Parkinson's disease and cardiovascular abnormalities: clinical and pathogenetic aspects

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Abstract

Parkinson's disease (PD) is a multisystem neurodegenerative disorder characterized by progressive loss of dopaminergic neurons in the substantia nigra. Cardiovascular dysfunction is an important non-motor component of PD, yet it remains underrecognized in clinical practice. Accumulating evidence indicates a high prevalence of orthostatic hypotension, coronary artery disease, and cardiac arrhythmias in patients with PD, significantly impacting morbidity and mortality. The aim of this review is to examine current data on the pathogenetic mechanisms and clinical features of cardiovascular disease in PD. We conducted a search for full-text publications in Russian and English over the past 20 years in the eLIBRARY.RU, PubMed, Google Scholar, and Web of Science databases using relevant keywords and phrases. The review demonstrates that cardiovascular disease in PD forms a continuum, sharing common autonomic and neurodegenerative mechanisms. Systematic screening, including blood pressure measurement in the standing position, prolonged ECG monitoring, assessment of the QT interval and heart rate variability, together with active management of traditional risk factors, is essential to reduce morbidity and mortality.

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Introduction

Parkinson's disease (PD) is the most common movement neurodegenerative disorder [1]. From a pathophysiological perspective, PD is a multifactorial disease whose main pathogenetic mechanism is the accumulation of α-synuclein aggregates in the substantia nigra of the midbrain. Excessive accumulation of α-synuclein aggregates leads to neurodegeneration of dopaminergic neurons in the nigrostriatal, mesolimbic, and mesocortical neural networks, which subsequently determine the clinical picture of the disease (motor and non-motor symptoms) [1–3].

The development of the full clinical PD picture is preceded by a prodromal period lasting 5–15 years, during which various non-motor symptoms may appear, including asthenia, apathy, cognitive impairment, hyposmia, insomnia, constipation, depression, sarcopenia, and urological disorders [2, 3]. The main motor manifestations are typically bradykinesia and muscle rigidity; resting tremor is also often part of the clinical pattern, but is not an obligatory symptom. As the disease progresses, gait disturbances and postural instability manifest as propulsion and falls, added to the core motor symptoms [4].

The global prevalence of PD is projected to exceed 17 million cases by 2040 [5]. Early diagnosis at the pre-motor stage and prevention of avoidable complications are therefore essential to reduce disability and mortality worldwide. PD is now recognized as a multisystem disorder in which α-synuclein pathology extends well beyond the nigrostriatal system. Autonomic dysfunction is a major non-motor feature and contributes to a range of cardiovascular abnormalities.

In PD, sympathovagal imbalance disrupts cardiovascular regulation, reducing heart rate variability, impairing baroreflex control, and altering circadian blood pressure patterns [6]. These disturbances may remain subclinical or present as functional disorders, and are often overlooked in routine practice [6–8]. Growing interest in cardiovascular disease in PD reflects not only the high prevalence of the disease in older populations, but also the recognized impact of autonomic dysregulation on mortality and complication risk [6–8]. Cardiovascular disease is a leading cause of death in PD, yet it is frequently overshadowed by motor symptoms. Evidence suggests that PD patients face a higher risk of myocardial infarction, ischemic stroke, heart failure, and sudden cardiac death compared to healthy controls [6].

Cardiovascular dysfunction not only impairs quality of life by increasing the risk of falls, syncope, and injuries, but is also associated with cognitive decline and higher mortality. Its pathophysiological basis involves progressive degeneration of postganglionic sympathetic and parasympathetic neurons innervating the heart and vessels, along with direct α-synuclein aggregation in the myocardium and epicardial adipose tissue — a phenomenon termed cardiac α-synucleinopathy. Recent multicenter studies confirm that cardiovascular involvement is an integral part of PD pathogenesis, warranting targeted screening, early diagnosis, and integration of cardiological care into standard patient management [8–10].

This review is motivated by the need to translate current knowledge on cardiovascular aspects of PD into clinical practice. Despite their high prevalence, these disorders often remain undiagnosed or are mistakenly attributed to aging or comorbidities.

This narrative review aims to analyze and synthesize current evidence on the clinico-pathogenetic links between PD and cardiovascular disease.

We included Russian and international experimental and clinical studies, predominantly from the last 20 years, evaluating cardiovascular pathology in PD. Searches were conducted in PubMed, Web of Science, Google Scholar, and eLIBRARY.RU using the following keywords: Parkinson's disease, cardiovascular disease, coronary artery disease, orthostatic hypotension (OH), cardiomyopathy, and cardiac arrhythmias.

