Supine–Standing Echocardiography Reveals a Shared Preload-Failure Haemodynamic Phenotype Across POTS, Long COVID, and Post-Vaccine Syndromes: A Pilot Cohort Study

Christopher Thomas, BScApp. MScSt. AMS. DMU, Dr Graham Exelby , MBBS

February 2026

Abstract

Background:

Postural orthostatic tachycardia syndrome (POTS), Long COVID–associated dysautonomia, and post-vaccine syndromes are typically defined by heart-rate responses and autonomic testing, with limited direct assessment of preload or forward flow. Emerging population-level data identify an orthostatic cardiac output–fall phenotype characterised by stroke-volume reduction despite preserved sympathetic activation, suggesting that impaired preload may represent a shared physiological substrate. However, the anatomical and haemodynamic basis of this phenomenon remains unresolved.

Objective:

To determine whether supine–standing echocardiography identifies a reproducible orthostatic preload-failure phenotype across dysautonomia cohorts, and to explore the contribution of venous return dynamics to this process.

Methods:

Patients were prospectively enrolled into predefined clinical cohorts (POTS spectrum, Long COVID–associated dysautonomia, post-vaccine syndromes, complex dysautonomia). Supine and standing transthoracic echocardiography was performed. Primary indices were left-ventricular outflow tract velocity–time integral (LVOT VTI) and aortic valve velocity–time integral (AV VTI) as surrogates of forward flow. Secondary measures included heart rate, systolic blood pressure, and superior vena cava (SVC) flow velocity. Analyses were descriptive, focusing on within-subject postural change.

Results:

Standing posture was associated with marked reductions in forward-flow indices across all cohorts, frequently exceeding 30–40%, substantially greater than expected physiological adaptation. These changes occurred despite preserved systolic function and variable autonomic compensation. Distinct haemodynamic response patterns emerged, reflecting heterogeneous compensatory strategies. Integration of SVC flow dynamics demonstrated variable venous return recruitment, with some patients exhibiting increased SVC velocity despite profound forward-flow collapse, while others showed blunted venous response. This dissociation suggests that orthostatic preload failure reflects impaired preload delivery rather than uniform hypovolaemia or primary autonomic failure.

Conclusion:Supine–standing echocardiography identified a reproducible haemodynamic phenotype of orthostatic preload failure across POTS, Long COVID, and post-vaccine syndromes within this pilot cohort. Ongoing posture-resolved echocardiographic assessment in clinical practice continues to demonstrate concordant haemodynamic patterns, supporting preload failure as a potentially shared physiological substrate warranting larger prospective validation studies.

These findings support a model in which impaired venous return delivery—arising from mechanical, central, or control-system dysfunction—represents a final common pathway, with autonomic and RAAS responses acting as secondary modulators. Posture-resolved echocardiography provides a clinically accessible method for mechanistic stratification and reframes orthostatic intolerance as a disorder of preload delivery rather than heart-rate regulation.

1.     Introduction

Orthostatic tolerance depends fundamentally on the ability to preserve cardiac preload and forward flow during the gravitational redistribution of blood that accompanies upright posture. In healthy individuals, standing results in transient venous pooling below the diaphragm, but this is rapidly buffered by coordinated mechanisms including splanchnic venoconstriction, thoracic inlet patency, effective venous return, intact baroreflex signalling, and early diastolic suction. The net effect is preservation of stroke volume and cardiac output, with only modest physiological reductions typically reported in the range of 5–15%.(Durstenfeld et al. (2022), Wieling et al (2022), Gisolf et al (2004).

Despite this well-established physiology, most contemporary diagnostic frameworks for orthostatic intolerance—including Postural Orthostatic Tachycardia Syndrome (POTS), Long COVID–associated dysautonomia, and post-vaccine symptom complexes—remain heart-rate-centric. Tilt-table testing and active stand protocols emphasise tachycardia thresholds and blood pressure behaviour, while direct assessment of preload, forward flow, or venous return is rarely performed. As a result, clinicians are often forced to infer haemodynamics indirectly, leading to persistent uncertainty regarding mechanism, heterogeneity, and treatment response.

