The right ventricle (RV) is of lesser importance in acquired heart disease, but its role is of increasing importance in congenital heart disease. It may function as a subpulmonary ventricle or as a subaortic (systemic) ventricle in transposition complexes. The RV has a remarkable ability to adapt to pressure and volume load, but its size and function are often overlooked. Patients usually develop symptoms only after RV dysfunction has occurred, and in many diverse clinical scenarios, late referral is common. Advanced RV enlargement and dysfunction are responsible for not only impaired functional capacity but also lethal ventricular arrhythmias and sudden death. Appropriate imaging of the size and function of the RV are important because timely surgery on the pulmonary and tricuspid valves may preserve RV size and function. Adults with congenital heart disease should be followed at centers where there is an understanding of these problems so that valvular surgery can be considered when appropriate.
]]>Kawasaki disease (KD) is an acute, self-limited vasculitis that typically occurs in young children and was first described by Japanese pediatrician Tomisaku Kawasaki in 1967. Although originally thought to be a rare condition, KD has become the most common cause of acquired heart disease in the pediatric age group in developed countries. The majority of patients with KD appear to have a benign prognosis, but a subset of patients with coronary artery aneurysms are at risk for ischemic events and require lifelong treatment. In the 4 decades that have passed since the initial recognition of KD, the number of patients reaching adulthood has continued to grow. Adult cardiologists will be increasingly involved in the management of these patients. Currently, there are no established guidelines for the evaluation and treatment of adult patients who have had KD. We review here the current literature that may be helpful to clinicians who care for adults who experienced KD in childhood.
]]>The aim of this study was to perform pathologic assessment on stent fracture.
Clinically, stent fracture has been reported in 1% to 2% of patients after drug-eluting stent (DES) implantation.
High-contrast film-based radiographs of 177 consecutive lesions from the CVPath DES autopsy registry were reviewed. Stent fracture was graded as I (single-strut fracture), II (≥2 struts), III (≥2 struts with deformation), IV (with transection without gap), and V (with transection causing gap in stent segment). The incidence of adverse pathologic findings (thrombosis and restenosis) was assessed histologically.
Stent fracture was documented in 51 lesions (29%; grade I = 10, II = 14, III = 12, IV = 6, and V = 9). Lesions with stent fracture had longer duration after implantation (172 days [interquartile range (IQR) 31 to 630 days] vs. 44 days [IQR 7 to 270 days], p = 0.004), a higher rate of Cypher (Cordis Corp., Miami Lakes, Florida) stent usage (63% vs. 36%, p = 0.001), longer stent length (30.0 mm [IQR 22.0 to 40.0 mm] vs. 20.0 mm [IQR 14.0 to 27.3 mm], p < 0.0001), and a higher rate of overlapping stents (45% vs. 22%, p = 0.003). Although fracture with grade I to IV did not have significant impact on the occurrence of adverse pathologic findings such as thrombosis and restenosis, 67% of the grade V fracture lesions were associated with adverse pathologic findings at fracture sites. Longer stent length, use of Cypher, and longer duration of implant were identified as independent risk factors of stent fracture by logistic regression analysis.
The incidence of stent fracture was 29% lesions at autopsy, which is much higher than clinically reported. A high rate of adverse pathologic findings was observed in lesions with grade V stent fracture, whereas fracture with grade I to IV did not have a significant impact on the pathological outcome.
This study sought to investigate the efficacy and safety of clopidogrel in women and men.
Previous analyses have shown sex-based differences in response to several antiplatelet medications. Little is known about the efficacy and safety of clopidogrel in women and men.
This study performed a meta-analysis of all blinded randomized clinical trials comparing clopidogrel and placebo (CURE [Clopidogrel in Unstable Angina to Prevent Recurrent Events], CREDO [Clopidogrel for the Reduction of Events During Observation], CLARITY–TIMI 28 [Clopidogrel as Adjunctive Reperfusion Therapy–Thrombolysis In Myocardial Infarction 28], COMMIT [Clopidogrel and Metoprolol in Myocardial Infarction Trial], and CHARISMA [Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance] trials), involving a total of 79,613 patients, of whom 30% were women. The relative efficacy and safety of clopidogrel at reducing cardiovascular events (cardiovascular death, myocardial infarction [MI], or stroke) in women and men was estimated using random-effects modeling.
