U.S. Fibromuscular Dysplasia Registry Yields Clues

MIAMI BEACH – The mystery shrouding fibromuscular dysplasia, a clinically important and surprisingly prevalent vascular disease of unknown etiology, began to lift with initial findings from 339 patients enrolled in the first U.S. registry for the disease. Baseline observations from the U.S. Registry for Fibromuscular Dysplasia (FMD), which enrolled its first patient in 2008 and currently has women as 91% of enrolled patients, show that the disease first occurs across a broad swath of age groups, with an age at first diagnosis ranging from 5 to 83 years old. In addition to the distinctive "string of beads" arterial fibrosis appearance that defines the disease and is apparent on imaging, and which usually occurs in the renal or carotid artery, or both, 19% of patients also had a dissection in an artery somewhere in their body (14% with a dissection in a carotid artery) and 17% had an arterial aneurysm somewhere (5% with a renal artery aneurysm and 4% with a carotid aneurysm).

These dissection and aneurysm prevalence rates were not appreciated to run so high in FMD patients. "It suggests a diffuse arteriopathy that can present in several different ways," Dr. Jeffrey W. Olin said at ISET 2012.

Another notable finding was that, besides hypertension, which was the most common presenting manifestation of FMD (seen in 66% of the registry patients at initial diagnosis), other common presenting symptoms included significant, often migraine-like headache in 53%, pulsatile tinnitus (a whooshing sound patients hear) in 30%, and dizziness in 28%. The high prevalence of headache in FMD was "first reported 30 years ago, but sort of got lost," Dr. Olin said in an interview. "A patient can have normal blood pressure and normal-appearing carotid and renal arteries but have terrible headaches and have FMD. Why? We don’t know. We have no idea what causes the headaches," said Dr. Olin, director of vascular medicine at Mount Sinai Medical Center in New York. Four percent of the registry patients had no symptoms on presentation; physicians found their FMD incidentally during imaging for other reasons.

Other flags to trigger suspicion of FMD include hypertension that begins before age 35 (although it can also start later in life), treatment-resistant hypertension, epigastric bruit and hypertension, renal infarction, cervical bruit in a patient less than 60 years old, transient ischemic attack or stroke in a patient less than 60 years old, or an aortic aneurysm in a patient less than 60 years old.

Perhaps the most surprising new finding so far from the registry is evidence for a strong family history of cardiovascular disease, with 81% of first- or second-degree relatives of FMD patients having hypertension, 59% with hyperlipidemia, 53% with a history of a stroke, 22% with an aneurysm, and 21% with a history of sudden death. The prevalence of a first- or second-degree relative also having a diagnosis of FMD was 7%, not much higher than the estimated 4% prevalence of FMD in the general population.

Dr. Olin and his associates from the registry hypothesize that patients who develop FMD have an as-yet unidentified genetic predisposition that interacts with an environmental trigger. His hope is that, by continuing to expand the registry and by receiving substantially more research support than FMD now gets, a more concerted research effort can address the genetic questions raised by the family-history findings.

Current treatment of FMD is symptom driven and usually focuses on trying to resolve patients’ hypertension, which is often treatment resistant.

"FMD is potentially treatable for hypertension," with endovascular treatment of affected renal arteries the standard intervention for patients with resistant hypertension, Dr. Robert A. Lookstein of Mount Sinai said in a separate talk at the meeting. Hypertension cure rates from balloon angioplasty, however, are "surprisingly low" – 45% in one meta-analysis – probably because of suboptimal interventional treatment.

Assessing a patient’s renal arteries before and during treatment using intravascular ultrasound (IVUS) and a pressure wire provides the key to successful resolution of hypertension by renal-artery angioplasty in FMD patients.

These two techniques, especially pressure-wire measurements, allow the operator to assess the patient’s renal arteries before and during treatment to determine whether the intervention is having a meaningful effect. "You can’t tell [whether the angioplasty produced benefit] by the angiography appearance alone," he cautioned. "You need to be compulsive with IVUS and measuring pressure gradients to determine where to start treatment and when to stop."