This limitation has become increasingly apparent as patients across ostensibly distinct diagnostic categories report strikingly similar symptom clusters: orthostatic intolerance, fatigue, cognitive impairment, exercise intolerance, post-exertional malaise, and upright head pressure. These shared clinical features raise the possibility that diverse triggers—viral, immunological, mechanical, or inflammatory—may converge on a common haemodynamic failure mode that is not adequately captured by heart-rate-based definitions.

Recent population-level evidence has begun to substantiate this hypothesis. In a large prospective study involving more than 6,000 participants across two independent cohorts, Xie et al.(2026) demonstrated a reproducible dichotomy in the immediate cardiac output response to active standing.

While the majority of individuals exhibited the expected transient rise in cardiac output, approximately 22–34% showed a paradoxical initial fall in cardiac output, a phenotype termed CO-fall (COF). This response was observed in young healthy adults as well as older populations, was highly consistent within individuals over time, and was associated with greater stroke-volume collapse, blunted heart-rate compensation, impaired baroreflex sensitivity, and adverse clinical outcomes including frailty, impaired mobility, cognitive decline, and increased falls risk.

Crucially, the CO-fall phenotype identified by Xie et al. was not explained by sodium intake, presumed hypovolaemia, or classical orthostatic hypotension, and was distinct from neurally mediated syncope. Sympathetic activation markers were elevated rather than absent, yet ineffective at preserving preload.  These findings identify failure of preload preservation—rather than deficient autonomic signalling—as the dominant haemodynamic abnormality.

However, while Xie et al. establish orthostatic preload failure as a common, reproducible, and clinically meaningful phenotype, their methodology relies on indirect estimates of stroke volume and cardiac output derived from pulse-contour analysis. As such, the anatomical, venous, and mechanical contributors to preload failure remain unresolved.

The study cannot determine where preload is lost, why sympathetic signalling fails to translate into effective venous return, or how this phenotype relates to conditions such as POTS, Long COVID, and post-vaccine syndromes that are increasingly encountered in clinical practice.

Supine–standing transthoracic echocardiography provides a practical and underutilised means of addressing this gap. By directly measuring preload-sensitive forward-flow indices—such as left-ventricular outflow tract and aortic valve velocity–time integrals—and markers of venous return, echocardiography allows real-time visualisation of haemodynamic behaviour across postural transition. This approach enables differentiation between physiological compensation and pathological preload collapse, and offers anatomical resolution that complements population-level haemodynamic studies.

The present pilot study applies supine–standing echocardiography across patients labelled with POTS, Long COVID–associated dysautonomia, and post-vaccine syndromes to test the hypothesis that these conditions converge on a shared haemodynamic phenotype characterised by orthostatic preload failure, with heterogeneity arising from differing compensatory strategies rather than distinct diseases. In doing so, this work provides mechanistic and anatomical resolution of the cardiac-output-fall phenotype described by Xie et al., reframing orthostatic intolerance as a disorder of preload preservation rather than a primary heart-rate or autonomic abnormality.

2.     Methods

Study population

Patients were enrolled from a specialised autonomic and post-viral clinic. Clinical cohort assignment (POTS spectrum, Long COVID–associated dysautonomia, post-vaccine syndromes, complex dysautonomia) was determined a priori based on clinical history and diagnostic assessment, independent of echocardiographic findings.

For inclusion in quantitative preload analysis, echocardiographic studies were required to contain paired supine and standing measurements of preload-sensitive forward-flow indices, specifically absolute values for both LVOT velocity–time integral (VTI) and aortic valve (AV) VTI obtained within the same examination session. These parameters were selected a priori as the primary surrogates of stroke volume and forward flow.

While a larger number of patients underwent supine–standing echocardiography, not all studies met these strict criteria for quantitative aggregation. In several cases, standing measurements were reported as relative differences only, or acquisition was curtailed due to symptom provocation, resulting in incomplete posture-paired datasets. In earlier examinations performed prior to full protocol standardisation, preload-specific indices were not consistently recorded in both postures.

Given the absence of established normative data for upright SVC Doppler, interpretation was based on within-subject supine-to-standing change, with emphasis on directionality and relative magnitude rather than absolute thresholds.

To preserve methodological rigor and avoid imputation or surrogate substitution, only studies with complete posture-matched forward-flow measurements were included in pooled quantitative analyses. Patients with partial datasets were retained descriptively and contributed to cohort characterisation but were excluded from quantitative preload-signature analysis.