Overall, clopidogrel was associated with a highly significant 14% proportional reduction in the risk of cardiovascular events (odds ratio [OR]: 0.86; 95% confidence interval [CI]: 0.80 to 0.93), with no significant differences in treatment effect between women and men. Among the 23,533 women enrolled, there were fewer cardiovascular events in the clopidogrel group compared with the placebo group (11.0% vs. 11.8%; OR: 0.93; 95% CI: 0.86 to 1.01). In women the risk reduction with clopidogrel seemed to be greatest for MI (OR: 0.81; 95% CI: 0.70 to 0.93), with the effects on stroke (OR: 0.91; 95% CI: 0.69 to 1.21) or total death (OR: 0.99; 95% CI: 0.90 to 1.08) not statistically significant. Among the 56,091 men enrolled, there were fewer cardiovascular events in those receiving clopidogrel compared with placebo (7.8% vs. 9.0%; OR: 0.84; 95% CI: 0.78 to 0.91), and the risk reduction was significant for MI (OR: 0.83; 95% CI: 0.76 to 0.92), stroke (OR: 0.83; 95% CI: 0.71 to 0.96), and total death (OR: 0.91; 95% CI: 0.84 to 0.97). Clopidogrel increased the risk of major bleeding in both women (OR: 1.43; 95% CI: 1.15 to 1.79) and men (OR: 1.22; 95% CI: 1.05 to 1.42).
Clopidogrel reduces the risk of cardiovascular events in both women and men.
The goal of this study was to define the frequency of stent gaps by 64-detector computed tomographic angiography (CTA) and their relation to in-stent restenosis (ISR), stent fracture (SF), and overlap failure (OF).
SF defined by catheter angiography or intravascular ultrasound has been implicated in ISR.
A total of 292 consecutive patients, with 613 stents, who underwent CTA were evaluated for stent gaps associated with decreased Hounsfield units. Correlations with catheter coronary angiography (CCA) were available in 143 patients with 384 stents.
Stent gaps were noted in 16.9% by CTA and 1.0% by CCA. ISR by CCA was noted in 46.1% of the stent gaps (p < 0.001) as determined by CCA, and stent gaps by CTA accounted for 27.8% of the total ISR (p < 0.001). In univariate analysis, stent diameter ≥3 mm was the only CCA characteristic significantly associated with stent gaps (p = 0.002), but was not a significant predictor by multivariate analysis. Bifurcation stents, underlying calcification, stent type, location, post-dilation, and overlapping stents were not observed to be predisposing factors. Excessive tortuosity and lack of conformability were not associated with stent gaps; however, their frequency was insufficient to permit meaningful analysis.
Stent gap by CTA: 1) is associated with 28% of ISR, and ISR is found in 46% of stent gaps; 2) is associated with ≥3-mm stents by univariate (p = 0.002) but not by multivariate analysis; 3) is infrequently noted on catheter angiography; and 4) most likely represents SF in the setting of a single stent, and may represent SF or OF in overlapping stents.
This study analyzed the association of left ventricular end-systolic diameter (LVESD) with survival after diagnosis in organic mitral regurgitation (MR) due to flail leaflets.
LVESD is a marker of left ventricular function in patients with organic MR but its association to survival after diagnosis is unknown.
The MIDA (Mitral Regurgitation International Database) registry is a multicenter registry of echocardiographically diagnosed organic MR due to flail leaflets. We enrolled 739 patients with MR due to flail leaflets (age 65 ± 12 years; ejection fraction: 65 ± 10%) in whom LVESD was measured (36 ± 7 mm).
Under conservative management, 10-year survival and survival free of cardiac death were higher with LVESD <40 mm versus ≥40 mm (64 ± 5% vs. 48 ± 10%; p < 0.001, and 73 ± 5% vs. 63 ± 10%; p = 0.001). LVESD ≥40 mm independently predicted overall mortality (hazard ratio [HR]: 1.95, 95% confidence interval [CI]: 1.01 to 3.83) and cardiac mortality (HR: 3.09, 95% CI: 1.35 to 7.09) under conservative management. Mortality risk increased linearly with LVESD >40 mm (HR: 1.15, 95% CI: 1.04 to 1.27 per 1-mm increment). During the entire follow-up (including post-surgical), LVESD ≥40 mm independently predicted overall mortality (HR: 1.86, 95% CI: 1.24 to 2.80) and cardiac mortality (HR: 2.14, 95% CI: 1.29 to 3.56), due to persistence of excess mortality in patients with LVESD ≥40 mm after surgery (HR: 1.86, 95% CI: 1.11 to 3.15 for overall death, and HR: 1.81, 95% CI: 1.05 to 3.54 for cardiac death).
