Erectile dysfunction as a harbinger for increased cardiometabolic risk.

In August 2003, the Minority Health Institute (MHI) convened an Expert Advisory Panel of cardiologists and urologists to design a new practice model algorithm that uses erectile dysfunction (ED) as a clinical tool for early identification of men with systemic vascular disease. The MHI algorithm noted ED as a marker for the presence of cardiovascular disease and suggested that ED may well be a cardiovascular risk equivalent warranting aggressive secondary prevention management strategies, even in the absence of other cardiac or peripheral vascular symptoms. The MHI algorithm stipulates that all men 25 years of age and older should be asked about ED as a routine part of the cardiovascular history during any office visit. The presence of ED should prompt an aggressive assessment for occult vascular disease; many men with erectile difficulty would benefit from early, aggressive management of cardiovascular risk factors with both lifestyle modification and pharmacotherapy to achieve optimal target goals under the existing treatment guidelines. Since publication of the algorithm in 2005, additional research studies have further supported the advisory panel recommendations.

Relation of C-reactive protein and other cardiovascular risk factors to penile vascular disease in men with erectile dysfunction.

Erectile dysfunction (ED) may be an early sign or symptom of cardiovascular disease (CVD). We examined the relation of traditional and emerging risk factors for CVD to the severity of penile vascular disease in men with ED and without clinical coronary artery disease (CAD). In total, 137 men with ED were evaluated for penile vascular disease severity by penile Doppler ultrasound. These men were divided into the following groups based on ultrasound results: normal, cavernous venous occlusive disease, mild arterial insufficiency, and severe arterial insufficiency. Traditional (fasting lipid panel, fasting glucose, age, BMI, smoking, Framingham coronary artery disease risk score) and emerging (C-reactive protein, Lp(a), homocysteine) risk factors for CVD were correlated to severity of penile vascular disease in men with ED and without clinical CAD. Using univariate analysis, penile Doppler groups showed significant positive correlation to CRP (r=0.21; < or = 0.05) and age (r=0.30; < or = 0.01). For CRP, this correlation remained significant even when adjusted for age (< or = 0.05). Men displaying evidence of penile arterial disease (mild and severe arterial insufficiency) were characterized by elevated CRP levels (0.17 mg/dl) compared to men with no evidence of arterial abnormalities in the penis (0.04 mg/dl). CRP levels correlate significantly with increasing severity of penile vascular disease as measured by penile Doppler.

Brachial artery elastic mechanics in patients with heart failure.

Studies of arterial elasticity in patients with heart failure (HF) have produced varying results. In addition, the direct effects of smooth muscle relaxation on arterial wall mechanics in these patients have not been well characterized. Nineteen patients with New York Heart Association class II to IV HF and 17 age- and size-matched normal subjects were studied by using a recently validated technique for measuring brachial arterial wall mechanics over a wide pressure range. The left brachial artery was imaged through a water-filled blood pressure cuff by use of an ultrasound wall-tracking system at baseline and after 0.4 mg sublingual nitroglycerin (NTG). Simultaneous radial artery pressure waveforms were recorded by tonometry. Transmural pressure (TP) was reduced by increasing water pressure in the cuff. Baseline area, compliance, and pulse wave velocity versus TP curves were similar in the normal subjects and the patients with HF. The incremental elastic modulus versus TP curve tended to be lower in the patients with HF. The wall-to-lumen ratio was increased in HF (P=0.05). NTG significantly shifted the area versus TP (P<0.001) and compliance versus TP (P<0.05) curves upward and the pulse wave velocity versus TP (P<0.05) curve downward in both groups. NTG also significantly (P<0.001) shifted the stress versus strain curve to the right in both groups but did not alter the incremental elastic modulus versus TP curve. We conclude that the brachial arterial wall-to-lumen ratio is increased in HF. This finding occurs together with a trend toward reduced arterial stiffness such that overall mechanical behavior of the brachial artery is preserved. Smooth muscle relaxation with NTG produces similar improvements in brachial arterial wall mechanics in normal subjects and in patients with HF.

Atherosclerotic plaque rupture: a fatigue process?