Echocardiographic protocol

All patients underwent standardised transthoracic echocardiography following a period of supine rest, with repeat measurements obtained after transition to standing posture.

Primary preload-sensitive indices:

• LVOT velocity–time integral (LVOT VTI)

• Aortic valve velocity–time integral (AV VTI)

Secondary measures:

• Heart rate

• Systolic blood pressure

• Superior vena cava (SVC) flow velocity

Derived measures

Percentage change was calculated as: %ΔVTI = [(VTI_standing − VTI_supine) / VTI_supine] × 100

Statistical analysis

Given the exploratory nature of this pilot cohort, analyses were descriptive. Results are presented as means and proportional distributions. No inferential statistics were applied.

All echocardiographic studies were performed or directly supervised by a senior cardiac scientist with over two decades of experience in advanced and critical-care echocardiography. Protocol development required real-time adaptation of acquisition techniques to accommodate severe orthostatic intolerance while preserving quantitative accuracy of preload-sensitive indices.

3.     Results

Cohort composition and echocardiographic completeness

Thirty-three patients were enrolled. Twelve patients had complete, technically adequate supine–standing echocardiographic datasets permitting quantitative analysis of preload-sensitive indices. One additional exercise-triggered POTS case was excluded from quantitative aggregation due to incomplete standing absolute values.  Standing Doppler acquisition was performed as early as tolerable after active stand, within a standardised window (typically 1–5 minutes upright). LVOT and AV VTI values were averaged across ≥3 cardiac cycles (≥5 where ectopy present). Patients were instructed to avoid Valsalva manoeuvres and to maintain relaxed respiration during acquisition.

Orthostatic changes in forward flow

Across all cohorts, standing posture was associated with a consistent reduction in forward-flow indices.

Mean percentage reductions:

• POTS spectrum: LVOT VTI −43%, AV VTI −49%

• Post-vaccine syndromes: LVOT VTI −36%, AV VTI −38%

• Long COVID–associated dysautonomia: LVOT VTI −33%, AV VTI −36%

More than 80% of patients demonstrated ≥30% reduction in at least one forward-flow index on standing. These changes occurred despite preserved resting systolic function and absence of structural heart disease.

Compensation heterogeneity

Compensatory responses varied markedly:

• Heart rate: Greatest mean increase in post-vaccine syndromes (+27 bpm), moderate increase in POTS spectrum (+19 bpm), heterogeneous responses in Long COVID.

• Blood pressure: Systolic changes were inconsistent and did not reliably reflect forward-flow collapse.

• SVC velocity: Most patients-high SVC and blunted SVC responders demonstrated increased standing SVC velocity, but the magnitude varied; some showed limited SVC recruitment despite marked forward-flow reduction.

Operational preload-signature patterns

Analysis of posture-paired forward-flow indices and compensatory responses revealed four reproducible operational preload-signature patterns. These patterns describe how patients respond haemodynamically to orthostatic preload loss, independent of diagnostic label, and reflect differing modes of compensation rather than distinct diseases.

Importantly, these patterns were observed across clinical cohorts (POTS, Long COVID, post-vaccine syndromes, and complex dysautonomia), indicating that diagnostic categories do not reliably segregate underlying haemodynamic behaviour.

1. High collapse / high compensation

(Mechanical–Venous Preload Failure dominant pattern)

This pattern is characterised by marked orthostatic collapse in forward flow, typically with ≥40–60% reduction in LVOT and/or AV velocity–time integrals, accompanied by robust compensatory responses. Compensation may include pronounced tachycardia and, where measured, substantial increases in superior vena cava velocity, reflecting aggressive venous recruitment.

Blood pressure is often relatively preserved despite severe forward-flow reduction, highlighting the inadequacy of conventional haemodynamic markers in detecting this pathology. This pattern is most consistent with mechanical–venous preload failure, in which structural or positional impedance to venous return (e.g. thoracic inlet restriction, vertebral–azygos diversion, abdominal or pelvic venous congestion) dominates the haemodynamic response. Patients with this pattern frequently exhibit severe orthostatic intolerance despite apparently “compensated” vital signs. These structural contributors are proposed mechanistic hypotheses based on clinical correlation and require dedicated vascular imaging validation in future studies.