In MR due to flail leaflets, LVESD ≥40 mm is independently associated with increased mortality under medical management but also after mitral surgery. These findings support prompt surgical rescue in patients with LVESD ≥40 mm but also suggest that best preservation of survival is achieved in patients operated before LVESD reaches 40 mm.
This study evaluated the safety and efficacy of ambrisentan for a period of 2 years in patients with pulmonary arterial hypertension (PAH).
Ambrisentan is an oral, once-daily endothelin receptor antagonist that is selective for the endothelin type A receptor. The ARIES-1 (Ambrisentan in Pulmonary Arterial Hypertension, Randomized, Double-Blind, Placebo-Controlled, Multicenter, Efficacy Studies) and ARIES-2 trials were the pivotal 12-week, placebo-controlled studies that led to the regulatory approval of ambrisentan (5 and 10 mg) for the treatment of PAH.
In the ARIES-1 and -2 studies, and the subsequent long-term extension protocol, the ARIES-E study, 383 patients received ambrisentan (2.5, 5, or 10 mg). Efficacy and safety assessments are presented from the time of the first dose of ambrisentan for all patients with post-baseline data.
After 2 years of ambrisentan exposure, the mean change from baseline in 6-min walk distance was improved for the 5-mg (+23 m; 95% confidence interval: 9 to 38 m) and 10-mg (+28 m; 95% confidence interval: 11 to 45 m) groups. Estimates of survival and freedom from clinical worsening for the combined dose group were 94% and 83%, respectively, at 1 year and 88% and 72%, respectively, at 2 years. The annualized risk of aminotransferase abnormalities >3x the upper limit of normal was ~2% per year; most of these events were mild and did not lead to discontinuation of drug.
Two years of ambrisentan treatment was associated with sustained improvements in exercise capacity and a low risk of clinical worsening and death in patients with PAH. Ambrisentan was generally well tolerated and had a low risk of aminotransferase abnormalities over the 2-year study period. (A Long Term Study of Ambrisentan in Pulmonary Arterial Hypertension Subjects Having Completed AMB-320 or AMB-321;
This prospective study evaluated the association of obesity and hypertension with left atrial (LA) volume over 10 years.
Although left atrial enlargement (LAE) is an independent risk factor for atrial fibrillation, stroke, and death, little information is available about determinants of LA size in the general population.
Participants (1,212 men and women, age 25 to 74 years) originated from a sex- and age-stratified random sample of German residents of the Augsburg area (MONICA S3). Left atrial volume was determined by standardized echocardiography at baseline and again after 10 years. Left atrial volume was indexed to body height (iLA). Left atrial enlargement was defined as iLA ≥35.7 and ≥33.7 ml/m in men and women, respectively.
At baseline, the prevalence of LAE was 9.8%. Both obesity and hypertension were independent predictors of LAE, obesity (odds ratio [OR]: 2.4; p < 0.001) being numerically stronger than hypertension (OR: 2.2; p < 0.001). Adjusted mean values for iLA were significantly lower in normal-weight hypertensive patients (25.4 ml/m) than in obese normotensive individuals (27.3 ml/m; p = 0.016). The highest iLA was found in the obese hypertensive subgroup (30.0 ml/m; p < 0.001 vs. all other groups). This group also presented with the highest increase in iLA (+6.0 ml/m) and the highest incidence (31.6%) of LAE upon follow-up.
In the general population, obesity appears to be the most important risk factor for LAE. Given the increasing prevalence of obesity, early interventions, especially in young obese individuals, are essential to prevent premature onset of cardiac remodeling at the atrial level.
The topic of the J-curve relationship between blood pressure and coronary artery disease (CAD) has been the subject of much controversy for the past decades. An inverse relationship between diastolic pressure and adverse cardiac ischemic events (i.e., the lower the diastolic pressure the greater the risk of coronary heart disease and adverse outcomes) has been observed in numerous studies. This effect is even more pronounced in patients with underlying CAD. Indeed, a J-shaped relationship between diastolic pressure and coronary events was documented in treated patients with CAD in most large trials that scrutinized this relationship. In contrast to any other vascular bed, the coronary circulation receives its perfusion mostly during diastole; hence, an excessive decrease in diastolic pressure can significantly hamper perfusion. This adverse effect of too low a diastolic pressure on coronary heart disease leaves the practicing physician with the disturbing possibility that, in patients at risk, lowering blood pressure to levels that prevent stroke or renal disease might actually precipitate myocardial ischemia. However, these concerns should not deter physicians from pursuing a more aggressive control of hypertension, because currently blood pressure is brought to recommended target levels in only approximately one-third of patients.