Role of α-synuclein in the pathogenesis of cardiovascular disease

In 2003, H. Braak et al. proposed that α-synuclein may spread throughout the nervous system, including the autonomic nervous system [7]. This hypothesis is now supported by growing evidence. Aggregates of α-synuclein have been found in autonomic peripheral ganglia of the gut and skin, connected to the central nervous system via the vagus nerve [8, 9]. Several studies have also demonstrated α-synucleinopathy in cardiac nerves [10–12]. N. Nishida et al. confirmed α-synuclein aggregation in the hearts of patients with dementia with Lewy bodies who died from sudden cardiac death [11]. Notably, J. Navarro-Otano et al. found that α-synucleinopathy can develop in epicardial adipose tissue in patients without parkinsonism, but with a high prevalence of non-motor symptoms typical of PD, such as constipation and insomnia [13].

Current concepts suggest that cardiac pathology in PD may result from the spread of α-synuclein aggregates beyond the central nervous system [10]. Recently, both sympathetic and parasympathetic nerves were found to be affected by α-synucleinopathy, causing autonomic dysregulation in a mouse model of PD [14].

A 2022 study by K. Javanshiri et al., analyzing a large series of autopsy material from patients with α-synucleinopathies (PD, multiple system atrophy, dementia with Lewy bodies), found a significantly higher prevalence of α-synuclein aggregates in coronary nerves compared to healthy controls [10]. Moreover, cardiac α-synucleinopathy positively correlated with the incidence of sudden cardiac death [10, 12].

In summary, current evidence strongly supports a key role for abnormal α-synuclein in cardiac nerves and tissues in autonomic dysfunction and serious cardiovascular complications, including sudden death, in neurodegenerative diseases such as PD and other synucleinopathies. The Braak hypothesis — proposing progressive spread of α-synuclein from the peripheral to the central nervous system (in an ascending direction) — is substantiated by multiple studies. This supports the view that cardiovascular disturbances in α-synucleinopathies reflect systemic dissemination of abnormal α-synuclein, making them an integral component of the neurodegenerative pathophysiology (Table 1).

 

Table 1. Overview of cardiovascular abnormalities in PD

Cardiovascular abnormality

Prevalence in PD patients

Main pathogenetic mechanisms

Clinical manifestations

Reference

OH

9.6–64.9%

Autonomic dysregulation

Dizziness, photopsia, tinnitus, weakness, syncope

15–24

Coronary artery disease

18–25%

Oxidative stress, mitochondrial dysfunction, systemic inflammation, metalloproteinase activation, physical inactivity

Chest pain, palpitations, dyspnea, weakness, poor exercise tolerance, nausea and vomiting

25–33

Takotsubo cardiomyopathy

–*

Norepinephrine-mediated "catecholamine surge"

Symptoms of acute coronary syndrome (acute chest pain radiating to the left arm, dyspnea, palpitations, fear of death)

34–39

Arrhythmia

28–30%

Sympathetic denervation

Palpitations, presyncope, poor exercise tolerance

38, 40–43

Note. *No reliable data available.

 

Orthostatic hypotension

Autonomic dysfunction in PD was recognized early in the study of the disease [15]. It disrupts the regulation of all autonomically innervated systems, including the heart. Cardiac autonomic dysfunction in PD may result from both sympathetic and parasympathetic denervation [16–18]. Moreover, recent evidence suggests that autonomic imbalance is a predictor of PD, typically preceding motor manifestations [15]. A 2013 Russian study showed that early changes involve increased sympathetic activity and decreased parasympathetic activity [17].

A major consequence of cardiac dysautonomia is orthostatic hypotension (OH). According to international consensus, OH is defined as a drop in systolic blood pressure of ≥ 20 mm Hg or diastolic blood pressure of ≥ 10 mm Hg within 3 minutes of active standing or passive head-up tilt testing [19]. OH is a debilitating condition and has been linked to increased mortality in the general population [20]. Its prevalence in PD varies widely across studies (9.6–64.9%), with a pooled prevalence of 30.1% (95% CI: 22.9–38.4%) in a meta-analysis [20]. D. Goldstein et al. reported that OH accounts for most hospitalizations in PD patients [21]. Moreover, survival rates are lower in PD patients with OH than in those without. Comorbid OH also increases healthcare costs by 2.5-fold compared to PD patients without OH [22].