2. High collapse / low compensation

(Central–Brainstem or impaired compensatory integration)

Patients in this group also demonstrate substantial orthostatic forward-flow collapse, but with blunted or inadequate compensatory responses. Tachycardia may be modest, delayed, or absent relative to the magnitude of preload loss, and venous recruitment appears limited.

This dissociation suggests impaired central integration of baroreflex and autonomic responses, rather than primary mechanical obstruction alone. Clinically, this pattern is often associated with prominent neurocognitive symptoms, head pressure, and intolerance to even brief upright posture. It aligns conceptually with central–brainstem preload failure, where cervical venous outflow resistance, elevated intracranial venous pressure, or disrupted autonomic integration limits effective compensation.

3. Moderate collapse / disproportionate tachycardia

(Compensatory overdrive with relative preload preservation)

This pattern is characterised by moderate reductions in forward flow on standing, typically less severe than in patterns 1 and 2, but accompanied by disproportionately large heart-rate increases. Blood pressure may remain stable or fluctuate minimally, and venous compensatory markers are variably engaged.

This phenotype reflects a state in which preload loss is present but not extreme, yet compensation is excessive relative to the haemodynamic deficit. Such a pattern is consistent with hyperadrenergic or RAAS-modulated compensation, where neurohumoral drive amplifies tachycardia in an attempt to maintain perfusion. This group provides an important bridge between preload failure and the historically described “hyperadrenergic POTS” phenotype, reframing the latter as a compensatory response rather than a primary disorder.

4. Complex dysautonomia pattern

(Mixed or unstable haemodynamic responses)

A smaller subset of patients exhibited variable or internally inconsistent haemodynamic responses, with fluctuating degrees of forward-flow reduction and compensation between measurements. These cases often had significant comorbidities, long disease duration, or multisystem involvement.

This pattern likely reflects layered pathology, in which mechanical, central, endocrine, immune, and metabolic factors interact dynamically. Rather than representing a distinct category, this group underscores how prolonged or recurrent preload failure can evolve into global autonomic instability over time.

Interpretation and implications- Cross-cohort convergence

Together, these operational preload-signature patterns demonstrate that orthostatic intolerance is best understood as a spectrum of preload failure with heterogeneous compensatory strategies, rather than a single autonomic disorder defined by heart-rate criteria. The prominence of the high-collapse / high-compensation pattern provides strong haemodynamic support for mechanical–venous preload failure (MVPF) as a major, under-recognised driver of POTS and related syndromes.

These operational patterns provide a functional framework that naturally leads to the mechanistic signature classification explored in subsequent analyses, integrating haemodynamic, structural, endocrine, immune, and metabolic domains.

These patterns were observed across cohorts, rather than being cohort-specific. When visualised in preload-signature space, patients from different diagnostic cohorts occupied overlapping regions, indicating a shared haemodynamic phenotype.

4.     Exemplar cases illustrating preload-failure signatures

To illustrate how distinct preload-failure signatures emerge from the integration of haemodynamic, structural, and clinical features, selected exemplar cases are presented. These cases were chosen based on the clarity of their haemodynamic patterns and their representativeness of broader cohort behaviour, rather than disease severity alone.

Exemplar 1: Mechanical–Venous Preload Failure (MVPF)

 Primary Diagnosis: POTS, worsened after COVID

This represents the most extreme example of mechanical–venous preload failure observed in the cohort and serves as an anchor case for this signature.

Supine–standing echocardiography demonstrated a profound collapse in forward flow, with LVOT VTI falling from approximately 18.0 to 7.5 (−58%) and AV VTI from approximately 25.0 to 8.0 (−68%), yielding a mean forward-flow reduction of ~63% on standing. This magnitude of reduction substantially exceeds ranges typically reported in healthy cohorts, where orthostatic stroke-volume reductions are generally in the order of 5–15%.

Notably, this collapse was accompanied by a marked compensatory increase in superior vena cava velocity (>100%), indicating aggressive venous recruitment in response to impaired preload delivery. Blood pressure was relatively preserved, underscoring the limitation of conventional haemodynamic markers in identifying this pathology.

Clinically, she exhibits severe orthostatic intolerance with features consistent with mechanical impedance to venous return. The combination of extreme forward-flow collapse and exaggerated venous compensation is characteristic of MVPF, in which structural or positional venous obstruction (e.g. thoracic inlet, vertebral–azygos diversion, abdominal or pelvic congestion) is hypothesised to be the dominant driver.