]]>The aim of this study was to determine the long-term effects of cardiac resynchronization therapy (CRT) in the European cohort of patients enrolled in the REVERSE (Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction) trial.
Previous data suggest that CRT slows disease progression and improves the outcomes of asymptomatic or mildly symptomatic patients with left ventricular (LV) dysfunction and a wide QRS complex.
We randomly assigned 262 recipients of CRT pacemakers or defibrillators, with QRS ≥120 ms and LV ejection fraction ≤40% to active (CRT ON; n = 180) versus control (CRT OFF; n = 82) treatment, for 24 months. Mean baseline LV ejection fraction was 28.0%. All patients were in sinus rhythm and receiving optimal medical therapy. The primary study end point was the proportion worsened by the heart failure (HF) clinical composite response. The main secondary study end point was left ventricular end-systolic volume index (LVESVi).
In the CRT ON group, 19% of patients were worsened versus 34% in the CRT OFF group (p = 0.01). The LVESVi decreased by a mean of 27.5 ± 31.8 ml/m2 in the CRT ON group versus 2.7 ± 25.8 ml/m2 in the CRT OFF group (p < 0.0001). Time to first HF hospital stay or death (hazard ratio: 0.38; p = 0.003) was significantly delayed by CRT.
After 24 months of CRT, and compared with those of control subjects, clinical outcomes and LV function were improved and LV dimensions were decreased in this patient population in New York Heart Association functional classes I or II. These observations suggest that CRT prevents the progression of disease in patients with asymptomatic or mildly symptomatic LV dysfunction. (REsynchronization reVErses Remodeling in Systolic Left vEntricular Dysfunction [REVERSE];
We investigated whether plasma amino-terminal pro-brain natriuretic peptide (NT-proBNP), a marker of cardiac dysfunction and prognosis measured in CORONA (Controlled Rosuvastatin Multinational Trial in Heart Failure), could be used to identify the severity of heart failure at which statins become ineffective.
Statins reduce cardiovascular morbidity and mortality in many patients with ischemic heart disease but not, overall, those with heart failure. There must be a transition point at which treatment with a statin becomes futile.
In CORONA, patients with heart failure, reduced left ventricular ejection fraction, and ischemic heart disease were randomly assigned to 10 mg/day rosuvastatin or placebo. The primary composite outcome was cardiovascular death, nonfatal myocardial infarction, or stroke.
Of 5,011 patients enrolled, NT-proBNP was measured in 3,664 (73%). The midtertile included values between 103 pmol/l (868 pg/ml) and 277 pmol/l (2,348 pg/ml). Log NT-proBNP was the strongest predictor (per log unit) of every outcome assessed but was strongest for death from worsening heart failure (hazard ratio [HR]: 1.99; 95% confidence interval [CI]: 1.71 to 2.30), was weaker for sudden death (HR: 1.69; 95% CI: 1.52 to 1.88), and was weakest for atherothrombotic events (HR: 1.24; 95% CI: 1.10 to 1.40). Patients in the lowest tertile of NT-proBNP had the best prognosis and, if assigned to rosuvastatin rather than placebo, had a greater reduction in the primary end point (HR: 0.65; 95% CI: 0.47 to 0.88) than patients in the other tertiles (heterogeneity test, p = 0.0192). This reflected fewer atherothrombotic events and sudden deaths with rosuvastatin.
Patients with heart failure due to ischemic heart disease who have NT-proBNP values <103 pmol/l (868 pg/ml) may benefit from rosuvastatin.
The aim of this study was to determine long-term results between bioprosthetic (BP) and mechanical (MP) aortic valves in middle-aged patients.
It has not been established which is the best aortic valve substitute in patients ages 55 to 70 years. We conducted a randomized study to compare long-term outcomes between BP and MP aortic valves.
Between January 1995 and June 2003, 310 patients were randomized to receive a BP or an MP aortic valve. Primary end points of the study were survival, valve failure, and reoperation.
One hundred fifty-five patients received a BP valve, and 155 patients received an MP valve. Four patients died, perioperatively, in the MP group (2.6%), and 6 patients died in the BP group (3.9%, p = 0.4). At late follow-up (mean 106 ± 28 months) 41 patients died in the MP group and 45 patients died in the BP group (p = 0.6). There was no difference in the survival rate at 13 years between the MP and BP groups. Valve failures and reoperations were more frequent in the BP group compared with the MP group (p = 0.0001 and p = 0.0003, respectively). There were no differences in the linearized rate of thromboembolism, bleeding, endocarditis, and major adverse prosthesis-related events (MAPE) between the MP and BP valve groups.