The mechanism of atherosclerotic plaque rupture is not known. Current theories focus on the acute triggers of plaque rupture and myocardial infarction such as increased shear or circumferential stress, rupture of the vasa vasorum and vasospasm. We hypothesize that a critical mechanism causing plaque rupture is fatigue failure, the catastrophic rupture of a material following exposure to high-cycle, low-amplitude repetitive stress. Comparisons between material fatigue and plaque rupture demonstrate that this hypothesis is consistent with known physiologic and epidemiologic data on plaque rupture.

Partial aortic valve fusion induced by left ventricular assist device.

BACKGROUND: Left ventricular assist devices (LVADs) may be used (1) as a bridging device to cardiac transplantation, (2) for permanent replacement of left ventricular function, and (3) as a bridge to recovery of ventricular function, for example, in recoverable myocardial disease. In this third group of patients, it is important that the LVAD does not produce changes in the heart that will have a deleterious effect on cardiac function once the device is removed. Furthermore, if the LVAD fails, survival depends on optimal function of the diseased heart. METHODS: All hearts with LVADs encountered as surgical specimens following heart transplantation or at autopsy at the Fairview-University of Minnesota Medical Center during the 5-month period August 1998 to January 1999 were examined for native valvular heart disease. The nature and extent of commissural fusion was noted and measured. Light microscopy was performed on any valve lesions. RESULTS: Four of 6 patients with HeartMate (Thermo Cardiosystems, Inc, Woburn, MA) LVADs showed evidence of commissural fusion (acquired aortic stenosis). In 1 patient, this condition was caused by an organizing thrombus uniting a 14-mm length of the commissural region of the right coronary and noncoronary cusps of the aortic valve. Fibrous commissural fusion due to totally organized thrombus in the other 3 patients affected one aortic commissure (2 patients, 2 mm and 4 mm, respectively) and two commissures (1 patient, 2 mm and 5 mm). Partial cuspal fusion in each case was due to permanent closure of the native aortic valve induced by the LVAD's operating in its automatic setting. Mean length of commissural fusion was 5.4 mm (range, 2 to 14 mm; standard deviation [SDI = +/-5.0 mm). Mean duration of implantation of the six LVADs was 180.3 days (range, 26 to 689 days; SD = +/-253.8 days). The LVADs of the 3 patients with fibrous fusion of the commissures had been implanted for an average of 252.3 days (range, 26 to 689 days; SD = +/-378.2 days). CONCLUSIONS: Normal function of the LVAD produces permanent closure of the native aortic valve. Stasis on the ventricular aspect of the aortic valve, combined with a low level of anticoagulation, favors thrombosis at this site. Thrombus organization leads to aortic stenosis of variable severity. This previously unsuspected complication was not detected clinically in any of our patients. Aortic stenosis may hold serious implications for patients in whom the LVAD acts as a bridge to recovery or in those in whom the LVAD fails. Prevention may be achieved by intermittently reducing LVAD pumping action. A built-in venting cycle would be of value in long-term implants. Thrombi on the aortic valve may also predispose patients to infective endocarditis, because bloodstream infection is common in patients with LVADs.

Effects of left ventricular assist devices on outcomes in patients undergoing heart transplantation.

BACKGROUND: Left ventricular assist devices (LVADs) are increasingly being used to "bridge" patients to heart transplantation. METHODS: Data from 40 consecutive status 1 heart transplantation patients treated with intravenous inotrope therapy (n = 20) or the HeartMate LVAD (n = 20) were retrospectively analyzed. RESULTS: Baseline clinical characteristics were similar in the two groups. At the time of transplantation, LVAD patients had significantly higher blood pressure and sodium with significantly lower blood urea nitrogen and creatinine. After transplantation, renal failure (52.6% versus 16.7%) and right heart failure (31.6% versus 5.6%) occurred more frequently (p < 0.05) in the inotrope group. Six-month survival after transplantation did not significantly differ in the inotrope or LVAD groups (73.7% versus 88.9%) but event-free survival was significantly (p < 0.05) lower in the inotrope group (15.8% versus 55.6%). Total hospital charges were significantly lower in the inotrope group ($213,860 +/- $107,560 versus $342,620 +/- $104,420), but average daily hospital charges were not different ($3,990 +/- $1,300 versus $4,130 +/- $2,050). CONCLUSIONS: Status 1 heart transplant patients treated with an LVAD as opposed to inotrope therapy have improved clinical and metabolic function at the time of transplant and improved survival to 6 months after transplant without major complications. Total costs are higher in the LVAD patients but average daily costs are similar.

