Abstract

Background

Noninvasive applanation tonometry (APT) is useful to assess aortic stiffness and pulse wave reflection. Moreover, APT can predict outcome in many conditions such as arterial hypertension. In this study, we test whether APT measurements relate to progression of aortic disease in Marfan syndrome (MFS).

Methods

We performed APT in 50 consecutive, medically treated adults with MFS (19 men and 31 women aged 32 ± 13 years), who had not undergone previous cardiovascular surgery. During 22 ± 16 months of follow-up, 26 of these patients developed progression of aortic disease, which we defined as progression of aortic root diameters ≥5 mm/annum (18 individuals), aortic surgery ≥3 months after APT (seven individuals), or onset of acute aortic dissection any time after APT (one individual).

Results

Univariate Cox regression analysis suggested an association of aortic disease progression with age (P = 0.001), total cholesterol levels (P = 0.04), aortic root diameter (P = 0.007), descending aorta diameter (P = 0.01), aortic root ratio (P = 0.02), and augmentation index (AIx@HR75; P < 0.006). Multivariate Cox regression analysis confirmed an independent impact on aortic disease progression exclusively for baseline aortic root diameters (hazard ratio = 1.347; 95% confidence interval (CI) 1.104–1.643; P = 0.003) and AIx@HR75 (hazard ratio = 1.246; 95% CI 1.029–1.508; P = 0.02). In addition, Kaplan–Meier survival curve analysis illustrated significantly lower rates of aortic root disease progression both with lower AIx@HR75 (P = 0.025) and with lower pulse wave velocity (PWV) values (P = 0.027).

Conclusions

We provide evidence that APT parameters relate to aortic disease progression in medically treated patients with MFS. We believe that APT has a potential to improve risk stratification in the clinical management of MFS patients.

Arterial stiffness parameters predict clinical outcomes in arterial hypertension, ischemic heart disease, end-stage renal disease, and other conditions with a risk of cardiovascular events.1 The current standard for assessing arterial stiffness and pulse wave reflection requires measurement of central pulse pressure (CPP), central systolic blood pressure (CSBP), the augmentation index (AIx), and carotid–femoral pulse wave velocity (PWV).1 Applanation tonometry (APT) is a noninvasive, highly reproducible, cost-efficient, and easy-to-use bedside test to assess all these parameters.2

Previous reports of APT in persons with Marfan syndrome (MFS) comprise an experience with only 40 individuals.2–4 MFS is caused by mutations in the gene coding for fibrillin-1, FBN1, resulting in manifestations involving the heart valves, the eyes, the lungs, the dura, and the skeleton. A major threat results from weak aortic tissue that leads to dilatation of the aortic root predisposing to aortic rupture or dissection.2,3 To date, we do not have good measures to identify MFS patients at increased risk for progression of their aortic disease. Thus, it appears appealing to use APT to stratify aortic risk in MFS. In the current study, we test the hypothesis that arterial stiffness or pulse wave reflection, or both relate to the progression of aortic disease in MFS.

Methods

Study design and population. We tested a set of clinical and hemodynamic variables for potential relation to progression of aortic disease in MFS. To this end, we investigated all patients with classical MFS without previous cardiovascular surgery or intervention. All patients were >17 years of age, all patients presented to our Marfan clinic within 2 years, and they all lived within the Hamburg metropolitan area.4 All patients had previously been subjected to our standardized diagnostic program with complete evaluation of clinical criteria listed in the Ghent nosology.4,5 We excluded patients on the basis of the following criteria: (i) rule-out of MFS according to our previously described diagnostic routines,4 (ii) patients with a history of any cardiovascular surgery or intervention including surgery of the heart valves, and surgery of the aorta including aortic stent grafts or any history of aortic dissection, (iii) patients with pacemakers, (iv) patients who were not in sinus rhythm or with heart rates (HRs) >100 beats/min as obtained on an initial 12-lead standard electrocardiogram, (v) individuals with systolic blood pressures ≥140 mm Hg or with diastolic blood pressures ≥90 mm Hg after a 15-min rest on standard sphygmomanometer, (vi) patients with left ventricular systolic ejection fraction <60%, or (vii) patients with any regurgitation or stenosis in heart valves of more than trivial degree on standard transthoracic echocardiography obtained on the day of APT. We continued all medical regimens during APT.