At 13 years, patients undergoing aortic valve replacement either with MP or BP valves had a similar survival rate as well the same rate of occurrence of thromboembolism, bleeding, endocarditis, and MAPE, but patients who had undergone aortic valve replacement with BP valves faced a significantly higher risk of valve failure and reoperation.
This study sought to examine the relationship between coronary artery calcium score (CACS) and single-photon emission computed tomography (SPECT) results for predicting the short- and long-term risk of cardiac events.
The CACS and SPECT results both provide important prognostic information. It is unclear whether integrating these tests will better predict patient outcome.
We followed-up 1,126 generally asymptomatic subjects without previous cardiovascular disease who had a CACS and stress SPECT scan performed within a close time period (median 56 days). The median follow-up was 6.9 years. End points analyzed were total cardiac events and all-cause death/myocardial infarction (MI).
An abnormal SPECT result increased with increasing CACS from <1% (CACS ≤10) to 29% (CACS >400) (p < 0.001). Total cardiac events and death/MI also increased with increasing CACS and abnormal SPECT results (p < 0.001). In subjects with a normal SPECT result, CACS added incremental prognostic information, with a 3.55-fold relative increase for any cardiac event (2.75-fold for death/MI) when the CACS was severe (>400) versus minimal (≤10). Separation of the survival curves occurred at 3 years after initial testing for all cardiac events and at 5 years for death/MI.
The CACS and SPECT findings are independent and complementary predictors of short- and long-term cardiac events. Despite a normal SPECT result, a severe CACS identifies subjects at high long-term cardiac risk. After a normal SPECT result, our findings support performing a CACS in patients who are at intermediate or high clinical risk for coronary artery disease to better define those who will have a high long-term risk for adverse cardiac events.
The purpose of this study was to determine whether intrinsic histological abnormalities of the pulmonary trunk (PT) are present from birth and interact with palliative surgery and/or repair.
Little is known about PT histology in patients with tetralogy of Fallot (TOF), especially in the era of surgical intervention in childhood.
We studied 39 formalin-fixed necropsy heart specimens with TOF and compared them with 17 normal control heart specimens. Sections of the PT and aorta were studied by light microscopy using various stains; histological findings were graded according to severity.
Among the TOF group (1 fetus, 11 infants, 14 children, and 13 adults), 11 patients had undergone palliative and 10 patients had undergone reparative surgery at a median age of 8 years (range 2.5 to 18 years). Histological changes of grade 2 or higher were present in 59% (medionecrosis), 36% (fibrosis), 56% (cystlike formation), and 56% (abnormal elastic tissue configuration) of TOF patients. Total histology grading scores were higher in TOF hearts (median 6, range 1 to 9) compared with controls (median 1, range 0 to 6; p < 0.0001). Histological abnormalities were present among infants (median score 3.5, range 1 to 9) and after palliative surgery (median score 5, range 2 to 9) or repair (median score 7.5, range 4 to 9).
Marked histological abnormalities in the PT of hearts with TOF exist compared with controls. These changes were present from infancy and among patients who had undergone palliative or reparative surgery, although operations in this cohort were performed late. Our data suggest that structural abnormalities of the PT, similar to these recently shown in the aorta, are intrinsic.
The aim of this study was to determine the impact of diabetes on oxidant balance and mitochondrial metabolism of carbohydrate- and lipid-based substrates in myocardium of type 2 diabetic patients.
Heart failure represents a major cause of death among diabetic patients. It has been proposed that derangements in cardiac metabolism and oxidative stress may underlie the progression of this comorbidity, but scarce evidence exists in support of this mechanism in humans.
Mitochondrial oxygen (O2) consumption and hydrogen peroxide (H2O2) emission were measured in permeabilized myofibers prepared from samples of the right atrial appendage obtained from nondiabetic (n = 13) and diabetic (n = 11) patients undergoing nonemergent coronary artery bypass graft surgery.
Mitochondria in atrial tissue of type 2 diabetic individuals show a sharply decreased capacity for glutamate and fatty acid-supported respiration, in addition to an increased content of myocardial triglycerides, as compared to nondiabetic patients. Furthermore, diabetic patients show an increased mitochondrial H2O2 emission during oxidation of carbohydrate- and lipid-based substrates, depleted glutathione, and evidence of persistent oxidative stress in their atrial tissue.
These findings are the first to directly investigate the effects of type 2 diabetes on a panoply of mitochondrial functions in the human myocardium using cellular and molecular approaches, and they show that mitochondria in diabetic human hearts have specific impairments in maximal capacity to oxidize fatty acids and glutamate, yet increased mitochondrial H2O2 emission, providing insight into the role of mitochondrial dysfunction and oxidative stress in the pathogenesis of heart failure in diabetic patients.
