Vasospasm in Systemic Sclerosis outside of peripheral circulation
Cardiac
Renal
Pulmonary
Pregnancy/placenta
Central nervous system
Penile
Systemic vasospasm
Migraine
Coronary syndrome X
Variant angina
Preeclampsia
Systemic Vasospasm in Systemic Sclerosis
Coronary Perfusion
Cardiac manifestations of SSc are quite prevalent, but rarely overtly clinically manifest. Small subsets of patients have symptomatic cardiac disease and it is this patient population that is at a higher risk for mortality [1]. In addition to primary cardiac complications in SSc, such as cardiomyopathy, other manifestations of SSc may secondarily lead to cardiac dysfunction. For example heart failure may result from dramatic hypertension that accompanies SSc renal crisis and right heart failure is typically the final consequence of pulmonary arterial hypertension. Myocardial dysfunction has been associated with other vascular complications including digital ulcers. There is an inverse relationship seen with calcium channel blocker use and heart dysfunction [2], suggesting the vasodilator properties of the calcium channel blocker prevents heart disease; thus giving evidence that vasospasm is playing a role in the subsequent myocardial injury and dysfunction.
Many studies have documented evidence of abnormal cardiac perfusion in patients with SSc, even amongst those without overt cardiac disease or symptomatology [3]. The cardiac perfusion deficits are typically not in a territory of involvement of larger epicardial vessels. However, these studies cannot differentiate vascular disease as a result of vasospasm from small vessel perturbation or the progressive underlying vasculopathy. In addition, other recent studies suggest possible macrovascular complications of the coronary circulation with the presence of coronary epicardial vessels pathology [4]. One possibility for cardiac perfusion abnormalities is the presence of coronary arterial/arteriolar vasospasm either in epicardial vessels (similar to variant angina) or smaller vessels (as in cardiac syndrome X) [5]. Several studies have examined whether the introduction of cold stimulus may cause or augment perfusion abnormalities amongst patients with SSc. Cold pressor testing (cold water immersion of the hand) if often used and coronary perfusion is measured by various methods before and after exposure. In one early study, amongst ten patients with SSc and evidence of heart failure, cold pressor testing did not lead to changes in ST segments on electrocardiogram (ECG) or change in ejection fraction on echocardiography but no direct or indirect measures of perfusion were obtained [6]. Another study found evidence that 10/13 patients with SSc without overt cardiac disease had transient decreases in myocardial perfusion measured via thallium scintigraphy and 12/13 with changes in left ventricular systolic function with segmental areas of hypokinesis after cold challenge procedures [7]. This study did not demonstrate ECG changes of ischemia nor did patients develop chest pain, suggesting that this effect was likely subclinical. Subsequent studies have also found high prevalence of cold-induced thallium defects. In one study of 63 unselected patents with limited systemic sclerosis, 64 % demonstrated cold-induced thallium defects [8]. This study, interestingly, also noted similar prevalence of thallium abnormalities amongst those with primary Raynaud phenomenon (57 %). Others have noted an association with the presence of cold-induced perfusion defects and measures of Raynaud severity; again implying a direct or indirect mechanistic link [9].
Once perfusion abnormalities were appreciated, other investigations were done to assess the anatomic changes in the coronary circulation. Coronary angiography in unselected SSc patients without overt cardiac disease demonstrated ectatic coronary arteries in 3/9 patients with diffuse SSc and 0/5 with limited cutaneous disease [10]. One patient demonstrated vasospasm during the angiography (but not cold induced). 7/14 patients had tortuous vessels and 3/14 had areas of stenosis (although one had risk factors for coronary artery disease). Another study did demonstrate higher frequency of atherosclerosis in smaller coronary arteries compared with controls [11]. There are other case studies demonstrating coronary artery vasospasm during routine cardiac catheterization, but there is yet to be an angiographic study clearly directly demonstrating “coronary Raynaud’s” as a significant contributor to the perfusion abnormalities seen in SSc.