This case illustrates how patients labelled as “POTS” may in fact harbour a primary mechanical preload disorder that is invisible to heart-rate–centric diagnostic frameworks.

Exemplar 2: Hybrid Mechanical–Central Preload Failure

Primary Diagnosis: POTS with post-vaccine exacerbation

This case demonstrates a mixed pattern in which significant forward-flow reduction on standing (mean reduction ~52%) is present alongside moderate but not extreme SVC recruitment. This pattern suggests partial mechanical impedance compounded by central autonomic or neurovascular dysregulation.

Clinically, her course shows a stepwise deterioration following vaccination superimposed on pre-existing vulnerability, supporting a hybrid mechanical–central signature. This subgroup highlights how inflammatory or immune triggers may unmask or amplify pre-existing mechanical constraints rather than acting as isolated causes.

Exemplar 3: Central–Brainstem Preload Failure (C-BPF)

Primary Diagnosis: Long COVID

This case represents a contrasting pattern in which forward-flow reduction is present (mean reduction ~41%) but venous compensatory responses are disproportionately high relative to mechanical burden, suggesting impaired central integration rather than dominant structural obstruction.

Her clinical phenotype is dominated by head pressure, cognitive dysfunction, and autonomic instability consistent with brainstem involvement. This pattern aligns with C-BPF, where impaired cervical venous outflow, elevated intracranial venous pressure, and glymphatic stagnation are hypothesised to disrupt autonomic control of preload.

Exemplar 4: RAAS- Amplified Preload Failure (Secondary Control-System Entrenchment)

Primary Diagnosis: POTS / Long COVID spectrum (phenotype varies by trigger)

This exemplar represents a subgroup in whom orthostatic preload failure is clearly demonstrated on supine–standing echocardiography, but in whom symptom persistence, volatility, and treatment resistance are disproportionately influenced by maladaptive RAAS behaviour.

Supine–standing echocardiography demonstrates moderate to marked orthostatic reduction in forward-flow indices (LVOT and/or AV VTI reductions typically in the 30–45% range), confirming preload failure as the initiating haemodynamic abnormality. However, in contrast to purely mechanical or centrally mediated patterns, compensatory responses are inconsistent and poorly stabilising over time.

Contemporaneous RAAS profiling in these patients demonstrates distinct failure-mode patterns rather than uniform suppression or activation. Observed profiles include blunted RAAS responses, renin–aldosterone uncoupling, renin-driven hyper-RAAS states, or labile oscillatory behaviour, consistent with secondary failure of volume–pressure hormonal integration rather than primary endocrine disease.

Mechanistically, these findings align with a model in which chronic preload failure, venous congestion, or neurovascular instability exposes the RAAS to persistent or oscillatory activation signals. Over time, this leads to maladaptive gain, signal uncoupling, or exhaustion within the RAAS control loop, amplifying haemodynamic instability and reducing physiological resilience. In a subset of patients—particularly those with renal venous congestion—RAAS activation may become a dominant pathological driver rather than a passive compensatory response.

Clinically, this pattern is characterised by variable response to salt loading, paradoxical benefit from angiotensin receptor blockade, and symptom persistence despite correction of upstream mechanical contributors. This exemplar demonstrates that RAAS dysregulation does not initiate preload failure, but can decisively shape disease trajectory, chronicity, and treatment response once orthostatic haemodynamic instability is established.

Rationale for exemplar-based presentation

These exemplar cases demonstrate that preload failure is not a uniform phenomenon but a final common haemodynamic pathway arising from distinct upstream mechanisms. By anchoring each signature to a clearly defined haemodynamic pattern, exemplar-based analysis allows mechanistic hypotheses to be tested without conflating trigger, diagnosis, and physiology.

5.     Qualitative concordance and derived findings in incomplete datasets

In addition to the quantitatively analysed subset, a further group of patients underwent supine–standing echocardiography in whom full posture-paired absolute measurements across all predefined indices were not available, precluding inclusion in pooled quantitative analysis. In these cases, standing measurements were reported as relative differences only, acquisition was curtailed due to symptom provocation, or not all preload-sensitive indices were captured within the same examination.