Heart failure is a syndrome characterized initially by left ventricular dysfunction that triggers countermeasures aimed to restore cardiac output. These responses are compensatory at first but eventually become part of the disease process itself leading to further worsening cardiac function. Among these responses is the activation of the sympathetic nervous system (SNS) that provides inotropic support to the failing heart increasing stroke volume, and peripheral vasoconstriction to maintain mean arterial perfusion pressure, but eventually accelerates disease progression affecting survival. Activation of SNS has been attributed to withdrawal of normal restraining influences and enhancement of excitatory inputs including changes in: 1) peripheral baroreceptor and chemoreceptor reflexes; 2) chemical mediators that control sympathetic outflow; and 3) central integratory sites. The interface between the sympathetic fibers and the cardiovascular system is formed by the adrenergic receptors (ARs). Dysregulation of cardiac beta1-AR signaling and transduction are key features of heart failure progression. In contrast, cardiac beta2-ARs and alpha1-ARs may function in a compensatory fashion to maintain cardiac inotropy. Adrenergic receptor polymorphisms may have an impact on the adaptive mechanisms, susceptibilities, and pharmacological responses of SNS. The beta-AR blockers and the inhibitors of the renin-angiotensin-aldosterone axis form the mainstay of current medical management of chronic heart failure. Conversely, central sympatholytics have proved harmful, whereas sympathomimetic inotropes are still used in selected patients with hemodynamic instability. This review summarizes the changes in SNS in heart failure and examines how modulation of SNS activity may affect morbidity and mortality from this syndrome.
]]>The purpose of this study was to determine the prognostic value of ST-segment resolution after primary percutaneous coronary intervention (pPCI) versus fibrinolysis.
Resolution of the ST-segment has been used as a surrogate end point in trials evaluating reperfusion in acute myocardial infarction; however, its prognostic significance may be limited to patients treated with fibrinolysis.
In the DANAMI-2 (DANish trial in Acute Myocardial Infarction-2) substudy, including 1,421 patients, the ST-segment elevation at baseline, pre-intervention, 90 min, and 4 h was assessed. The ST-segment resolution was grouped as follows: 1) complete ≥70%; 2) partial 30% to <70%; and 3) no resolution <30%. End points were 30-day and long-term mortality and reinfarction.
The ST-segment resolution at 90 min was more pronounced after pPCI (median 60% vs. 45%, p < 0.0001), and a catch-up phenomenon was observed at 4 h. In the fibrinolysis group, 30-day and long-term mortality rates were significantly higher among patients without ST-segment resolution, whereas reinfarction rates were higher with complete ST-segment resolution. The ST-segment resolution was not associated with the 2 end points in the pPCI group. By multivariate analysis, ST-segment resolution at 4 h was an independent predictor of lower mortality, but higher reinfarction rates among patients receiving fibrinolytic therapy.
The ST-segment resolution at 90 min was more complete after pPCI, suggesting better epicardial and microvascular reperfusion, whereas no difference between treatment strategies was seen at 4 h. The ST-segment resolution at 4 h correlated with decreased mortality, but increased reinfarction rates among patients receiving fibrinolytic therapy, whereas no association was seen for patients receiving pPCI. Consequently, 4-h ST-segment resolution remains an important prognosticator after fibrinolysis, but may be overemphasized as a surrogate end point after pPCI.
Our aim was to assess the predictive value of myocardial infarct size assessed with late gadolinium-enhanced (LGE) magnetic resonance imaging (MRI) in medically treated patients with chronic myocardial infarction relative to contractile reserve on low-dose dobutamine magnetic resonance (DSMR) for long-term event-free survival.
Information on the relative merits of scar tissue and contractile reserve to predict long-term prognosis in patients with chronic myocardial infarction is lacking.
A total of 177 patients with known coronary artery disease and scar tissue on LGE MRI were enrolled. Left ventricular (LV) functional parameters at rest and during low-dose DSMR were assessed, and the wall motion score index was calculated.
Eleven patients (6.2%) suffered an event during follow-up (average 20.3 months). Infarct size was a stronger predictor of events than LV ejection fraction and LV volumes at rest and during low-dose DSMR. Myocardial infarct size was used to separate patients at high risk (spatial extent ≥6 segments, n = 98) from those at low risk (spatial extent <6 segments, n = 79) for mortality. In the subgroup of patients at high risk, transmurality of infarct was not a predictor of events. However, the presence of contractile reserve (n = 63) was associated with a significantly higher number of events (12.7%) compared with no change in wall motion score index (6.7%; n = 15; p = 0.008).
