Abstract
Cardiovascular symptoms are common in Parkinson’s disease (PD), either as non-motor symptoms (NMS) of PD or as coexisting cardiovascular diseases (CVD), since both PD and CVD primarily affect the elderly population. Autonomic dysfunction in PD often involves blood pressure issues, including orthostatic hypotension, postprandial hypotension, and supine hypertension (SH). The combination of these NMS is particularly challenging to diagnose and treat. Other atherosclerotic vascular diseases, such as stroke or myocardial infarction, appear to be more common in PD patients. Prophylactic measures, such as statins or managing hypertension/SH, are essential for PD patients with an elevated risk of CVD, although PD patients usually undergo polypharmacy due to the short half-life of levodopa and the requirement of multiple drugs for CVD. This review presents studies in the literature on the current state-of-the-art therapy for CVD in PD.
Introduction
Parkinson’s disease (PD) impacts 1–2 individuals per 1000 people. Its prevalence rises with age, affecting 1% of the population over 60 years old. 1 The aging population is also more susceptible to cardiovascular diseases (CVD), which are a leading cause of death in this age group. 2 Besides the motor symptoms, bradykinesia, rest tremor, and rigidity defining PD, there are numerous non-motor symptoms (NMS), which can precede the onset of motor symptoms or occur in the course of the disease. NMS include neurobehavioral changes (e.g., depression, dementia), sleep disorders, sensory impairments (e.g., hyposmia and pain), and autonomic dysfunction (e.g., blood pressure abnormalities, gastrointestinal dysfunction, urinary dysfunction, and sexual dysfunctions).3,4 These symptoms are often underdiagnosed, because the primary focus of treatment lies on motor symptoms, and patients often do not report NMS. In recent years, potential connections between PD and heart disease have gained attention. PD is a neurodegenerative disorder characterized by the abnormal accumulation of misfolded, phosphorylated α-synuclein in neurons, glial cells, or both. The misfolding, aggregation, and subsequent spread of pathological α-synuclein inclusions from cell to cell resemble the characteristics of bona fide prions.5–8 The disease primarily presents with motor symptoms that are clinically dominant, resulting from damage to the cells in the substantia nigra and the subsequent depletion of dopamine. 9 PD is highly heterogeneous and seems to consist of several subtypes due to the nature of the wide spreading of α-synuclein aggregations and variability of NMS. 10 Cardiovascular autonomic dysfunction (CAD) is present in 30%—40% of patients with PD, though only a minority shows symptoms. 11 The Braak hypothesis suggests that the accumulation of alpha-synuclein begins in the lower medulla and the anterior olfactory bundle, and then spreads through the pons to the midbrain. This progression potentially impacts various non-dopaminergic nuclei along the way, such as the locus coeruleus and the raphe area, even before the substantia nigra is significantly affected. 12 In addition to the impaired dopaminergic pathways, cholinergic-, serotonergic-, and noradrenergic pathways are affected, leading to different NMS in PD. Noradrenaline is a key transmitter in the sympathetic nervous system, innervating the vascular system and the heart. The deficient sympathetic noradrenergic pathways in PD can be responsible for CAD-like orthostatic hypotension (OH) in PD. Besides CAD, PD may also be linked to cardiomyopathies, ischemic stroke, coronary heart disease, arrhythmias, and conduction defects. 10 Blood pressure abnormalities, such as OH, can have a considerable negative impact on the quality of life of PD patients and their caregivers. The presence of OH in PD is associated with an elevated risk of falls and syncope, increasing the hospitalization days and emergency room visits.13,14 It has also been linked to increased mortality, faster disease progression, and cognitive impairment. 15 In this review, we aim to discuss the cardiovascular symptoms (CS) associated with PD and their treatment.