During the study period, we evaluated a total of 189 consecutive outpatients who presented to our Marfan center with proven or suspected MFS.4 Among these individuals, we identified 50 consecutive patients who complied with our study criteria and who yielded adequate APT measurements in all cases. This study group comprised 19 men and 31 women at a mean age of 32 ± 13 years (range 18–66 years). To assess outcome measures, we obtained follow-up echocardiography 6 or 12 months after APT, and then at yearly intervals to assess progression of the aortic root diameter. In addition, all patients were followed by phone interview using a structured questionnaire to document aortic events including aortic dissection or aortic intervention. The Hamburg Research Ethics Committee approved our APT protocol (number 2791) and follow-up study (number WF-30/08), which were both in accordance with the principles of the Declaration of Helsinki.

Clinical study variables. We analyzed 24 clinical variables at the time of APT for potential impact on progression of aortic disease using a standardized protocol (Table 1). We assessed age at the time of APT, gender, body weight, body height, body mass index, and body surface area according to standard criteria.4 We measured maximum aortic diameters at the level of the aortic sinuses on transthoracic echocardiography,6 and diameters of the ascending aorta and the descending aorta on magnetic resonance angiography at established levels.7 We calculated aortic root ratios as described by Roman et al.6 As part of our clinical routine,2 we put patients on prophylactic medication. A β-blocker medication comprised intake of metoprolol or bisoprolol at dosages administered according to classical protocols.8,9 Only with drug intolerance, we replaced β-blockers, and titrated dosages of angiotensin-converting enzyme inhibitors (ramipril), or AT1 blockers (valsartan or candesartan) until systolic blood pressures were below 110 mm Hg. We considered intake of any of these drugs as “aortic protective medication.” Accordingly, 43 patients were on a single drug, two individuals received a combination of drugs, and five patients (all in the progression group) refused or did not tolerate any medication. All medications were continued during APT and at follow-up. We considered active smoking with any inhalative intake of nicotine within ≤7 days prior to APT, and we assessed fasting blood glucose levels and fasting lipid levels ≤24 h of the study.

Table 1

Patient characteristics

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We used the Gray severity scores to grade disease severity of MFS.10 Accordingly, we graded cardiovascular manifestations “mild” with aortic dilatation, not requiring surgery, and being observed >40 years of age, “moderate” with dilatation observed at 20–40 years, and “severe” with dilatation diagnosed <20 years, or with surgical treatment, and “absent” with absence of any of these features. Based on manifestations of the vertebral column, the sternum, the joints, the palate, body growth pattern, and history of pneumothorax, we scaled skeletal manifestations “normal” with <2 skeletal features, “mild” with 2–4 features, “moderate” with 5–6 features, and “severe” with ≥7 features. We graded ocular involvement “mild” with severe myopia (>6 diopters), “moderate” with additional retinal detachment, and “severe” with lens subluxation or dislocation, and “absent” without any of these features.10 We analyzed severity scores as categorical data (Tables 1 and 2).

Table 2

Univariate Cox regression analysis with progression of aortic disease as dependent variable

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Hemodynamic study variables. In addition to the clinical variables, we examined hemodynamic variables with potential impact on progression of aortic disease using a standardized protocol (Table 1). We obtained radial artery waveforms from the wrist of the dominant arm using a high-fidelity micromanometer (SPC-301; Millar Instruments, Houston, TX). A validated transfer function (SphygmoCor; AtCor Medical, Sydney, Australia) generated the corresponding central waveforms, and the integral SphygmoCor software determined the CSBP, central diastolic and central mean blood pressures, AIx, the time to the peak/shoulder of the first (T1) and second pressure wave components (T2) during systole, the time to return of the reflected pressure wave (Tr), ejection duration, the CPP, and the HR (Figure 1).11 AIx is defined as the ratio of augmentation to CPP, which we expressed as a percentage: AIx = (AugP/PP) × 100, where AugP is the augmentation pressure and PP is pulse pressure. Because the AIx is influenced by the HR, we used the AIx adjusted to a HR of 75 beats/min (AIx@HR75).12 We obtained the mean arterial pressure and the subendocardial viability ratio (also known as the Buckberg's ratio) from integrals of the central waveform. We assessed the peripheral pulse pressure as the difference between systolic and diastolic blood pressures in the radial artery. To measure the carotid–femoral PWV, we sequentially recorded electrocardiogram-gated carotid and femoral artery waveforms; the travelled distance of the pulse wave was assessed as the distance from the suprasternal notch to the femoral artery with subtraction of the distance from the carotid to the suprasternal notch (Table 1).13