Myocardial infarct size on LGE MRI is a stronger predictor of clinical outcome than contractile reserve in medically treated patients with myocardial infarction. In patients with large myocardial scar, the presence of contractile reserve is more important for the prediction of events than scar tissue.
This study evaluates the effect of pre-operative angiotensin-converting enzyme inhibitor (ACEI) therapy on early clinical outcomes after coronary artery bypass grafting (CABG).
Therapy with ACEIs has been shown to reduce the rate of mortality and prevent cardiovascular events in patients with coronary artery disease. However, their pre-operative use in patients undergoing CABG is still controversial.
A retrospective, observational, cohort study was undertaken of prospectively collected data on 10,023 consecutive patients undergoing isolated CABG between April 1996 and May 2008. Of these, 3,052 patients receiving pre-operative ACEI were matched to a control group by propensity score analysis.
Overall rate of mortality was 1%. Pre-operative ACEI therapy was associated with a doubling in the risk of death (1.3% vs. 0.7%; odds ratio [OR]: 2.00, 95% confidence interval [CI]: 1.17 to 3.42; p = 0.013). There was also a significant difference between the ACEI and control group in the risk of post-operative renal dysfunction (PRD) (7.1% vs. 5.4%; OR: 1.36, 95% CI: 1.1 to 1.67; p = 0.006), atrial fibrillation (AF) (25% vs. 20%; OR: 1.34, 95% CI: 1.18 to 1.51; p < 0.0001), and increased use of inotropic support (45.9% vs. 41.1%; OR: 1.22, 95% CI: 1.1 to 1.36; p < 0.0001). In a multivariate analysis, pre-operative ACEI treatment was an independent predictor of mortality (p = 0.04), PRD (p = 0.0002), use of inotropic drugs (p < 0.0001), and AF (p < 0.0001).
Pre-operative therapy with ACEI is associated with an increased risk of mortality, use of inotropic support, PRD, and new onset of post-operative AF.
Our aim was to determine the effects of high-dose (2 g) nicotinic acid (NA) on progression of atherosclerosis and measures of vascular function.
NA raises high-density lipoprotein cholesterol (HDL-C) and reduces low-density lipoprotein cholesterol and is widely used as an adjunct to statin therapy in patients with coronary artery disease. Although changes in plasma lipoproteins suggest potential benefit, there is limited evidence of the effects of NA on disease progression when added to contemporary statin treatment.
We performed a double-blind, randomized, placebo-controlled study of 2 g daily modified-release NA added to statin therapy in 71 patients with low HDL-C (<40 mg/dl) and either: 1) type 2 diabetes with coronary heart disease; or 2) carotid/peripheral atherosclerosis. The primary end point was the change in carotid artery wall area, quantified by magnetic resonance imaging, after 1 year.
NA increased HDL-C by 23% and decreased low-density lipoprotein cholesterol by 19%. At 12 months, NA significantly reduced carotid wall area compared with placebo (adjusted treatment difference: –1.64 mm2 [95% confidence interval: –3.12 to –0.16]; p = 0.03). Mean change in carotid wall area was –1.1 ± 2.6 mm2 for NA versus +1.2 ± 3.0 mm2 for placebo. In both the treatment and placebo groups, larger plaques were more prone to changes in size (r = 0.4, p = 0.04 for placebo, and r = –0.5, p = 0.02 for NA).
In statin-treated patients with low HDL-C, high-dose modified-release NA, compared with placebo, significantly reduces carotid atherosclerosis within 12 months. (Oxford Niaspan Study: Effects of Niaspan on Atherosclerosis and Endothelial Function; NCT00232531)
This study sought to evaluate respiratory disturbances as potential triggers for arrhythmia in patients with sleep-disordered breathing (SDB).
SDB is associated with an increased risk of atrial fibrillation and nonsustained ventricular tachycardia (NSVT) as well as a predilection for sudden cardiac death during nocturnal sleeping hours. However, prior research has not established whether respiratory disturbances operate as triggers for nocturnal arrhythmias.
Overnight polysomnograms from the Sleep Heart Health Study (n = 2,816) were screened for paroxysmal atrial fibrillation and NSVT. We used the case-crossover design to determine whether apneas and/or hypopneas are temporally associated with episodes of paroxysmal atrial fibrillation or NSVT. For each arrhythmia, 3 periods of sinus rhythm were identified as control intervals. Polysomnograms were examined for the presence of respiratory disturbances, oxygen desaturations, and cortical arousals within a 90-s hazard period preceding each arrhythmia or control period.