If it is assumed that cold induced coronary Raynaud’s or any episodic coronary vasospasm exists, the question remains whether this has any clinical consequence. This was examined in a prospective study of 51 patients who underwent baseline evaluation for “cardiac Raynaud” and follow up measures of left ventricular function at a mean duration of 7 years after baseline studies [12]. This study demonstrated that 29 %(15/51) of patients, all of whom had no clinical cardiac disease with negative stress tests, had evidence of cold-induced perfusion abnormalities demonstrated by myocardial contrast echocardiography; 8/51 had evidence of severe cold-induced changes (>4 SD more than controls). Amongst those with severe cold-induced perfusion changes, there was significantly lower ejection fraction and left ventricular volume at follow up and persistent evidence of cold induced reductions in mean blood flow and volume by perfusion studies. In multivariable analysis, severe “cardiac Raynaud” was the only independent predictor of these outcomes in the left ventricle. Those with severe cold-induced changes in blood flow were noted to have significantly longer disease duration than those without but otherwise there were no other significant difference is disease subtype and demographic features. Interestingly there is compelling longitudinal observational data that the use of calcium channel blockers is associated with a significant protective effect with regards to long term left ventricular function [2]. Whether the mechanism of this effect is via reducing vasospasm and therefore decreasing ischemia–reperfusion injury remains to be seen. Other studies have demonstrated reversal of perfusion defects in the acute setting with treatment with calcium channel blockers [13]. Calcium channel blockers alternatively may also have other effects some as well including a direct impact on myocardial contraction [11].
Renal Vascular Bed and Scleroderma Renal Crisis
It has been observed by several experts that SSc renal disease occurs more commonly in the colder months of the year (personal observation/communications). This observation and other data have prompted investigation into the possibility of a cold induced renal vasospasm or “renal Raynaud’s phenomenon” as the trigger for scleroderma renal crisis. Data supporting the concept of “renal Raynaud’s” dates back for decades. It was first suggested in 1956 by Sokoloff et al. and further investigated by Cannon et al. who demonstrated that cold pressor challenge led to changes in renal cortical blood flow [14, 15]. Early histopathologic evidence of small and medium sized vessels structural abnormalities are seen in patients with SSc including those with no history of renal dysfunction, hypertension, proteinuria, or elevated renin levels [15]. However, the relationship of these vascular changes to the development of a clinically important renal crisis is still not evident. Renal Doppler ultrasonography also has demonstrated increased vascular resistance among patients with SSc without clinical evidence of renal disease compared to normal controls [16]. This and other studies suggest that changes in blood flow correlate with disease duration and others with nailfold capillary abnormality severity [17, 18]. Taking all these study data, we can conclude that, similar to what occurs in the heart, there is prevalent subclinical vascular disease in the renal vascular bed, but it is unclear that there is a direct link of “renal Raynaud’s” and the development of the life-threatening renal crisis of scleroderma.
The evidence supports that patients with SSc have subclinical vascular thickening and reduced reserve in flow in the kidney. The cold-responsiveness in renal blood flow has been examined by several groups as well. Cold water exposure to the hand was able to reduce glomerular filtration rates in a small sample of patients with SSc who were without overt renal disease [19]. Cannon et al. demonstrated decrease in 133Xe washout after exposure of the hands to cold [15]. Kovalchik et al. demonstrated elevated renin levels in response to cold. Interestingly, this was more prominent amongst those with more vascular changes seen on renal biopsy [20]. Neither finding, however, seemed to predict future renal dysfunction [19]. Patients with early SSc without renal disease had measures of renal vascular resistance (by pulsatility index, a measure of renal arterial resistance) and renin levels after cold immersion which demonstrated increase compared to controls; however, this was not statistically significant [21]. Therefore, studies to date have not clearly linked the possible cold-induced perfusion abnormalities to clinical manifest renal disease or “renal Raynaud’s” as a trigger for scleroderma renal crisis. One cannot conclude that cold induced renal vascular vasospasm does not occur because this question has been insufficiently investigated to date.