Central pulse wave. AIx, augmentation index; AugP, augmented pressure; CDBP, central diastolic blood pressure; CPP, central pulse pressure; CSBP, central systolic blood pressure; ED, ejection duration; IP, inflection point; T1, time of first peak; T2, time of second peak; Tr, time of reflected wave.

APT protocol. All subjects gave written informed consent prior to APT. All arterial stiffness measurements were performed by the same two investigators in accordance with the international guidelines.13 Specifically, all measurements were made in the same room at a constant temperature (20 °C), they were unaffected by external environmental influences, and they were made after 15 min of baseline resting in supine position. All individuals were awake, did not speak during APT, and refrained from smoking, eating, and drinking beverages containing caffeine ≥3 h before assessment. The blood pressure level was measured oscillometrically at the upper arm (Omron HEM 750; Omron Healthcare, Kyoto, Japan) and entered into the SphygmoCor system for calibration of the pulse waves.13 The investigators were blinded to clinical data, diagnoses, or therapy of study patients. They averaged values from three consecutive measurements, with acceptance as valid only when standard deviation of beat-to-beat data did not exceed 10% of its mean and complying with the internal SphygmoCor quality control criteria.

Follow-up studies. We performed a phone interview in all study patients using a structured questionnaire to document aortic events including aortic dissection or aortic intervention. In addition, we assessed the current health status in all patients including major adverse cardiovascular events as listed by Kip et al.14 We performed follow-up echocardiography 6 or 12 months after APT, and then at yearly intervals to assess progression of the aortic root diameter.11 We defined “progression of aortic disease” as (i) a progression of aortic root diameters ≥5 mm/annum, (ii) a requirement to perform aortic surgery or aortic intervention ≥3 months after APT, or (iii) an onset of acute aortic dissection at any time after APT.2,8. In five patients with ≤6 months follow-up after APT, we performed phone interviews documenting uneventful outcome but did not obtain an echocardiogram; we considered these patients as uneventful. No patient died or developed other major adverse cardiovascular events14 or exhibited evidence of progression at other sites of the aortic vessel or required other major surgery or interventions.

Data analysis and literature review. We tested 24 clinical variables and 15 hemodynamic variables for association with progression of aortic disease. Quantitative data were expressed as means ± standard deviation and qualitative data as numbers (percentage). We compared qualitative data by the Fisher's exact test and quantitative data by the Mann–Whitney test (Table 1). We estimated time-to-event curves using the Kaplan–Meier method and compared curves with the logrank test (Figure 2). We studied the effects of all the parameters with univariate Cox regression analysis (proportional hazards model; Table 2). Afterwards, we performed a statistical adjustment using multivariate regression analysis including those variables statistically significant in the univariate analysis (Table 3). Comparisons were considered significant in the presence of a P value <0.05.

Table 3

Multivariate Cox regression analysis with progression of aortic disease as dependent variable

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Kaplan–Meier curves for estimating the cumulative aortic disease progression rates. (a) AIx@HR75 and (b) PWV measurements were divided into 50 percentiles for analysis and compared with the logrank test. The statistical difference between patients with increased vs. lower PWV, however, is explained by nearly 10 years of age difference between both groups. AIx, augmentation index; APT, applanation tonometry; HR, heart rate; PWV, pulse wave velocity.