Left ventricular assist device bridge therapy for acute myocardial infarction.

BACKGROUND: Patients with acute myocardial infarction (AMI) complicated by cardiogenic shock have a high mortality rate. Current treatment modalities remain suboptimal for these patients. METHODS: From April 1995 to March 1998, 7 patients were identified as having AMI associated with cardiogenic shock. All received intraaortic balloon pump assistance, in addition to maximal inotropic support. RESULTS: The mean preoperative cardiac index was 2.0+/-0.3 L/min/m2 and pulmonary capillary wedge pressure was 23+/-6 mm Hg. Three patients received thrombolytic therapy and 4 patients underwent percutaneous transluminal coronary angioplasty without success. Left ventricular assist devices (LVADs) were implanted as bridge therapy to heart transplantation. One patient died from recurrence of a ventricular septal defect during LVAD support. Six patients were transplanted successfully after mean LVAD support of 59+/-33 days. Five patients are alive and well at a mean follow-up of 898+/-447 days. One patient died 3 days after transplantation from acute allograft dysfunction. CONCLUSIONS: Timely application of LVADs as bridge therapy to heart transplantation in these critically ill patients can be lifesaving, and should be investigated further.

Endothelial dysfunction in patients with heart failure: relationship to disease severity.

BACKGROUND: Heart failure is associated with abnormal endothelium-dependent vasodilation. However, the relationship of this abnormality to heart failure severity has not been well defined. METHODS AND RESULTS: We used strain-gauge plethysmography to assess forearm blood flow (FBF) responses to endothelium-dependent, endothelium-independent, and reactive hyperemic stimuli in normal subjects (n = 29) and in patients with mild (n = 26) and severe (n = 41) heart failure. FBF responses to intra-arterial methacholine (0.3, 1.5, 3.0 microg/min) were significantly (P < .005) and similarly reduced in patients with mild (2.8 +/- 0.4, 5.9 +/- 0.7, and 7.7 +/- 1.1 mL/min/dL) and severe (2.7 +/- 0.4, 5.4 +/- 0.7, and 6.9 +/- 0.9) heart failure compared with normal subjects (4.5 +/- 0.4, 9.4 +/- 1.0, and 12.0 +/- 1.1). FBF responses to nitroprusside (1, 5, 10 microg/min) were significantly reduced in mild (2.4 +/- 0.3, 6.7 +/- 1.1, and 11.9 +/- 2.0, P < .05) and severe (1.9 +/- 0.2, 5.1 +/- 0.5, and 7.3 +/- 0.9, P < .001) heart failure groups compared with normal subjects (3.8 +/- 0.5, 10.8 +/- 1.2, and 14.9 +/- 1.2). However, FBF responses were reduced to a greater extent (P < .001) in mild heart failure compared with severe heart failure. Peak reactive hyperemia was significantly impaired only in severe heart failure. There was no correlation between methacholine responses and ejection fraction, maximum oxygen consumption, wedge pressure, or serum norepinephrine. CONCLUSION: Impaired endothelium-dependent vasodilation is present and near maximum in mild heart failure. Endothelial dysfunction may be an early finding in human heart failure.

Vascular ATP-dependent potassium channels, nitric oxide, and human forearm reactive hyperemia.