CAD in PD
Neurogenic orthostatic hypotension
Neurogenic orthostatic hypotension (nOH) can lead to significant and potentially disabling symptoms and is linked to a higher risk of morbidity and mortality, especially due to the increased danger of falls. Clinical symptoms of OH include sleepiness, dizziness, neck pain (“coat hanger pain”), fatigue, syncope after standing up, or blurred vision. The prevalence of OH in PD is about 30%, with a range across studies from 9.6% to 64.9%.14,16 It is characterized by a sustained decrease in systolic blood pressure (SBP) of at least 20 mm Hg and/or a sustained decrease in diastolic blood pressure of at least 10 mm Hg within the first 3 min after standing.10,17 To distinguish nOH from OH with other causes, the increase of the heart rate (HR) has to be less than 15 beats per minute (bpm) after standing up18,19 or the ratio of HR and BP fall is less than 0.5 (ΔHR/ΔSBP). 20 Non-neurogenic OH due to absolute hypovolaemia (vomiting, diarrhea, exsiccoses) or relative hypovolaemia (heart failure (HF)), nephrotic syndrome, pathological vasodilatation leads to an elevated HR, whereas nOH shows no increase in HR. 17 In PD, damage to the central noradrenergic system, postganglionic sympathetic neurons, and the baroreflex is mainly responsible for the failure of sympathetic fibers innervating blood vessels and the heart. These abnormalities result in an insufficient response to gravitational forces on the effective circulatory volume during standing, caused by impaired vasoconstriction and excessive venous blood pooling. 21 For the therapeutic strategies, it is important that, besides the neurogenic orthostatic hypotension (nOH), other reasons for OH must be considered. The primary non-neurogenic factor known to trigger OH is hypovolemia, which can be either absolute (e.g., due to diarrhea, dehydration, bleeding, hemodialysis, adrenal insufficiency, or hypoaldosteronism) or relative, when hypovolemia may result from vasodilation (caused by alcohol, medication, heat, carcinoid syndrome, or mastocytosis) or venous pooling (as seen in cirrhosis). HF is another common condition associated with OH, with complex and multifactorial underlying mechanisms.14,21,22 The occurrence of OH is not correlated with the duration of the disease or its course. 23 OH in PD may occur before or after levodopa treatment. Levodopa can possibly influence OH, but it is not its trigger. 24 Mei et al. investigated 928 PD patients of whom 224 patients developed a spontaneous OH before levodopa intake. Of the 704 patients without spontaneous OH, OH occurred in 321 after levodopa intake.25,26 As levodopa has the potential to induce hypotension, particularly in older patients, it might have an amplifying effect on OH.25,27 The strength of this effect seems to be dose dependent. In a trial with 83 PD patients, Su et al. showed that after intake of 250 and 375 mg levodopa/benserazide, blood pressure decreased significantly in both the supine and standing positions. The SBP in the 3-min standing position was notably affected by the dose of levodopa/benserazide. However, no significant changes were observed in the 125 mg group. 28 As levodopa is essential for the medical treatment, especially of advanced PD, high single doses of levodopa should be avoided in PD patients suffering OH or arterial hypotension. An “active standing test” (AST) or a “head up tilt test” (HUT) must be performed if PD patients show symptoms of OH. AST has a better availability, but for patients who are not able to stand long enough, the HUT is more practical. The duration of the supine position should be at least 5 min. Some patients experience a delayed OH, where the blood pressure fall emerges after more than 3 min, why the standing phase should be over 5 min. The first measurement after standing up should be performed after 1 min.18,29 In comparison to delayed OH, classical OH has worse outcomes in motor, non-motor, cognitive, and cortical thickness in PD patients as shown by Joseph et al. 17 The authors also stated that there was no difference between delayed OH and PD patients without OH, whereas only patients (285) with early drug-naïve PD were enrolled for this study. If OH is diagnosed, a 24 h ambulatory blood pressure monitoring (ABPM) should be added to reveal postprandial hypotension (PPH) or supine hypertension (SH). 19 The next step should be a medication review, as several drugs can worsen the symptoms of OH. Table 1 shows medications that may exacerbate or cause symptoms of OH. If the current medication has to be adjusted, attention should be paid to the amount of blood pressure reduction and to whether the patient suffers additional SH or PH. Cardiological examination with cardiac ultrasound and electrocardiogram should be performed to rule out HF, and a blood sample to rule out anemia or metabolic anomaly. Figure 1 shows recommended diagnostic steps.
Medications that may exacerbate or cause symptoms of OH.
OH, orthostatic hypotension.
Diagnostic steps for OH in PD.