OH in PD is primarily neurogenic, resulting from damage to postganglionic noradrenergic sympathetic fibers innervating the heart and blood vessels [23]. Normally, the transition from supine to standing unloads baroreceptors, triggering norepinephrine release from postganglionic sympathetic neurons and compensatory vasoconstriction that maintains stable blood pressure. In patients with α-synucleinopathies, this mechanism is either absent or attenuated, leading to OH. Neuroimaging and morphological studies provide strong evidence of postganglionic sympathetic denervation in the myocardium, linked to α-synuclein accumulation and loss of nerve terminals [23–26]. Similar changes occur in sympathetic fibers regulating vascular tone, with reduced norepinephrine release and insufficient vasoconstriction upon standing, further exacerbating OH [26].

The clinical presentation of OH is often non-specific, including fatigue, low mood, and impaired concentration; moreover, OH may mimic motor fluctuations induced by antiparkinsonian medications [23, 24]. Postprandial hypotension due to excessive splanchnic blood pooling can worsen symptoms [23]. Meals high in carbohydrates cause vasodilation and postprandial hypotension, the severity of which is linked to insulin release [25].

Thus, OH in PD is not merely a common complication, but a pathogenetically determined consequence of systemic neurodegeneration mediated by abnormal α-synuclein. Accumulation of α-synuclein aggregates in peripheral autonomic structures — including sympathetic ganglia and cardiac nerve plexuses — leads to cardiac denervation and impaired central blood pressure regulation, forming the morphofunctional basis for severe OH.

The clinical importance of OH is underscored by its association with falls, reduced quality of life, and increased mortality. Since α-synuclein pathology in the cardiovascular system may develop early, even at prodromal stages, unexplained OH may have diagnostic value. Therefore, management of PD patients should include not only management of motor symptoms, but also active screening and treatment of autonomic dysfunction. Future therapies targeting α-synuclein aggregation and spread may offer pathogenetic treatment for both motor and cardiovascular manifestations of the disease.

Coronary artery disease

Evidence is growing that patients with PD may develop coronary artery disease (CAD). Given the advanced age of PD patients, CAD risk is also influenced by classic factors: atherosclerosis, diabetes, dyslipidemia, hypertension, and smoking [25–27]. A 2005 Canadian study of 500 PD patients found no increase in CAD prevalence compared to age- and sex-matched controls [27]. However, a later study of over 4,000 Chinese PD patients identified CAD as one of the most common comorbidities [28, 29]. Moreover, myocardial infarction is a leading cause of death and is significantly more frequent in PD patients [18, 29].

Shared pathogenetic mechanisms linking PD and CAD include oxidative stress, mitochondrial dysfunction, and systemic inflammation [28]. Additionally, autonomic dysfunction characteristic of PD contributes to CAD development and progression [15]. Notably, OH in PD has been associated with an increased risk of CAD, possibly due to reduced myocardial perfusion leading to ischemia [29]. Thus, OH may represent a mechanism linking PD to CAD.

Current theories on the PD–CAD link point to a significant role of matrix metalloproteinases (MMPs) [29]. MMPs are a family of proteins responsible for tissue remodeling and degradation of the extracellular matrix. They play a key role in atherosclerosis and CAD pathogenesis, and vascular endothelial damage in CAD may further activate MMPs via release of free radicals and pro-inflammatory cytokines [30]. MMP activation increases blood–brain barrier permeability, leading to microglial activation and dopaminergic neurodegeneration [31]. Moreover, MMP activation can promote α-synuclein aggregation, a key event in PD pathogenesis [15, 29, 30]. Thus, MMPs are involved in both CAD and PD and may mediate their association. In addition, PD patients are prone to physical inactivity due to both non-motor (cognitive impairment, depression) and motor (bradykinesia, tremor, rigidity) symptoms, which is a major CAD risk factor [3, 32]. Regular physical activity is cardioprotective, but PD patients have markedly reduced activity levels, correlating with disease stage [3, 32].

CAD is a preventable disease, manageable through lifestyle modification, physical activity, and pharmacotherapy [33]. Therefore, further investigation of the clinico-pathogenetic links between PD and CAD is essential for preventive management strategies.