Pulmonary Artery Vasospasm as a Contributor to Pulmonary Hypertension
Several single case reports demonstrating evidence of cold-induced increase in pulmonary artery pressure measured during invasive procedures suggest that vasospasm may play a role in the development or progression of pulmonary hypertension [22–24]. There is some evidence that hypoxia-induced vasoconstriction occurs as demonstrated a decrease in pulmonary vascular resistance with oxygen therapy in patients with fibrotic lung disease [24]. This implies that hypoxia secondary to fibrotic lung disease may in turn contribute to vasoconstriction [25]. One study using a measurement of pulmonary perfusion by 81M Krypton infusion demonstrated a decrease in perfusion after hand cold exposure in four of eight patients with SSc [26]. Multiple studies of the effect of cold exposure pulmonary circulation have examined changes in diffusing capacity for carbon monoxide (DLCO) as an indirect measurement of pulmonary vasoreactivity. There have been varied results from these investigations despite very similar methodologies. This was first investigated by Wise et al. in 1982 who demonstrated no change in DLCO with cold exposure (hand and total body cooling) among nine patients with SSc and an increase in the DLCO in five patients with either lupus or primary Raynaud [27]. The investigators interpreted these findings to reflect an abnormal ability to redistribute blood flow in the lung and thus no increase the DLCO occurred due to underlying structural vascular disease in patients with SSc. This was subsequently investigated in patients with SSc, primary Raynaud and healthy controls by measurement of (DLCO) after cold pressor testing [28]. This study did not demonstrate decreases in DLCO after cold exposure in any group, but the primary Raynaud group did have an increase in DLCO which was not seen in healthy controls or scleroderma patients. Gastaud et al. similarly studied four groups (primary Raynaud, SSc without Raynaud, other connective tissue disease with Raynaud, normal controls) before and after cold exposure to the hand for 2 min [29]. In this study, patients with SSc showed a decrease in DLCO after cold exposure while the patients with primary Raynaud increased the DLCO. Fahey et al. studied five controls, seven connective tissue disease patients with Raynaud, and five with primary Raynaud. DLCO decreased in primary Raynaud group, at 15, 45, 120 min after cold exposure. In those with connective tissue disease and Raynaud’s the DLCO was low at baseline but the DLCO did not decrease with cold exposure [30]. It is unclear why there is such disparity in these studies. More often, those with primary Raynaud were found to have increase in DLCO and this may be related to increase sympathetic tone and heart rate after cold exposure leading to an increase in pulmonary blood flow. Alternatively, induction of Raynaud’s may shift blood from the skin centrally and increase blood flow. Patients with underlying structural disease of the pulmonary vessel would then have an inability to increase blood flow and the DLCO would remain low or unchanged. Another study did not examine cold pressor testing, but did note improvement in DLCO in patients with SSc without pulmonary hypertension after acute administration of nifedipine and this effect was more pronounced in those with lower DLCO [31].
Shuck et al. more directly studied the possibility of pulmonary artery vasospasm by performing cold challenge during right heart catheterization in four patients with SSc and pulmonary fibrosis, and four with limited SSc (without lung fibrosis), none of whom had pulmonary hypertension. Patients underwent hand cold water challenge during right heart catheterization. No change in mean pulmonary artery pressure of pulmonary vascular resistance was noted even with increases in aortic pressure and systemic vascular resistance [32]. A later study in those with proven pulmonary hypertension also failed to demonstrate changes in hemodynamic parameters after cold exposure (mean pulmonary artery pressure and pulmonary vascular resistance) in a group of 21 patients with SSc [33].
It appears that the propensity of the data suggest that pulmonary vasospasm is not triggered by cold exposure to the hands and that Raynaud’s phenomenon per se and does not appear to be a likely contributing factor to the development of pulmonary hypertension. The studies however to not exclude the possibility of vasoconstriction playing a role in progression of pulmonary vascular disease; also acute provocation studies may be insufficient to totally exclude a role for cold exposure.
Vasospasm in Other Vascular Beds
There are several case reports of transient cerebrovascular ischemia among patients with SSc. One case demonstrated transient global amnesia in a patient with SSc and history of concurrent headaches and Raynaud attacks [34]. Another case demonstrated hemiplegic migraine in a patient with CREST syndrome [35]. This patient’s migraines began concurrently with her other SSc symptoms except for Raynaud phenomenon which had been present for 15 years prior. Cerebral perfusion defects were seen in 9/12 patients with systemic lupus with Raynaud, 4/7 patients with lupus alone and 3/9 patients with SSc with Raynaud [36]. Upon cold provocation, two more patients with SLE and Raynaud developed cerebral perfusion defects; none of the lupus patients without Raynaud developed defects. Two of the three patients with abnormal baseline perfusion had worsening perfusion with cold exposure among the patients with SSc, but no new defects were noted in the 6/9 patients with SSc with normal baseline studies. Another study suggested that SSc patients with radiographic evidence (CT or MRI) of cerebral vasculopathy on retrospective analysis had a higher frequency of other vascular manifestations of scleroderma including pulmonary hypertension and SSc renal crisis [37].