After adjusting the current medication, non-pharmacological measures must follow (Figure 2). Ensuring sufficient intravascular volume is crucial for preventing OH. If possible, a minimum intake of 2 L of water and 6 g of salt (using salt tablets if needed) is recommended. However, optimal fluid and sodium intake should be tailored to each patient’s needs.30,31 Patients should be advised to transition gradually from a supine to a standing position and to avoid standing still for long periods. Other factors that can worsen OH include heat, alcohol consumption, and large meals, as these can cause splanchnic vasodilation.32–34 Patients with OH often suffer additionally from SH, whereby diagnostic criteria are SBP ⩾140 mm Hg, diastolic blood pressure ⩾90 mm Hg, or both. 35 It is recommended that they sleep with the head elevated, 20–30 cm above the bed level, as slight tilting angles do not offer significant improvement. 36 Besides improving SH, this technique can decrease nocturia and prevent overnight volume depletion by activating the renin–angiotensin system, which leads to converting angiotensinogen into angiotensin I and further to angiotensin II. Angiotensin II is a powerful vasoconstrictor that also promotes the reabsorption of sodium in the tubules. In addition, it triggers the release of aldosterone from the adrenal cortex, which further enhances the reabsorption of both water and sodium. 37 The reduced blood pressure due to decreased baroreceptor afferent activity in sleeping with an elevated head, which increases the sympathetic outflow to the heart and blood vessels, along with reduced vagal (parasympathetic) nerve activity to the heart, also reduces the glomerular filtration pressure. 38 Moderate physical conditioning to strengthen the lower body should be integrated in the therapy of OH, preferably recumbent bicycle-riding, rowing machine, or water-based activities. Before physical exercise, sufficient hydration needs to be ensured.37,39 Gravitationally challenging exercises, such as treadmill walking or running, should be avoided in patients with distinctive symptomatic OH. Contracting a group of lower body muscles, crossing the legs, raising the toes, and bending at the waist temporarily boost venous return and peripheral vascular resistance. These actions have been shown to effectively increase blood pressure in patients with OH, as well as in those with vasovagal syncope.40,41 Elevated core body temperature should be avoided or maintained at a moderate level. Especially when the surrounding temperature is high, intensive exercise, saunas, or hot tubs may deteriorate OH symptoms. It might be helpful to use a chair while showering. Our patients with OH often report dizziness right after ascending stairs hastily, which may indicate a higher core temperature. Another therapeutic option can be found in compression garments. Abdominal binder seems to be more effective than tight high compression stockings, but less practical. Okamoto et al. 42 showed that an automated abdominal inflatable binder with 40 mmHg compression was equally effective as midodrine in the treatment of OH. In patients with OH/nOH, sympathetic activity is insufficient to counteract blood pooling in the splanchnic circulation after eating. In nOH, there is a deficiency in sympathetic vasoconstrictor nerve activity, leading many patients to experience severe hypotension within 2 h of eating. For patients with PH, it is therefore recommended to have smaller, more frequent meals.43,44 Caffeine can also reduce PH. 45 As nOH symptoms are more frequent in the morning due to forced nocturnal diuresis and subsequent hypovolaemia, it is helpful for patients to drink 400–500 ml fast, immediately after waking up in the morning because regardless of daily water intake, rapidly drinking approximately 500 ml of cold water can raise SBP by more than 30 mmHg in many patients with OH, due to a gastropressor response,46,47 this technique is also helpful when blood pressure is low and in general.
Non-pharmacological treatment of OH.
Patient education and non-pharmacological treatments are fundamental to the management of OH. If pharmacological treatment should become necessary, the objective must be to treat the symptoms, and this has to be adapted to each patient’s activities, on an as-needed basis.
Midodrine is an FDA-approved prodrug that is metabolized into desglymidodrine, a selective alpha-1 adrenoreceptor agonist, which raises vascular resistance and blood pressure. In several clinical trials, midodrine led to a notable increase in both systolic and diastolic blood pressure, along with modest improvements in orthostatic symptoms.48–50 It has a half-life of 3–4 h and elevates the blood pressure for about 2–3 h, and the dosage here is 2.5–15 mg. As midodrine has the potential for worsening SH, it should not be given within 5 h before bedtime. 51
Etilefrine, a sympathomimetic alpha-1 adrenoceptor agonist, can alleviate symptoms of OH in PD patients. It has a shorter half-life of 2 h, with a peak blood level after about 45 min, which can be used for PD patients with unforeseeable fluctuations of blood pressure. It can be given three times daily with 2.5–10 mg. 52
Droxidopa is an orally taken norepinephrine (NE) prodrug that is converted into norepinephrine in both the central nervous system and peripheral tissues, including the sympathetic nerve endings. It has been clinically assessed in phase III studies, showing significant improvements in symptoms of nOH, including dizziness, lightheadedness, weakness, fatigue, as well as enhancements in activities of daily living.53–55 Dosage of Droxidopa ranges from 100 to 600 mg three times daily during waking hours. It is FDA-approved but is not available or approved, respectively, in most countries.