Thus, systemic α-synucleinopathy may serve as a pathogenetic mechanism linking PD and CAD. This pathology is not confined to the brain; peripheral autonomic denervation of the heart is the rule rather than the exception in these diseases. A potential mechanism for CAD is cardiovascular autonomic neuropathy, leading to cardiac denervation, impaired coronary flow regulation, and silent myocardial ischemia. Cardiovascular complications — arrhythmias, OH, and sudden death — are leading causes of mortality in PD, necessitating a redefinition of CAD as a pathogenetically linked complication rather than a mere comorbidity. A multidisciplinary approach with routine cardiological monitoring is essential for early detection and management of cardiovascular risk in patients with α-synucleinopathies.

Cardiomyopathy

Stress-induced cardiomyopathy (Takotsubo syndrome, TS) deserves special attention — an acute, usually reversible myocardial dysfunction driven by excessive catecholamine release, or a "catecholamine storm". TS is most often triggered by sudden stressors, including intense emotional events (bereavement, psychological trauma, panic attack, or unexpected joyful news), medical conditions (COPD, asthma, pheochromocytoma), sepsis, surgery (abdominal procedures), and iatrogenic factors (chemotherapy, abrupt withdrawal of β-blockers or opioids) [34, 35].

Neurological disorders account for a significant proportion of TS triggers in major international registries, with PD featuring among the neurodegenerative conditions [34, 35]. A norepinephrine-mediated "surge" is thought to play a key role in its pathogenesis [35, 36]. Numerous studies indicate that PD involves not only dopaminergic neurodegeneration but also damage to other brain regions, such as the locus coeruleus — the main noradrenergic nucleus of the CNS and a central regulator of norepinephrine biosynthesis [35–37]. Degenerative changes in locus coeruleus neurons disrupt norepinephrine biosynthesis and accumulation, resulting in episodic norepinephrine-mediated "surges" in neurotransmission. Through secondary messenger systems (β-adrenoceptors), these surges activate lipid peroxidation, damaging cardiomyocyte and sarcoplasmic reticulum membranes responsible for Ca2+ transport. Ca2+ overload then uncouples oxidative phosphorylation in mitochondria, reducing ATP content and activating myofibrillar proteases and mitochondrial phospholipases [35–37]. These metabolic changes lead to contractures and necrosis of cardiomyocyte groups, along with profound impairment of myocardial contraction and relaxation [37].

Clinically, TS may mimic acute coronary syndrome: acute chest pain radiating to the left arm, dyspnea, palpitations, and fear of death. For early detection, patients with PD should be evaluated based on clinical indications; in the presence of acute coronary syndrome-like features, standard diagnostic algorithms should be followed with consideration of TS, including echocardiography with global longitudinal strain assessment and natriuretic peptide measurement [37–39]. When acute coronary syndrome is suspected, clinicians should remain alert to the possibility of TS and pursue appropriate diagnosis and management [35].

Thus, neurodegeneration in PD — driven by α-synuclein accumulation — affects not only dopaminergic but also noradrenergic neurons in the locus coeruleus. This damage disrupts norepinephrine regulation and triggers pathological catecholamine surges that directly precipitate TS. Current evidence suggests that TS may be mediated by α-synucleinopathy, underscoring the importance of thorough cardiovascular risk assessment and the potential benefit of preventive cardiological monitoring in PD patients.

Cardiac arrhythmias and conduction disturbances

Recent epidemiological studies show that cardiac arrhythmias are significantly more common in PD patients than in the general population, though their severity and type vary (Table 2) [40–44]. A systematic review and meta-analysis by F. Cereje et al. found no significant increase in atrial fibrillation risk across the overall PD population [40]. However, stratification by age revealed a trend toward higher atrial fibrillation risk in patients with early-onset PD (onset before age 45) [40]. Bradyarrhythmias are also more frequent in PD. A 2025 US national inpatient analysis reported higher rates of bradyarrhythmias and pacemaker implantation in hospitalized PD patients compared to controls [41]. Pre-clinical rhythm disturbances, reflected by heart rate variability (HRV), are also common. A meta-analysis by K.G. Heimrich et al. confirmed significant reductions in both time-domain and spectral HRV parameters in PD, indicating autonomic dysfunction and an arrhythmogenic substrate [42]. Radionuclide studies demonstrate marked reduction in postganglionic sympathetic innervation of the heart in PD. Loss of noradrenergic control impairs chronotropic and inotropic responses, increases electrical heterogeneity of repolarization, and predisposes to arrhythmias [38].