The U.S. Registry for FMD began with seven U.S. centers enrolling patients and now involves 10 centers and has enrolled more than 500 patients. The first 339 enrollees included 44% who were patients at the Cleveland Clinic and 20% who were patients at Mount Sinai. The average age of the enrolled patients at first symptom appearance was 47 years old; first diagnosis was an average of more than 4 years later, at an average age of 52 years old.

Vascular bed involvement among the first registry patients included one or both renal arteries in 69%, at least one extracranial carotid in 62%, vertebral arteries in 19%, and mesenteric arteries in 12%. At the time of enrollment, 7% of patients had a history of coronary artery disease and 10% had a history of stroke. The arterial fibrosis characteristic of FMD notably appears in portions of the renal and carotid arteries where atherosclerotic disease usually does not occur – in the distal renal artery and in the distal carotid, "higher than physicians usually look when they do carotid ultrasound" examinations, Dr. Olin said.

When he finds carotid fibrosis, Dr. Olin starts those patients on a daily aspirin, although the benefit of this strategy hasn’t been proven. If carotid lesions are substantial, treatment by angioplasty is possible; carotid stenting is not used on FMD patients, nor is endarterectomy, as there is no atherosclerotic plaque to remove, he said.

Dr. Olin has been a consultant to Merck, and chairs the advisory board of the Fibromuscular Dysplasia Society of America. Dr. Lookstein said he has been a consultant to Medrad and Cordis.

MIAMI BEACH – The mystery shrouding fibromuscular dysplasia, a clinically important and surprisingly prevalent vascular disease of unknown etiology, began to lift with initial findings from 339 patients enrolled in the first U.S. registry for the disease. Baseline observations from the U.S. Registry for Fibromuscular Dysplasia (FMD), which enrolled its first patient in 2008 and currently has women as 91% of enrolled patients, show that the disease first occurs across a broad swath of age groups, with an age at first diagnosis ranging from 5 to 83 years old. In addition to the distinctive "string of beads" arterial fibrosis appearance that defines the disease and is apparent on imaging, and which usually occurs in the renal or carotid artery, or both, 19% of patients also had a dissection in an artery somewhere in their body (14% with a dissection in a carotid artery) and 17% had an arterial aneurysm somewhere (5% with a renal artery aneurysm and 4% with a carotid aneurysm).

These dissection and aneurysm prevalence rates were not appreciated to run so high in FMD patients. "It suggests a diffuse arteriopathy that can present in several different ways," Dr. Jeffrey W. Olin said at ISET 2012.

Another notable finding was that, besides hypertension, which was the most common presenting manifestation of FMD (seen in 66% of the registry patients at initial diagnosis), other common presenting symptoms included significant, often migraine-like headache in 53%, pulsatile tinnitus (a whooshing sound patients hear) in 30%, and dizziness in 28%. The high prevalence of headache in FMD was "first reported 30 years ago, but sort of got lost," Dr. Olin said in an interview. "A patient can have normal blood pressure and normal-appearing carotid and renal arteries but have terrible headaches and have FMD. Why? We don’t know. We have no idea what causes the headaches," said Dr. Olin, director of vascular medicine at Mount Sinai Medical Center in New York. Four percent of the registry patients had no symptoms on presentation; physicians found their FMD incidentally during imaging for other reasons.

Other flags to trigger suspicion of FMD include hypertension that begins before age 35 (although it can also start later in life), treatment-resistant hypertension, epigastric bruit and hypertension, renal infarction, cervical bruit in a patient less than 60 years old, transient ischemic attack or stroke in a patient less than 60 years old, or an aortic aneurysm in a patient less than 60 years old.

Perhaps the most surprising new finding so far from the registry is evidence for a strong family history of cardiovascular disease, with 81% of first- or second-degree relatives of FMD patients having hypertension, 59% with hyperlipidemia, 53% with a history of a stroke, 22% with an aneurysm, and 21% with a history of sudden death. The prevalence of a first- or second-degree relative also having a diagnosis of FMD was 7%, not much higher than the estimated 4% prevalence of FMD in the general population.