Fludrocortisone has been used off-label for the treatment of OH and nOH for many years. Although the evidence supporting its use in these conditions is limited, it is recommended in treatment guidelines based on expert opinion. 56 The medication enhances renal sodium and water reabsorption, which increases intravascular blood volume. Dosage starts with 0.05 mg/day or 0.1 mg every other day, up to 0.3 mg/day. The main side effects are SH and hypokalemia, and it should be used with caution in patients with HF. 57
Pyridostigmine, an acetylcholinesterase inhibitor, has the potential to increase the sympathetic reaction to orthostatic stress by enhancing cholinergic neurotransmission at peripheral cholinergic synapses. A number of small studies have noted a slight improvement in OH symptoms. Typical dosage is 30–60 mg once to three times a day, and it might be useful for patients with residual sympathetic function who have less severe symptoms. Up-to-date pyridostigmine is off-label use.58–61
Ampreloxetine is a novel, investigational, long-acting NE reuptake inhibitor with the potential to reduce blood pressure fall in these patients by enhancing residual sympathetic function. nOH is a disorder with reduced NE release from postganglionic sympathetic neurons innervating the peripheral vasculature. Synucleinopathies are associated with postganglionic patterns of neuronal cell loss in PD or preganglionic and postganglionic damage in the case of multiple system atrophy. Regardless of where the lesion is located, patients with synucleinopathies may have impaired NE release, leading to insufficient vasoconstriction and a drop in blood pressure upon standing. 62 Kaufmann et al. found an increase of seated blood pressure of 15.7 mmHg 4 h after ampreloxetine and a 14.2 mmHg decrease after placebo. The authors stated only a minimal effect on supine blood pressure throughout the treatment with ampreloxetine. By enhancing remaining sympathetic activity, NET inhibition may offer a pharmacological alternative to midodrine and droxidopa. 63
Norepinephrine transport inhibitors such as reboxetine and sibutramine selectively enhance sympathetic tone under stress by preventing the reuptake of norepinephrine in sympathetic neuronal synapses. In double-blind, randomized, crossover trials, both reboxetine and sibutramine have been demonstrated to block or diminish the vasovagal reflex during tilt testing. 64
Neurogenic supine hypertension
Neurogenic supine hypertension (nSH) in patients with nOH is defined as a SBP of 140 mmHg or higher, or a diastolic blood pressure of 90 mmHg or higher, after 5 min of rest in the supine position. 19 The prevalence of nSH in PD varies from study to study between 30% and 53%.65–68 Severe SH in patients with synucleinopathies is associated with an increased risk of cardiovascular events and a reduced life expectancy.69,70 The aim of treating nSH in patients with synucleinopathies is to reduce the risk of end-organ damage while avoiding the exacerbation of hypotension, thereby decreasing morbidity and mortality. After the diagnosis of nSH with long-term blood pressure measurement a medication review has to be made, if antihypertensive medication can be shifted to the nighttime and/or replaced with drugs that have a shorter half-life like captopril (12.5–25 mg) with 8–12 h duration of action 71 or nifedipin (5–10 mg) with a duration of action from 3 to 5 h. 72 Non-pharmacological measures are sleeping with the head tilted up 73 and avoiding the supine position during the day. 74 Drinking alcohol or eating a high-calorie snack before bedtime can also lead to a reduction of nSH.75,76 Local passive heat can be utilized to reduce blood pressure. Applying a heating pad at 40–42°C to the abdomen for 2 h effectively decreased overnight blood pressure in patients with SH. 77 A non-pharmacological method for treating SH involves the overnight use of continuous positive airway pressure (8–12 cm H2O). This approach reduced nighttime blood pressure, was linked to lower nighttime diuresis, and helped to improve symptoms of nOH in the morning. 78 If pharmacological treatment is required, short-acting antihypertensive agents such as captopril, clonidine, losartan, hydralazine, or nitroglycerin are recommended, whereas captopril has a brisk blood-lowering effect and should be used with caution. 19
Non-dipping and reverse dipping
Non-dipping, defined as a reduced decrease of blood pressure of less than 10% in sleep, is common in PD. Tulba et al. found that 1744 (75.53%) of 2309 PD patients from 27 studies presented a non-dipper status in a 24 h blood pressure measurement. Reverse dipping, characterized as no reduced blood pressure in sleep, was found in 477 (40.46%) of 1179 PD patients from 18 studies. 79 The lack of a normal dipping pattern is an independent risk factor for cognitive impairment in patients with PD. 80 In addition, patients with non-dipper status appear to be more prone to psychotic symptoms. 81 PD patients suffering reverse dipping show a higher left ventricular mass and have a higher prevalence, such as arterial hypertension patients, than PD patients with normal dipping status. 82 As the prevalence of non-dipping and reverse dipping PD is high and can have these negative consequences, it is recommended to screen all PD patients with ABPM. Therapeutic measures should include a review of medication, with antihypertensive medication being postponed before nighttime; non-pharmacological measures should be taken in the same way as for SH.