Vascular ATP-dependent potassium (K+ATP) channels open and contribute to reactive hyperemia (RH) in animals. The contribution of K+ATP channels to ischemic vasolidation during RH and interactions with endothelium-derived nitric oxide have not been well characterized in human subjects. RH blood flow responses (mL/dL) following 5 minutes of cuff occlusion were measured using strain-gauge plethysmography in 22 normal human subjects age 42 +/- 2 years. Measurements were obtained at baseline and following intra-arterial administration of the K+ATP channel closer glibenclamide, the nitric oxide synthase inhibitor L-N-monomethyl arginine (L-NMMA), or both drugs simultaneously. Glibenclamide (100 micrograms/min) did not change basal flow (2.7 +/- 0.3 to 2.7 +/- 0.3 mL/min/dL), but L-NMMA (8 mumol/min) and combined glibenclamide and L-NMMA significantly (p < 0.05) decreased basal flow (3.0 +/- 0.5 to 2.0 +/- 0.2 and 3.3 +/- 0.5 to 2.5 +/- 0.3, respectively). Glibenclamide significantly (p < 0.01) decreased RH flow (18.2 +/- 1.3 to 14.8 +/- 1.3) and excess flow (5.3 +/- 1.2 to 1.3 +/- 1.3). L-NMMA significantly (p < 0.05) decreased RH flow (21.2 +/- 1.8 to 18.9 +/- 1.9) and tended to decrease excess flow (6.1 +/- 2.2 to 3.9 +/- 2.5). Combined drug infusion significantly (p < 0.1) decreased RH flow (21.6 +/- 2.2 to 18.0 +/- 2.4) and excess flow (6.3 +/- 1.6 to 1.6 +/- 1.6), with reductions in RH and excess flow similar to those following glibenclamide infusion alone. We conclude that forearm vascular K+ATP channels are closed at baseline. They open and contribute to RH vasodilation. The addition of nitric oxide inhibition to K+ATP channel blockade does not result in additive or synergistic inhibition of RH.

Intravascular ultrasound studies of arterial elastic mechanics.

A number of new methods are available for the measurement of large artery elastic properties in human subjects in vivo. One powerful tool which has recently been applied to the study of large artery mechanics is intravascular ultrasound (IVUS). IVUS studies are performed using a high frequency ultrasound transducer mounted on the tip of a catheter. This catheter is inserted into a blood vessel and detailed cross-sectional images of the vessel, are obtained from within the lumen. IVUS techniques have been used to study wall mechanics of the human aorta, as well as peripheral and coronary arteries in normal human subjects and in patients with vascular disease. This paper reviews IVUS studies of human arterial elasticity and discusses the strengths and weaknesses of this emerging technique as it is applied to the understanding of arterial mechanical properties.

In vivo human brachial artery elastic mechanics: effects of smooth muscle relaxation.

BACKGROUND: The effects of smooth muscle relaxation on arterial wall mechanics are controversial. We used a new, in vivo, noninvasive technique to measure brachial artery wall mechanics under baseline conditions and following smooth muscle relaxation with nitroglycerin (NTG). METHODS AND RESULTS: Eight healthy, normal subjects (6 male, 2 female; age 30+/-3.1 years) participated in the study. The nondominant brachial artery was imaged through a water-filled blood pressure cuff using an external ultrasound wall-tracking system at baseline and following 0.4 mg sublingual NTG. Simultaneous radial artery pressure waveforms were recorded by tonometry. Transmural pressure (TP) was reduced by increasing water pressure in the cuff. Brachial artery area, unstressed area, compliance, stress, strain, incremental elastic modulus (Einc), and pulse wave velocity (PWV) were measured over a TP range from 0 to 100 mm Hg. Baseline area versus TP curves generated 30 minutes apart were not significantly different. NTG significantly shifted area versus TP (P<0.0001) and compliance versus TP (P<0.001) curves upward, whereas the Einc versus TP (P<0.05) and PWV versus TP (P<0. 01) curves were shifted downward. NTG also significantly shifted stress versus strain (P<0.01) and Einc versus strain (P<0.01) curves to the right. CONCLUSIONS: We conclude that brachial artery elastic mechanics can be reproducibly measured over a wide range of TP and smooth muscle tone using a new noninvasive ultrasound technique. Smooth muscle relaxation with NTG increases isobaric compliance and decreases isobaric Einc and PWV in the human brachial artery.

Echocardiographic characteristics of successful deployment of the Das AngelWings atrial septal defect closure device: initial multicenter experience in the United States.