Despite these limitations, the directionality of haemodynamic change was concordant with the fully analysed cohort. Where standing measurements were available—either as absolute values or reported supine–standing differences—forward-flow indices consistently demonstrated reduction on standing, reflected by decreases in LVOT velocity–time integral (VTI), AV VTI, or both. Importantly, no cases exhibited preserved or increased forward flow on standing, and no contradictory haemodynamic behaviour was observed in association with orthostatic symptoms.

Qualitative patterns of compensation were likewise consistent with those seen in the quantitatively analysed subset. Incomplete datasets demonstrated directionally similar changes in heart rate, blood-pressure behaviour, and, where measured, superior vena cava velocity, indicating comparable compensatory responses despite incomplete posture-paired capture.

In a subset of these incomplete examinations, sufficient information was available to derive percentage change in at least one forward-flow index, based on the presence of absolute supine values together with either absolute standing values or reported supine–standing differences. Derived reductions in LVOT VTI and/or AV VTI in these cases were directionally and proportionally concordant with those observed in the primary analysed cohort, supporting phenotypic consistency beyond the strictly analysable subset. These derived values are reported descriptively and were not pooled with the primary quantitative analysis due to incomplete capture of all posture-paired indices required for uniform aggregation.

Together, these observations indicate that patients excluded from formal quantitative analysis due to incomplete datasets did not demonstrate a distinct or opposing haemodynamic phenotype, and that the preload-failure signal observed in the primary cohort was consistent across the broader study population.

6.     Discussion

This study provides posture-resolved echocardiographic evidence that patients labelled with POTS, Long COVID–associated dysautonomia, and post-vaccine syndromes share a common haemodynamic abnormality: marked orthostatic reduction in forward flow consistent with preload failure.  Although this was an exploratory pilot cohort, the consistency and magnitude of the observed haemodynamic changes—and their continued reproducibility in subsequent ongoing clinical assessments—suggest that the identified preload-failure phenotype is unlikely to represent isolated cohort-specific behaviour.

Across all cohorts, transition from supine to standing posture was associated with reductions in LVOT and AV velocity–time integrals that substantially exceeded the modest 5–15% reductions generally reported in healthy individuals during physiological orthostatic adaptation. These reductions occurred despite preserved resting systolic function and in the absence of structural heart disease, indicating that impaired preload delivery—rather than intrinsic myocardial dysfunction—is the dominant haemodynamic disturbance.  These observations should be interpreted as defining a reproducible haemodynamic phenotype rather than establishing the specific anatomical or molecular mechanisms underlying preload failure.

These findings align closely with the cardiac output–fall (COF) phenotype described by Xie et al., who demonstrated that a significant proportion of individuals exhibit a paradoxical reduction in cardiac output upon standing, despite preserved or increased sympathetic activation. Their work established orthostatic preload failure as a reproducible population-level phenotype associated with adverse functional outcomes.

The present study extends those observations by directly visualising forward-flow behaviour using supine–standing echocardiography. Rather than inferring stroke-volume collapse from pulse-contour analysis, we observed marked posture-dependent reductions in preload-sensitive indices, confirming that forward-flow compromise occurs upstream of compensatory heart-rate and blood-pressure responses.

Importantly, our data demonstrate that autonomic activation does not reliably translate into effective preload preservation. In many patients, tachycardia and increased superior vena cava velocity coexisted with profound forward-flow reduction, indicating that compensatory mechanisms were engaged but insufficient. This resolves a central ambiguity in heart-rate–centric models of orthostatic intolerance: heart-rate response reflects compensation, not mechanism.

While Xie et al. describe impaired peripheral sympathetic transmission as a contributor to the COF phenotype, our findings suggest that orthostatic preload failure arises through multiple convergent pathways rather than a uniform autonomic deficit. Operational preload-signature patterns identified in this cohort reflect heterogeneity in compensatory expression—mechanical–venous dominance, central integration impairment, compensatory overdrive, or mixed instability—but these patterns were distributed across diagnostic categories. Diagnostic labels did not segregate haemodynamic behaviour. Instead, patients with diverse clinical triggers converged on a shared physiological substrate: impaired preload delivery upon standing.