Men with SSc have a high prevalence of erectile dysfunction [38]. This is presumed to be related to changes in the microvasculature of the penis. One study evaluating skin temperature of the penis suggests that baseline penile temperature is lower among SSc men than in controls and that recovery of flow with cooling is also slower amongst men with SSc [39]. There are no studies clearly linking acute episodes of cold-induced vasoconstriction to erectile dysfunction, however.
Scleroderma and Pregnancy
There are numerous case reports of SSc renal crisis occurring in the setting of pregnancy in patients with SSc. Pathologically, renal crisis and eclampsia are virtually indistinguishable. The etiology of preeclampsia is related to vascular insufficiency in the placenta, leading to a cascade of regulatory angiogenic mediators which to a generalized endothelial dysfunction with multiple end-organ manifestations (headache, seizures, renal dysfunction). There is also known epidemiologic associations between preeclampsia and antecedent and subsequent vascular disease. Women with preexisting vascular disease, such as hypertension, systemic lupus, and renal insufficiency have a higher risk of subsequent preeclampsia. Interestingly, those with preeclampsia also have a higher rate of future development of SSc [40]. Patients with SSc had an OR of 2.6 for prior hypertensive complications of pregnancy and OR of 3.9 for prior pregnancy complicated by intrauterine growth restriction. A direct link between Raynaud and preeclampsia has not been investigated, but hand-cooling of pregnant women led to increases in blood pressures and this effect was more pronounced in those with a history of preeclampsia [41].
Coexistence of Disorders of Abnormal Vascular Reactivity
Migraine and Raynaud
Migraine headache and Raynaud phenomenon have been linked epidemiologically in several large studies. This has previously been hypothesized to be related to altered vasomotor reactivity with vasodilation the proposed cause of migraines and exaggerated vasoconstriction in Raynaud phenomenon. However, it is now believed that migraine pathophysiology is not primarily a disorder of vasodilation. As discussed below, the complex series of events that lead to migraine seem to involve cortical spreading depression and trigeminal neurovascular sensitization.
Despite new insights into pathogenesis, there is evidence of an epidemiologic connection between the migraine headache and Raynaud’s phenomenon. Both seem to be the most prevalent in young women with Raynaud occurring in as many as 10 % of young women in their teens and twenties and migraines occurring in about 12 % of women. Both have a familial component, although likely to be polygenetically influenced. de Trafford et al. surveyed 1,000 patients with primary Raynaud and found that 7 % more were being treated for migraine compared to controls [42]. Another study surveyed migraine patients compared to healthy controls and found that 26 % of migrainous patients had Raynaud’s phenomenon compared to 6 % of controls [43]. Raynaud’s phenomenon was more common in those with classic migraine than common migraine (33 % vs. 22 %). Leppert et al. surveyed 3,000 Swedish women, and found that 19 % noted symptoms compatible with Raynaud’s, 79 % of which had been given a definite diagnosis [44]. Among those with Raynaud, there was a higher number with recurrent headaches (although not specifically migraines). O’Keeffe et al. studied 41 patients with Raynaud’s and healthy controls matched for age and sex, and found the prevalence of migraine was higher in those with Raynaud’s than in those without (58.5 % vs. 24.4 %) [45].
Migraine and Scleroderma
The prevalence of migraine was assessed in a series of 191 patients with connective tissue disease [46]. Migraine symptoms were assessed by mailed questionnaire and classified as classical or common migraines. Migraine was diagnosed in 46 % of Sjögren’s syndrome, 32 % of SSc, 12 % of rheumatoid arthritis, and 11 % controls. The presence of Raynaud (assessed by questionnaire) across groups was associated with migraine.
This data all seem to suggest and epidemiologic link between Raynaud phenomenon and migraine headache. The exact pathologic mechanism remains unclear. It had been presumed that the shared susceptibility between the two disorders was one of generalized abnormal vasoreactivity. However, current concepts of migraine pathogenesis (see below) have downplayed the role of vasodilation raising the possibility that this link may have another basis. While epidemiologic studies are suggestive of some genetic susceptibility to Raynaud phenomenon, large-scale genetic studies are lacking (see Chap. 3 for more details). However, there are some genetic susceptibility genes associated with migraine headaches. There are as many as 12 genes identified as possible susceptibility genes with at least one having a fairly clear possible mechanistic implication. Further work in this area likely deserves attention. In addition, further more detailed studies looking for confounding factors (such as medication use) should be undertaken.
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