The AngelWings device is a newer transcatheter device used for closure of secundum atrial septal defects (ASD) and patent foramen ovale (PFO), which consists of a self-centering, 2-disk system. Transesophageal echocardiography (TEE) plays a pivotal role in the deployment of the 2 disks of this device, on the appropriate sides of the atrial septum. The objective of this study is to describe the echocardiographic findings associated with successful deployment of the AngelWings device for closure of ASD and PFO. We evaluated the TEE studies of 70 patients enrolled in 4 United States centers, for closure of ASD and PFO with the AngelWings device. The TEE characteristics of successful and unsuccessful deployments were analyzed. Residual shunts across the atrial septum were assessed by TEE at the end of the procedure, 24 hours later by transthoracic echocardiography, and at 6 months by TEE. The deployment of the device was successful in 65 patients (93%). In the unsuccessful group, ASD size by TEE was larger (13.4 +/- 3.1 vs 8.9 +/- 4.7 mm, p <0.05). TEE was successful in identifying snagging of the device by intracardiac structures and prolapse of corners of the left or right atrial disk through the ASD, features that were difficult to identify by fluoroscopy. The echocardiographic characteristics outlined here are important guidelines for successful deployment of the AngelWings device.

Apoptosis, Bcl-2, and proliferating cell nuclear antigen in the failing human heart: observations made after implantation of left ventricular assist device.

BACKGROUND: Heart failure is characterized by progressive left ventricular remodeling, a complex process that results from cell growth and cell death. The quantitative contribution of apoptotic cells toward left ventricular remodeling has varied widely in tissue removed from cardiomyopathic hearts. Apoptosis has been responsive to angiotensin-converting enzyme inhibition in experimental heart failure, but the dynamics and responsiveness to chronic left ventricular unloading have not been studied. METHODS AND RESULTS: We studied 8 patients with severe heart failure before and after chronic left ventricular unloading with a left ventricular assist device (LVAD). Tissue from the left ventricular apex removed at the time of LVAD implantation was examined for apoptosis using the technique of terminal deoxynucleotidyl transferase deoxyuridine triphosphate-biotin nick end-labeling (TUNEL) in 10 patients. These same hearts explanted at the time of cardiac transplantation were then examined for apoptosis after patients had been on the LVAD for 99 +/- 20 (SEM) days. An additional 10 patients with equally severe heart failure who underwent heart transplantation without the use of an LVAD served as controls. Eight hearts obtained at autopsy approximately 6 hours after death from patients who died of non-cardiovascular disease causes served as non-heart failure controls. Additionally, 6 hearts were examined by immunohistochemistry for the antiapoptotic protein, Bcl-2, and for the repair and/or proliferation marker, proliferating cell nuclear antigen (PCNA), before and after LVAD. Apoptosis was not detected in the tissue sections from the hearts of 8 patients at the time of LVAD implantation. Only 1 of these patients had limited apoptosis (< 1 apoptotic cell/1,000 myocytes) after LVAD insertion. Three of 10 patients with severe heart failure who did not receive an LVAD but underwent transplantation showed limited apoptosis (< 1 apoptotic cell/1,000 myocytes). Likewise, none of the control hearts from patients who died of noncardiovascular disease manifested apoptosis. Six of 6 patients overexpressed Bcl-2 at the time of LVAD insertion. In all these patients, Bcl-2 returned to negligible levels after chronic unloading of the heart. Likewise, PCNA was abundantly expressed in 5 of 6 failing hearts at the time of LVAD implantation and was reduced in 4 of 5 hearts after chronic unloading by LVAD. CONCLUSION: Apoptosis is a rare or inconsistent finding in the failing human heart. Overexpression of such indicators of cellular stress and DNA replication and/or repair as Bcl-2 and PNCA in heart failure may be altered by optimizing left ventricular loading conditions by such mechanical devices as the LVAD.

Effects of short-term forearm exercise training on resistance vessel endothelial function in normal subjects and patients with heart failure.