These observations support a reframing of orthostatic intolerance syndromes as disorders of preload preservation rather than primary disorders of heart rate. Heart-rate thresholds, tilt-table classifications, and symptom descriptors capture downstream manifestations of a haemodynamic instability whose initiating event is failure to maintain forward flow.

6.1 RAAS as a Secondary Modulator

Integration with contemporaneous RAAS profiling clarifies the role of neurohumoral regulation within this framework. Across cohorts, RAAS abnormalities did not demonstrate a consistent linear relationship with the magnitude of orthostatic forward-flow reduction within this cohort.  Instead, RAAS patterns appeared to modulate stability, symptom persistence, and therapeutic response once preload failure was established. 

Distinct RAAS behaviours—blunted activation, renin–aldosterone uncoupling, ren in-driven amplification, or labile oscillation—were observed across haemodynamic signatures, but none uniformly predicted the degree of orthostatic collapse. These findings are most consistent with a control-system model in which RAAS dysregulation functions as a secondary amplifier rather than a primary initiator of preload failure.

Once haemodynamic instability becomes chronic, maladaptive RAAS signalling may reduce vascular flexibility, amplify microvascular dysregulation, and entrench symptom persistence. This interpretation reconciles previously conflicting RAAS findings in POTS and Long COVID by situating hormonal behaviour downstream of preload failure rather than as an isolated endocrine disorder.

6.2 Convergence Across Diagnostic Categories

The absence of haemodynamic segregation by diagnostic label is notable. Patients assigned to POTS, Long COVID, or post-vaccine cohorts demonstrated overlapping preload-signature patterns and similar magnitudes of orthostatic forward-flow reduction. Differences in heart-rate response, blood-pressure behaviour, and venous recruitment reflected variation in compensatory strategy rather than distinct underlying diseases.

This convergence suggests that diverse triggers—viral, inflammatory, mechanical, immune, or stress-related—may lower the threshold for preload instability, but the haemodynamic endpoint remains shared. Orthostatic preload failure therefore represents a final common physiological pathway through which heterogeneous upstream factors manifest as orthostatic intolerance.

Supine–standing echocardiography provides a practical means of identifying this substrate. By directly measuring preload-sensitive forward-flow indices across posture transition, it complements population-level haemodynamic studies and offers anatomical and physiological resolution not captured by heart-rate–based criteria alone.

Taken together, these findings support orthostatic preload failure as the central haemodynamic abnormality across multiple dysautonomia-labelled syndromes, with autonomic and RAAS responses shaping clinical expression rather than defining disease category.

6.3 Venous Return as the Missing Link in Preload Failure

Core argument:

• LVOT VTI defines forward-flow collapse 

• SVC defines venous return behaviour 

• The mismatch between the two: → reveals the site of failure

7.     Limitations

This study has several important limitations.

First, this was an exploratory pilot cohort with a modest sample size, and analyses were descriptive rather than inferential. Findings should therefore be interpreted as hypothesis-generating rather than definitive.

Second, the study did not include a contemporaneous healthy control group undergoing identical supine–standing echocardiographic assessment. This study contributes early normative and pathological observations in upright SVC physiology, an area not previously characterised in orthostatic intolerance.  Healthy individuals are not routinely subjected to standing echocardiography with preload-sensitive measurements, and such protocols are not part of standard cardiovascular assessment.

However, the magnitude of forward-flow reductions observed in this cohort substantially exceeds physiological variation reported in the echocardiographic literature. Prior studies in healthy individuals demonstrate that transition from supine to upright posture is typically associated with modest reductions in stroke volume and VTI, generally in the range of 5–15%, with preserved compensatory mechanisms maintaining effective forward flow.( Wieling et al (2022), Gisolf et al (2004). In contrast, the reductions observed in the present cohort—frequently exceeding 30–40%—are markedly greater than the modest reductions typically reported in healthy subjects (5–15%).

Third, blood pressure and heart rate responses alone were insufficient to characterise haemodynamic compromise, underscoring a limitation of conventional autonomic assessment and reinforcing the need for direct preload-sensitive measurements. While superior vena cava velocity was used as a compensatory marker, comprehensive venous imaging and invasive haemodynamic validation were not performed at this stage.

Beat-to-beat haemodynamic monitoring was not performed concurrently with echocardiography; therefore direct comparison with pulse-contour–derived cardiac output responses as described by Xie et al. was not possible.