 

Table 2. Characteristics of major cardiac arrhythmias in Parkinson's disease

Arrhythmia type

Features in PD

Pathogenetic mechanism

Clinical significance

References

Atrial fibrillation

Increased risk in younger patients (< 50 years)

Autonomic dysregulation

Higher stroke risk; ECG monitoring required

38, 40

Bradyarrhythmias

Higher rates of hospitalization and pacemaker implantation

Sympathetic denervation, conduction impairment

Syncope; may require pacemaker

38, 41

Reduced heart rate variability

Decreased spectral parameters

Parasympathetic denervation

Marker of autonomic dysfunction; predictor of arrhythmias and adverse outcomes

38, 42, 44

QT prolongation

Correlates with disease severity and Hoehn–Yahr stage

Autonomic dysregulation

Risk of sudden cardiac death; ECG monitoring required

40–44

 

QT interval prolongation is of particular concern, as it is associated with sudden cardiac death risk. A systematic review by S.W. Rabkin found QT prolongation in PD patients, correlating with disease severity and Hoehn-Yahr stage [43]. Prolonged QT and reduced HRV may serve as predictors of more serious arrhythmias in PD [40–44].

Thus, cardiac arrhythmias in PD may be driven by systemic α-synucleinopathy leading to autonomic degeneration and sympathetic myocardial denervation. The clinical spectrum includes reduced heart rate variability, QT prolongation, bradyarrhythmias, and atrial fibrillation. Early detection and management of these arrhythmias are crucial for improving patient prognosis. Further multicenter studies using prolonged ECG monitoring and standardized diagnostic criteria are needed to determine true prevalence and risk factors.

Conclusion

This review of current Russian and international literature supports a clear conclusion: cardiovascular disturbances are not merely comorbidities but a clinically significant and often underestimated component of PD. The accumulation of abnormal α-synuclein plays a key role in their pathogenesis — not only in the CNS but also in peripheral autonomic structures regulating cardiac and vascular function. This pathomorphological substrate underlies a continuum of cardiovascular pathology in PD, in which OH, coronary artery disease, and arrhythmias emerge as interrelated manifestations of systemic neurodegeneration and autonomic failure. Given the central role of α-synucleinopathy, improving prognosis and quality of life requires not only targeted cardiac screening and modification of classic risk factors, but also consideration of the specific features of neurogenic cardiovascular involvement. Future multicenter prospective studies should aim to clarify the true prevalence and interrelationships of these disorders and to define optimal prevention and treatment algorithms.

To enable early detection and prevention of cardiovascular complications in PD patients, regular cardiac screening is recommended. The screening algorithm should be stepwise. The first step includes annual orthostatic testing and ECG with QT interval assessment. If abnormalities are detected (QTc > 450/460 ms) and/or the patient reports palpitations or irregular heartbeat, 24-hour ECG monitoring is indicated; 24-hour ambulatory blood pressure monitoring is recommended when OH is confirmed or suspected. Key criteria for cardiology referral include: clinically significant arrhythmias; QTc prolongation > 450/460 ms (> 500 ms is a critical threshold); refractory OH; and planning for neurosurgical interventions.

We believe that the development and implementation of a unified algorithm integrating standard neurological care with comprehensive cardiological support grounded in the understanding of α-synuclein's role is a strategic priority for substantially improving long-term outcomes and prognosis in PD patients.

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About the authors

Zaynutdikhuzha F. Sayfitdinkhuzhaev

Siberian State Medical University

Author for correspondence.
Email: sayfutdinxodjaev2002@gmail.com
ORCID iD: 0009-0007-2184-2708

Laboratory Assistant-Researcher, Departmental Scientific and Educational Laboratory of Cognitive Neurophysiology of Psychosomatic Relationships

Russian Federation, Tomsk

Natalia G. Zhukova

Siberian State Medical University

Email: sayfutdinxodjaev2002@gmail.com
ORCID iD: 0000-0001-6547-6622

Dr. Sci. (Med.), Professor, Department of Neurology and Neurosurgery

Russian Federation, Tomsk

Olga V. Guseva

Siberian State Medical University

Email: sayfutdinxodjaev2002@gmail.com
ORCID iD: 0000-0001-8659-9832

Cand. Sci. (Med.), Associate Professor, Department of Hospital Therapy with a Course in Rehabilitation, Physiotherapy and Sports Medicine

Russian Federation, Tomsk

Irina A. Zhukova

Siberian State Medical University

Email: sayfutdinxodjaev2002@gmail.com
ORCID iD: 0000-0001-5679-1698

Cand. Sci. (Med.), Associate Professor, Expert, Clinical Research Center

Russian Federation, Tomsk

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