Dr. Olin and his associates from the registry hypothesize that patients who develop FMD have an as-yet unidentified genetic predisposition that interacts with an environmental trigger. His hope is that, by continuing to expand the registry and by receiving substantially more research support than FMD now gets, a more concerted research effort can address the genetic questions raised by the family-history findings.

Current treatment of FMD is symptom driven and usually focuses on trying to resolve patients’ hypertension, which is often treatment resistant.

"FMD is potentially treatable for hypertension," with endovascular treatment of affected renal arteries the standard intervention for patients with resistant hypertension, Dr. Robert A. Lookstein of Mount Sinai said in a separate talk at the meeting. Hypertension cure rates from balloon angioplasty, however, are "surprisingly low" – 45% in one meta-analysis – probably because of suboptimal interventional treatment.

Assessing a patient’s renal arteries before and during treatment using intravascular ultrasound (IVUS) and a pressure wire provides the key to successful resolution of hypertension by renal-artery angioplasty in FMD patients.

These two techniques, especially pressure-wire measurements, allow the operator to assess the patient’s renal arteries before and during treatment to determine whether the intervention is having a meaningful effect. "You can’t tell [whether the angioplasty produced benefit] by the angiography appearance alone," he cautioned. "You need to be compulsive with IVUS and measuring pressure gradients to determine where to start treatment and when to stop."

The U.S. Registry for FMD began with seven U.S. centers enrolling patients and now involves 10 centers and has enrolled more than 500 patients. The first 339 enrollees included 44% who were patients at the Cleveland Clinic and 20% who were patients at Mount Sinai. The average age of the enrolled patients at first symptom appearance was 47 years old; first diagnosis was an average of more than 4 years later, at an average age of 52 years old.

Vascular bed involvement among the first registry patients included one or both renal arteries in 69%, at least one extracranial carotid in 62%, vertebral arteries in 19%, and mesenteric arteries in 12%. At the time of enrollment, 7% of patients had a history of coronary artery disease and 10% had a history of stroke. The arterial fibrosis characteristic of FMD notably appears in portions of the renal and carotid arteries where atherosclerotic disease usually does not occur – in the distal renal artery and in the distal carotid, "higher than physicians usually look when they do carotid ultrasound" examinations, Dr. Olin said.

When he finds carotid fibrosis, Dr. Olin starts those patients on a daily aspirin, although the benefit of this strategy hasn’t been proven. If carotid lesions are substantial, treatment by angioplasty is possible; carotid stenting is not used on FMD patients, nor is endarterectomy, as there is no atherosclerotic plaque to remove, he said.

Dr. Olin has been a consultant to Merck, and chairs the advisory board of the Fibromuscular Dysplasia Society of America. Dr. Lookstein said he has been a consultant to Medrad and Cordis.

MIAMI BEACH – The mystery shrouding fibromuscular dysplasia, a clinically important and surprisingly prevalent vascular disease of unknown etiology, began to lift with initial findings from 339 patients enrolled in the first U.S. registry for the disease. Baseline observations from the U.S. Registry for Fibromuscular Dysplasia (FMD), which enrolled its first patient in 2008 and currently has women as 91% of enrolled patients, show that the disease first occurs across a broad swath of age groups, with an age at first diagnosis ranging from 5 to 83 years old. In addition to the distinctive "string of beads" arterial fibrosis appearance that defines the disease and is apparent on imaging, and which usually occurs in the renal or carotid artery, or both, 19% of patients also had a dissection in an artery somewhere in their body (14% with a dissection in a carotid artery) and 17% had an arterial aneurysm somewhere (5% with a renal artery aneurysm and 4% with a carotid aneurysm).

These dissection and aneurysm prevalence rates were not appreciated to run so high in FMD patients. "It suggests a diffuse arteriopathy that can present in several different ways," Dr. Jeffrey W. Olin said at ISET 2012.