A proportion of patients were unable to tolerate prolonged upright posture during echocardiographic acquisition due to symptom severity. In these cases, standing imaging was necessarily abbreviated or incomplete. This limitation reflects the clinical reality of advanced orthostatic intolerance and may bias the dataset toward underestimation of haemodynamic collapse rather than exaggeration.

Finally, additional mechanistic domains—including renin–angiotensin–aldosterone system profiling, heart-rate variability, metabolic and amino-acid analyses, genetic data, and structural venous or cervical imaging—were intentionally excluded from this initial paper to preserve analytic independence. Integration of these domains is planned in subsequent studies and may further refine preload-signature stratification.

The proportion of patients included in quantitative preload analysis reflects the requirement for complete posture-paired forward-flow measurements rather than data quality limitations. This conservative approach prioritised analytical validity and avoids over-interpretation of incomplete echocardiographic datasets.

Despite the pilot nature of this cohort, continued implementation of posture-resolved echocardiographic protocols in subsequent clinical assessments has demonstrated highly concordant preload-sensitive haemodynamic behaviour across additional patients not included in the present analysis.

The consistency, directionality, and magnitude of the observed forward-flow reductions across diagnostic cohorts strongly support the central conclusion that orthostatic preload failure represents a shared haemodynamic phenotype warranting further investigation.  Future studies incorporating contemporaneous healthy controls undergoing identical posture-resolved echocardiographic protocols will be required to formally define pathological thresholds. Formal prospective expansion and external replication remain necessary.

8.     Conclusion

This study demonstrates that patients labelled with POTS, Long COVID–associated dysautonomia, and post-vaccine syndromes share a reproducible haemodynamic phenotype characterised by marked orthostatic reduction in forward flow, consistent with preload failure. Using supine–standing echocardiography, we directly observed reductions in LVOT and aortic velocity–time integrals that substantially exceed normal physiological adaptation and occur independently of diagnostic category.

However, the integration of venous return dynamics refines this interpretation. The observed dissociation between forward-flow collapse and superior vena cava behaviour indicates that orthostatic preload failure reflects impaired preload delivery rather than a primary deficit of cardiac function or circulating volume alone. Variability in SVC response suggests distinct venous recruitment phenotypes, implicating heterogeneous upstream mechanisms including mechanical impedance to venous return, impaired central autonomic integration, and maladaptive control-system responses.

These findings support a unifying physiological model in which diverse triggers—viral, inflammatory, mechanical, or immune—converge on a shared failure of preload delivery. Within this framework, heart-rate and blood-pressure responses represent compensatory outputs rather than defining features of disease, explaining the limited specificity of conventional diagnostic criteria.

Integration with RAAS profiling further supports a control-system paradigm in which hormonal dysregulation acts as a secondary amplifier of instability rather than a primary initiating factor. Once preload delivery becomes chronically impaired, maladaptive RAAS signalling may contribute to symptom persistence, vascular dysregulation, and reduced physiological resilience.

Taken together, these observations reposition orthostatic intolerance syndromes as disorders of preload delivery within a broader neurovascular–venous framework. Supine–standing echocardiography, incorporating both forward-flow and venous return assessment, provides a practical and mechanistically informative tool for identifying this phenotype in clinical practice.

Recognition of this shared haemodynamic substrate offers a pathway toward improved patient stratification, integration with structural and neurovascular imaging, and the development of targeted therapeutic strategies that address the underlying physiology rather than its compensatory manifestations.

Acknowledgements

The authors wish to formally acknowledge the unique contribution of Mr Christopher Thomas BScApp, MScSt, AMS, DMU, whose expertise in advanced echocardiography was foundational to this work.

This study required the development and execution of a non-standard supine–standing echocardiographic protocol in patients with severe orthostatic intolerance, where conventional acquisition strategies are often not feasible. Mr Thomas’s extensive background in cardiac physiology, critical-care echocardiography, and advanced functional assessment enabled accurate, reproducible capture of preload-sensitive forward-flow indices under physiologically challenging conditions.

His willingness to engage with an unconventional clinical question, adapt acquisition techniques in real time, and apply deep physiological judgement was essential to the success of this study. Without his acceptance of this technical and conceptual challenge, the haemodynamic insights presented here would not have been possible.

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