexist, vary together, and are both present despite a group mean ejection fraction in the preserved range. Three observations deserve emphasis.

Autonomic impairment across a mixed cardiac cohort

The autonomic profile we observed — reduced SDNN and RMSSD with an elevated LF/HF ratio and depressed baroreflex sensitivity — is the signature of sympathetic predominance with vagal withdrawal that has been documented after myocardial infarction and in chronic heart failure.2,5,7 Our contribution is to demonstrate it across a heterogeneous group that includes valvular disease, a population in which autonomic assessment is rarely performed. The magnitude of BRS reduction is consistent with the ATRAMI investigators’ observation that depressed baroreflex function carries prognostic weight independent of ejection fraction.3,11 Two caveats about interpretation apply. The LF/HF ratio is a convenient but contested index of “sympathovagal balance”: LF power reflects baroreflex function rather than pure sympathetic outflow, and the ratio should be read as a descriptive summary rather than a physiological quantity.12,13,14 In addition, most of our patients were receiving beta-blockade as guideline-directed therapy, which raises HRV; the values reported here are therefore likely to underestimate the underlying autonomic derangement rather than exaggerate it.

Deformation abnormality with preserved ejection fraction

Mean LVEF was 52.4%, which in isolation would be reported as normal. Mean GLS was −15.8%, which is impaired by any contemporary threshold. This dissociation is the clearest practical message of the study: an ejection fraction–only assessment would have classified a large part of this cohort as having normal systolic function. The finding is consistent with validation and outcome literature showing that GLS detects contractile impairment before LVEF declines, that it reflects infarct size in patients with preserved global function, and that it tracks histological fibrosis burden.15,17,19,24 The accompanying reduction in strain rate (−0.89 s−1) points in the same direction, since strain rate is comparatively less load-dependent and closely indexes contractility.21,22

Neuro-mechanical coupling

The moderate correlation between SDNN and GLS magnitude (r = 0.42, p < 0.001) supports a coupling between neural regulation and myocardial mechanics rather than two independent axes of disease. A plausible mechanistic account runs through the subendocardium. Chronic sympathetic activation raises myocardial oxygen demand, shortens diastolic perfusion time, promotes interstitial and perivascular fibrosis, and impairs sarcoplasmic calcium handling.8,23,28 The subendocardial longitudinal fibres are the most vulnerable to each of these insults by virtue of their perfusion territory and fibre orientation, and they are precisely the fibres whose function GLS quantifies.23,25 Reduced vagal tone would compound the effect by removing the buffering influence on heart rate and on inflammatory signalling.9,30. The subgroup data are consistent with this reading. Patients with heart failure — the group with the greatest expected neurohumoral activation — showed both the lowest SDNN and the most impaired GLS, and the rank order across subgroups was identical for the two measures. Causality cannot be inferred from a cross-sectional design, and the relationship is plausibly bidirectional: impaired mechanics elevate filling pressures, which themselves drive reflex sympathetic activation.

Clinical implications

Two implications follow, both particularly relevant to resource-constrained settings. First, in patients with heart disease and a normal ejection fraction, a normal LVEF should not be taken as evidence of normal systolic function; deformation imaging identifies a substantial burden of impairment that would otherwise be missed. Second, where speckle tracking is unavailable — as it is in most secondary-level Indian centres — a 5-minute electrocardiographic recording yielding SDNN provides an inexpensive, non-proprietary signal that correlates with myocardial mechanics and may help triage which patients warrant referral for advanced imaging. Neither test replaces the other; the point is that when only one is available, the autonomic measure carries mechanical information.

Limitations

This was a single-centre study, which limits generalisability. The cross-sectional design precludes any inference about causal direction or prognosis; longitudinal follow-up would be required to establish whether autonomic indices predict subsequent deformation decline or clinical events. Sample size, while adequate for the primary correlation, limits power within diagnostic subgroups, and the valvular group in particular (n = 25) is small. Beta-blocker and renin-angiotensin system inhibitor use was not stratified in the present analysis and represents an important confounder of HRV. Inter-vendor variability in strain software affects absolute GLS values, so our thresholds should be applied cautiously across platforms, although the use of a single vendor-independent package and a single blinded analyst limits internal variability. Finally, patients with atrial fibrillation and implanted devices were necessarily excluded to permit valid HRV analysis, which selects against a higher-risk segment of the heart failure population and may attenuate the observed associations.

In patients with established heart disease and a preserved mean ejection fraction, cardiac autonomic dysfunction and impaired longitudinal myocardial deformation were both prevalent and were significantly related to one another, with the greatest impairment in both domains among patients with heart failure. These findings support a neuro-mechanical model of cardiac dysfunction in which neural and mechanical deterioration proceed together, and argue for incorporating deformation imaging — and, where it is unavailable, simple heart rate variability assessment — into the evaluation of patients whose ejection fraction appears normal. Prospective longitudinal studies are needed to determine whether the relationship observed here carries prognostic information beyond that provided by either measure alone.

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