Another notable finding was that, besides hypertension, which was the most common presenting manifestation of FMD (seen in 66% of the registry patients at initial diagnosis), other common presenting symptoms included significant, often migraine-like headache in 53%, pulsatile tinnitus (a whooshing sound patients hear) in 30%, and dizziness in 28%. The high prevalence of headache in FMD was "first reported 30 years ago, but sort of got lost," Dr. Olin said in an interview. "A patient can have normal blood pressure and normal-appearing carotid and renal arteries but have terrible headaches and have FMD. Why? We don’t know. We have no idea what causes the headaches," said Dr. Olin, director of vascular medicine at Mount Sinai Medical Center in New York. Four percent of the registry patients had no symptoms on presentation; physicians found their FMD incidentally during imaging for other reasons.

Other flags to trigger suspicion of FMD include hypertension that begins before age 35 (although it can also start later in life), treatment-resistant hypertension, epigastric bruit and hypertension, renal infarction, cervical bruit in a patient less than 60 years old, transient ischemic attack or stroke in a patient less than 60 years old, or an aortic aneurysm in a patient less than 60 years old.

Perhaps the most surprising new finding so far from the registry is evidence for a strong family history of cardiovascular disease, with 81% of first- or second-degree relatives of FMD patients having hypertension, 59% with hyperlipidemia, 53% with a history of a stroke, 22% with an aneurysm, and 21% with a history of sudden death. The prevalence of a first- or second-degree relative also having a diagnosis of FMD was 7%, not much higher than the estimated 4% prevalence of FMD in the general population.

Dr. Olin and his associates from the registry hypothesize that patients who develop FMD have an as-yet unidentified genetic predisposition that interacts with an environmental trigger. His hope is that, by continuing to expand the registry and by receiving substantially more research support than FMD now gets, a more concerted research effort can address the genetic questions raised by the family-history findings.

Current treatment of FMD is symptom driven and usually focuses on trying to resolve patients’ hypertension, which is often treatment resistant.

"FMD is potentially treatable for hypertension," with endovascular treatment of affected renal arteries the standard intervention for patients with resistant hypertension, Dr. Robert A. Lookstein of Mount Sinai said in a separate talk at the meeting. Hypertension cure rates from balloon angioplasty, however, are "surprisingly low" – 45% in one meta-analysis – probably because of suboptimal interventional treatment.

Assessing a patient’s renal arteries before and during treatment using intravascular ultrasound (IVUS) and a pressure wire provides the key to successful resolution of hypertension by renal-artery angioplasty in FMD patients.

These two techniques, especially pressure-wire measurements, allow the operator to assess the patient’s renal arteries before and during treatment to determine whether the intervention is having a meaningful effect. "You can’t tell [whether the angioplasty produced benefit] by the angiography appearance alone," he cautioned. "You need to be compulsive with IVUS and measuring pressure gradients to determine where to start treatment and when to stop."

The U.S. Registry for FMD began with seven U.S. centers enrolling patients and now involves 10 centers and has enrolled more than 500 patients. The first 339 enrollees included 44% who were patients at the Cleveland Clinic and 20% who were patients at Mount Sinai. The average age of the enrolled patients at first symptom appearance was 47 years old; first diagnosis was an average of more than 4 years later, at an average age of 52 years old.

Vascular bed involvement among the first registry patients included one or both renal arteries in 69%, at least one extracranial carotid in 62%, vertebral arteries in 19%, and mesenteric arteries in 12%. At the time of enrollment, 7% of patients had a history of coronary artery disease and 10% had a history of stroke. The arterial fibrosis characteristic of FMD notably appears in portions of the renal and carotid arteries where atherosclerotic disease usually does not occur – in the distal renal artery and in the distal carotid, "higher than physicians usually look when they do carotid ultrasound" examinations, Dr. Olin said.

When he finds carotid fibrosis, Dr. Olin starts those patients on a daily aspirin, although the benefit of this strategy hasn’t been proven. If carotid lesions are substantial, treatment by angioplasty is possible; carotid stenting is not used on FMD patients, nor is endarterectomy, as there is no atherosclerotic plaque to remove, he said.

Dr. Olin has been a consultant to Merck, and chairs the advisory board of the Fibromuscular Dysplasia Society of America. Dr. Lookstein said he has been a consultant to Medrad and Cordis.