Postprandial hypotension
PH is characterized by a decrease in SBP of at least 20 mmHg within 30 min after eating. The prevalence of postprandial hypotension (PH) in PD is about 50%. 83 For PD patients with nOH and PH, it is advised to avoid meals high in glycemic index carbohydrates and sugary beverages. Instead, low glycemic index carbohydrates are preferred, and smaller, more frequent meals should be consumed. In addition, alcohol should be avoided during the day, as it acts as a vasodilator.74,84 By antagonizing vasodilatory peptide release and adenosine antagonist effect, caffeine and octreotide are possible pharmacological options to reduce PH.45,85 The alpha-glucosidase inhibitor acarbose has been demonstrated to effectively reduce PH when given 25–50 mg 10 min before the meals, by reducing the absorption of simple carbohydrates, which stimulates the release of gut peptides.86,87 In our experience, PD patients with OH and symptomatic PH benefit from etilefrine given before meals, because of the short half-life of 2 h. We would recommend initially 2.5 mg; if necessary, increase up to 15 mg. As some patients respond better to midodrine, it can be given with 2.5 mg up to 10 mg about 30 min before meals.
CVD and HF in PD
As the prevalence of PD affects elderly people and increases with aging, PD patients also face a higher risk of CVD and HF. Several studies have examined the link between PD and non-autonomic heart diseases, with the intention of revealing a connection between the pathogenesis of the two diseases. Zesiewicz et al. 88 found that the prevalence of HF is more than twice as high in PD patients compared to non-PD controls. A meta-analysis by Hu and Xu showed that PD patients had a higher risk of stroke with an odds ratio of 1.49 compared to non-PD patients. The pooled analysis did not show an increased risk for myocardial infarction (MI) or cardiovascular mortality in PD. 89 A Korean population-based study also found, besides the increased likelihood for stroke in PD patients (odds ratio 1.43), an elevated risk for MI with an odds ratio of 1.42 compared to non-PD patients. In this study, chronic HF was more frequent in the PD group with an odds ratio of 1.65. 90 A cross-sectional observational study by Acharya et al., using data from the Luxembourg Parkinson’s Study on 676 PD patients and 874 non-PD controls, showed that patients with a history of CVD had a higher risk of developing PD. CVD history was higher with 18.9% in PD patients versus 9.3% in non-PD patients, while the odds ratio was 1.56. The risk was stronger in males than in females. The history of hypertension was significantly higher at 42.1% in PD versus 34.3% in the non-PD group, and anamnesis of diabetes was more frequent in PD patients with 9% versus 6.1% in non-PD patients. 91 In a retrospective cohort study by Lim et al., which included 1211 patients with PD and 86,000 controls, the risk of CVD and the rate of major adverse cardiovascular events (MACE) were higher in patients with PD. However, after propensity score matching, there were no significant differences in MACE between the PD group and the non-PD group. In patients with PD, both higher disease severity and the presence of cardiovascular risk factors (CRF) were associated with an increased rate of cardiovascular events, but not in PD patients without CRF. 92 Using single nucleotide polymorphisms from the International PD Genomics Consortium publicly accessible genome-wide association studies, Zhou et al. 93 found that PD is associated with an increased risk of coronary artery disease, stroke, ischemic stroke, and cardioembolic stroke, but not for other CVDs. The mechanisms of the links between CVD and HF in PD are not known. The authors from the above-mentioned studies assume inflammatory processes, which underlie both diseases, as a possible explanation. Furthermore, reduced physical activity due to motor symptoms in PD may play a role. Swallow et al. 94 examined the cardiovascular risk of recent onset PD patients, using the QRISK2-2015 prediction algorithm. The results demonstrated that statins were underused in PD patients with increased cardiovascular risk, compared to PD patients