BACKGROUND: Exercise training improves endothelium-dependent vasodilation in animals. This study was designed to determine whether forearm exercise training improves endothelium-dependent vasodilation in control subjects and patients with heart failure, a disease associated with abnormal endothelium-dependent vasodilation. METHODS AND RESULTS: We used strain gauge plethysmography to assess the effects of short-term forearm exercise training on resistance vessel function in 11 control subjects and 7 patients with New York Heart Association class II and III heart failure. Subjects performed 30 minutes of handgrip exercise four times a week for 4-6 weeks. In the control subjects, exercise training increased forearm blood flow (FBF) responses to intra-arterial acetylcholine (20 microg/min) from 6.9 +/- 3.1 to 12.2 +/- 3.0 mL/min/100 mL and peak reactive hyperemic FBF responses from 38.1 +/- 5.6 to 47.4 +/- 5.6 (P < .05). Basal FBF and responses to nitroprusside, L-N-monomethyl arginine and acute forearm exercise were not significantly changed. In the patients with heart failure, chronic forearm exercise did not significantly change any of the above-measured parameters. CONCLUSION: Forearm exercise training improves endothelium-dependent vasodilation and peak hyperemic FBF in control subjects but not in patients with heart failure. These data suggest that resistance vessel abnormalities may not be as readily modifiable by exercise training in patients with heart failure compared with control subjects.

Management of recurrent ventricular tachycardia with ventricular assist device placement.

Life-threatening, recurrent ventricular tachycardia developed in a 54-year-old heart transplant candidate with ischemic cardiomyopathy. The episodes of ventricular tachycardia were refractory to aggressive medical management and implantable cardiac defibrillator placement. A Heartmate left ventricular assist device was implanted, in combination with isolated right coronary artery bypass grafting, which abolished any further episode of ventricular tachycardia. The patient successfully underwent cardiac transplantation 79 days later.

Smooth muscle relaxation: effects on arterial compliance, distensibility, elastic modulus, and pulse wave velocity.

Compliance, distensibility, incremental elastic modulus (E(inc)), and pulse wave velocity are all terms used to describe the mechanical properties of arteries. Previous studies assessing the effects of smooth muscle relaxation on each of these parameters have produced conflicting results. Our laboratory has previously demonstrated that intrabrachial infusion of nitroglycerin in normal human subjects results in a large increase in brachial artery compliance without changing arterial wall stiffness as measured by E(inc). In the present study, the relationships among compliance, distensibility, E(inc), and pulse wave velocity under different levels of vascular tone are shown using data acquired by intravascular ultrasound as well as theoretical curves. We demonstrate that the effects of smooth muscle relaxation can be depicted as 2 separate steps: (1) a rightward shift to a new theoretical curve describing the relationship between 2 of the above elastic parameters that is solely due to changes in vessel geometry and (2) a shift along the new curve that is dependent on changes in wall stiffness.

Memory improvement following cardiac transplantation.

Seventeen patients with severe cardiomyopathy underwent neuropsychological evaluation prior to and at least 1 year after successful heart transplantation. Study candidates were screened, and individuals with a history of stroke, cardiac arrest, or medical and neurological conditions which might affect brain function were excluded. Pre-transplant testing revealed normal intelligence and normal attentional, language, and executive abilities but impaired recent memory. Following heart transplant, memory functioning improved significantly, reaching normal levels. Other cognitive abilities remained unchanged. Results suggest that cardiomyopathy is associated with mesial temporal dysfunction, possibly attributable to inadequate or reduced cerebral blood flow and related hypometabolism. This cerebral dysfunction is potentially reversible following successful transplantation, which restores cardiac output and cerebrovascular perfusion.

Risk of left ventricular assist device as a bridge to heart transplant following postinfarction ventricular septal rupture.

Heart transplantation is an effective treatment for end-stage heart failure. However, due to the persistent shortage of donor hearts, many patients die awaiting a transplant. Implantable left ventricular assist devices are now available as a reliable bridge to cardiac transplantation. This report presents a patient with terminal heart failure as a result of a post-myocardial infarction ventricular septal rupture (VSR), who underwent a successful placement of the HeartMate left ventricular assist device (LVAD) and velour patch closure of an apical VSR. Despite this therapy, the patient expired after developing a second VSR, which created a high-flow right-to-left shunt and caused hypoxic irreversible brain injury. We suggest that use of a left ventricular assist device as a bridge to transplantation be approached with extreme caution in a patient with a postinfarction ventricular septal rupture.