We used MEDLINE (key words: Marfan syndrome, tonometry, pulse wave analysis, aortic stiffness, distensibility, aneurysm, and aorta) to screen the literature for original data on noninvasive measurements of aortic elastic properties in MFS. We identified 20 reports that we screened for baseline patient characteristics, methods, and results of stiffness measurements as compared to control groups or changes with β-blocker therapy (Table 5).7,,,,,,,,,,,,,,,,,,,33 We used SPSS software (SPSS for Windows, Release 13.0; SPSS, Chicago, IL) for all statistical analyses.

Results

During a mean follow-up of 22 ± 16 months (range 3–53 months), 26 patients developed criteria of progression including 18 individuals with isolated progression of their aortic diameters, seven persons who underwent a David type 1 operation, and one patient with surgery for acute aortic dissection. The remaining 24 patients did not exhibit any criteria for progression of aortic disease. No patient died or developed other major adverse cardiovascular events or required other major surgery or interventions.

Analysis of clinical variables showed that age at APT (P < 0.001), body weight (P = 0.006), body mass index (P = 0.001), HR (P = 0.004), and diameters of the descending aorta (P = 0.03) were increased in patients with progression of aortic root disease as compared to patients without progression (Table 1). Univariate Cox regression analysis identified increased age (P = 0.001), increased total cholesterol levels (P = 0.04), larger diameters of the aortic root (P = 0.007) and of the descending aorta (P = 0.01), and an increased aortic root ratio (P = 0.02) in patients with aortic progression during follow-up (Table 2).

Comparison of hemodynamic variables yielded decreased values for aortic T1 (P = 0.001), Tr (P < 0.0001), and subendocardial viability ratio (P = 0.001) in patients with progression of aortic disease (Table 1). Commensurately, patients with progression exhibited increased values for CPP (P = 0.02), PVW (P = 0.006), and AIx@HR75 (P < 0.0001). Univariate Cox regression confirmed an impact on aortic progression during follow-up only for AIx@HR75 (P < 0.006; Table 2).

Multivariate Cox regression analysis established an independent impact on aortic progression after APT exclusively for AIx@HR75 (P = 0.02) and aortic root diameters (P = 0.003). Conversely, multivariate analysis excluded an independent impact of age (P = 0.3), descending aortic diameters (P = 0.9), and total cholesterol levels (P = 0.9; Table 3). Kaplan–Meier curve analysis showed significantly lower rates of aortic disease progression both with lower AIx@HR75 (P = 0.025) and with lower PWV values (P = 0.027; Figure 2).

Discussion

We performed the current study to test the hypothesis that arterial stiffness or pulse wave reflection, or both relate to the progression of aortic disease in MFS. Indeed, multivariate Cox regression analysis corroborated that AIx@HR75 was independently associated with aortic disease progression, and Kaplan–Meier curve analysis documented lower rates of aortic disease progression both with lower AIx@HR75 (P = 0.025) and with lower PWV values. We believe that clinical decisions such as timing of follow-up intervals, or medical treatment, or earlier timing of prophylactic surgery may benefit from APT-based risk assessment.

Hemodynamic variables

AIx@HR75 is an indirect marker of aortic stiffness that is known to increase already in younger healthy individuals, whereas PWV is a direct measure of aortic stiffness that increases later in the life of healthy individuals.1,34 Normal aging of the aortic vessel relates to histologic changes known as “cystic medial necrosis,” which reflects degeneration of smooth muscle cells and elastic fibers within the aortic media, and which occurs particularly early and markedly in MFS.35 Accordingly, the changes of APT parameters may follow an accelerated but similar pattern of age-dependent changes as in normal vascular aging, with AIx@HR75 increasing earlier and to a higher degree than PWV, as found in our young MFS patients (Figure 2). Ikonomidis et al. investigated patients with systemic vasculitis and found that left ventricular diastolic dysfunction was associated with both increased AIx and aortic dilatation.36 Their findings allow us to speculate that pathogenesis of left ventricular diastolic dysfunction, which we recently described in MFS11 may also be linked to increased AIx related to aortic wall degeneration.37

We analyzed individuals with AIx@HR75 values above and below the 80% CI of the expected mean of the AIx@HR75 (Figure 3, Table 4). Interestingly, all three individuals with AIx@HR75 values <80% CI were on β-blockers or on AT1 blockers, and exhibited aortic diameter regression or stable diameters, whereas four individuals with AIx@HR75 >80% CI developed aortic disease progression. Two of these individuals were not on medication. These observations document agreement of outlying AIx@HR75 with aortic disease progression.