with manifest CVD. Statins were prescribed to 37.2% of individuals with high vascular risk, 15.1% with medium vascular risk, and 6.5% with low vascular risk, compared to 75.3% of those with CVD. The inconsistent results of the studies prevent reliable conclusions from being drawn about the links between PD, CRFs, and MACEs. In any case, CRFs in patients with PD must be examined and treated in the same way as in other patients, according to the actual CVD guidelines. Self-evidently healthy diet, regular exercise, smoking cessation, weight management, managing blood pressure, cholesterol control, and diabetes management should also be applied for PD patients. The specific challenges in treating these risk factors and MACE primarily lie in managing the demanding blood pressure settings due to the high prevalence of nOH, SH, and non-dipping in PD. It has to be mentioned that strict BP control (systolic BP 130–139 mmHg and diastolic BP <80 mmHg) as recommended by the European Society of Hypertension may induce OH in PD patients. 95
Conclusion/practical suggestions
Managing CSs in PD patients requires individual approaches due to the variability of PD symptoms, side effects of PD medication, and coexisting CVD. Autonomic CSs present a major challenge for patients with PD. While the CVD and MACE of PD patients do not differ significantly from those of non-PD patients, it is obvious, that monitoring risk factors and treatment according to the guidelines is essential given that PD mainly affects the elderly. Neurological and cardiological diagnostic steps have to be considered, regarding the clinical presentation of PD symptoms and the medication of each PD patient. Hereinafter, we will discuss typical problems and symptom constellations of PD patients with CS. PD patients with symptomatic nOH or PH, peripheral edema in the lower legs, and no HF or renal insufficiency are often treated with diuretics, despite also receiving dopamine agonists (DA) and/or amantadine, which can cause edema as a side effect.96,97 In this case, DAs and amantadine should be discontinued/reduced and compensated, for instance, by increasing the levodopa dose or adding MAO-B/COMT inhibitors. Medical compression stockings have to be prescribed simultaneously in all these patients, if there are no contraindications like peripheral artery disease. As OH in PD can be asymptomatic in up to 38% and patients often don’t report typical symptoms like dizziness, unexplained falls, syncope, lightheadedness, fatigue, blurred vision, shoulder, neck, or low-back pain upon standing, we would recommend screening all PD patients for OH, especially if they receive antihypertensive drugs.13,98 First, the AST or HUT test should be performed, if pathological ABPM is recommended, because it can identify other abnormal blood pressure patterns commonly observed in PD patients, including nSH, nocturnal hypertension, and a non-dipping pattern. If patients are unable to stand and a HUT test is unavailable, we would recommend measuring blood pressure in the supine and sitting positions. If the SBP decreases by 10–19 mmHg, we would assume OH and adapt the treatment. Beta-blockers are often needed to treat PD patients with atrial fibrillation, CAD, or HF. As these can increase OH, one would try to reduce them as far as possible. From a cardiological point of view, low blood pressure values (and low HRs) are necessary to protect the heart and kidneys. If PD patients with severe fluctuations in blood pressure become symptomatic in the context of OH or PPH, for example, in the sense of syncope or falls, blood pressure medication should be administered in close consultation with the cardiologists. In PD patients treated with antihypertensives, with pronounced OH with strongly fluctuating blood pressure, especially very high blood pressure values in the supine position and frequent orthostatic syncopes after sitting up, higher blood pressure values in the lying position may have to be tolerated to reduce the frequency of loss of consciousness and the risk of injury from falls. CSs in PD remain a challenge and require close cooperation between patients, caregivers, cardiologists, and neurologists.