We used fractional polynomial regression of degree 2 to find the best transformation of age to predict the observed AIx@HR75% values. We identified the best linear fit with 1/age2; E(AIx@75%) = 25.492 – 9189.836 × (1/age2); R2 = 0.32. The red dots identify individuals with measurements below or above the 80% confidence interval of the age-dependent expected mean of the AIx@HR75 (Table 4). AIx, augmentation index; HR, heart rate.

Table 4

Patients below or above the 80% CI of normal AIx@HR75

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Clinical variables

Besides AIx@HR75, our study identified aortic root diameters as a predictor of aortic disease progression. This finding reflects the well-established concept derived from the law of Laplace that risk of aortic rupture increases with enlarged aortic radius.38 The current study, however, shows that AIx@HR75 related to aortic progression independently of aortic diameters and thus adds new information for aortic risk stratification. Because both variables from aortic anatomy and aortic tissue property measurements predict aortic disease progression, future strategies will need to be based on combined information from aortic imaging and APT.

Interestingly, Gray and colleagues identified the cardiovascular severity score as the best predictor of death in MFS, which they observed at a mean age of 45.3 ± 16.5 years.10 In contrast, our closely monitored patients were >10 years younger and none of them died. Moreover, due to the design of our study, most patients had only mild or moderate cardiovascular disease. This may explain why cardiovascular severity did not relate to aortic progression in our study. Moreover, there was no impact of skeletal or ocular severity, or of blood glucose, lipid levels, or active smoking on the progression of aortic disease. To the best of our knowledge, there is no clinical study that identified a role of classical cardiovascular risk factors in the development of aortic aneurysms in MFS.9 However, our study group and follow-up intervals may be too small for final conclusions.

Previous studies

Classical studies used a wide spectrum of methods but rarely APT. These studies selected MFS patients with aortic root dilatation for absence of previous aortic surgery, aortic complications, or medication and compared them with healthy controls. Not surprisingly, these studies consistently found stiffer aortas in MFS than in controls. We identified a total of 12 studies using a large scope of methods and parameters including aortic distensibility, aortic stiffness, and PWV to corroborate increased aortic stiffness in MFS (Table 5). However, arterial stiffness measurements have not become part of routine clinical care because methods applied to date, including sophisticated angiographic, magnetic resonance imaging, and ultrasound technology, are time-consuming, costly, not standardized, and unavailable for clinical routine. Standardized, time-efficient, and easy-to-use APT overcomes such limitations.1,39 Unfortunately, such studies do not yield clues about how to identify aortic risk in individual patients to guide their clinical management.

Table 5

Reported results from noninvasive analysis of aortic tissue properties in MFS

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Interestingly, data from three centers confirmed altered pulse wave reflection with increased AIx in 14 MFS patients24,33 but did not demonstrate significant increase of AIx in 26 patients.29 In addition, we identified five studies that compared aortic stiffness prior to and after administering β-blockers to MFS patients (Table 5). Only two of these studies documented improved aortic tissue properties β-blockers,7,22 and thus, Haouzi et al. suggested heterogeneous response to β-blockers in MFS.20 Our study confirms progression of aortic disease in >50% of all study patients under β-blocker medication.

Study limitations

We used progression of aortic diameters and clinical aortic events as a compound outcome variable because we felt that both factors reflect aortic root disease progression. Larger cohorts are required to analyze echocardiographic and clinical variables as two separate end points. Moreover, severity scores, medication, PWV, and CPP may emerge as additional predictors during longer follow-up or in patients at higher age. APT also remains to be evaluated in children and adolescents with MFS, and in other aortic syndromes such as Loeys-Dietz syndrome.4 Thus, further studies need to establish APT for routine clinical care in the entire spectrum of patients encountered in a Marfan clinic.

We provide evidence that APT parameters relate to aortic disease progression in medically treated patients with MFS. We believe that APT has a potential to improve aortic risk stratification in the clinical management of MFS patients.

Disclosure

The authors declared no conflict of interest.

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