Fifty-seven participants with a wide range of SDB contributed 62 arrhythmias (76% NSVT). The odds of an arrhythmia after a respiratory disturbance were nearly 18 times (odds ratio: 17.5; 95% confidence interval: 5.3 to 58.4) the odds of an arrhythmia occurring after normal breathing. The absolute rate of arrhythmia associated with respiratory disturbances was low (1 excess arrhythmia per 40,000 respiratory disturbances). Neither hypoxia nor electroencephalogram-defined arousals alone increased arrhythmia risk.
Although the absolute arrhythmia rate is low, the relative risk of paroxysmal atrial fibrillation and NSVT during sleep is markedly increased shortly after a respiratory disturbance. These results support a direct temporal link between SDB events and the development of these arrhythmias.
We sought to determine the prevalence of nocturnal oxygen desaturation and obstructive sleep apnea (OSA) in a population of patients with hypertrophic cardiomyopathy (HCM).
The coexistence of sleep apnea and HCM, 2 common cardiovascular conditions, has been largely unrecognized in the treatment of patients with HCM. The nocturnal hypoxia-induced hyperadrenergic state in OSA is expected to worsen hemodynamics and outcomes in HCM.
One hundred subjects with HCM between June 1, 2006, and July 14, 2008, were screened with nocturnal oximetry. Clinical variables were collected for statistical analysis. Oximetry was classified abnormal (suspicion of sleep-disordered breathing) in the presence of repetitive desaturation (≥5 events/h) followed by a rapid return to baseline oxygen saturation (SaO2) level with a decrease of ≥4% and threshold of 90%.
Seventy-one (71%) patients with HCM had abnormal nocturnal oximetry (71 ± 9%, 95% confidence interval: 62% to 80%). Subjects with abnormal oximetry were older (age 59.5 ± 15.3 years) and more were hypertensive (n = 39 [55%]) than those with normal oximetry (age 45.8 ± 18.5 years, n = 9 [31%], p < 0.001, p = 0.03). Patients with HCM were more symptomatic in the presence of abnormal oximetry (New York Heart Association functional class II to III) (62% vs. 83%, p = 0.023). HCM patients had a higher prevalence of abnormal nocturnal oximetry (n = 71, 71%) compared with a control group of similar age and sex distribution (n = 49, 49%) (p = 0.001).
Abnormal nocturnal oximetry is common in patients with HCM, suggesting that OSA is prevalent. OSA may impact hemodynamics and symptoms in HCM. Further studies are needed to determine the long-term benefit of OSA treatment on hemodynamics and disease progression in HCM.
The hypothesis proposed is that heart failure (HF) is associated with a reactive hyperadrenergic state that increases circulating plasma free fatty acids (FFAs), which leads to impaired glucose metabolism and insulin resistance. We propose that increased FFA-induced mitochondrial uncoupling and substantial oxygen wastage is closely associated with the generation of reactive oxygen species, inflammatory markers, and the development of insulin resistance. The therapeutic aims of metabolic therapy are as follows: 1) to decrease hyperadrenergic drive; 2) to inhibit lipotoxicity and glucotoxicity; and 3) to increase glucose uptake by muscle. These aims are achieved, respectively, by the following: 1) the use of beta-adrenergic blockade and all measures that relieve the mechanical load on the heart; 2) the use of drugs that inhibit fatty acid oxidation (trimetazidine, perhexiline), although without clinical evidence that the heart is their major site of action in HF; and 3) increase of the transport of glucose into the cells by exercise and metformin. Of these measures, only data concerning the reduction of mortality as the result of exercise are available. Of all the other measures, there are substantial positive data on the use of trimetazidine that demonstrate metabolic and clinical benefit with almost no side effects, but data from a large outcome trial are lacking. Our data suggest a major extracardiac site of trimetazidine action. Ranolazine, which inhibits the late sodium inward current, requires testing in human HF. Insulin to reduce hyperglycemia and FFAs is untested in HF, with incretins such as glucagon-like peptide-1 on the horizon. Other future therapies may include malonyl-coenzyme A regulators to inhibit fatty acid oxidation, fish oil omega-3, and activators of protein kinase C-epsilon.
]]>The need for mechanical assistance of the failing heart, whether acute after a myocardial infarction or permanent in patients with end-stage heart failure, has increased with improvements in medical therapy and a growing aged population. Over the past few decades, much progress has been made in the development and refinement of ventricular assist devices (VADs), medical devices capable of maintaining circulatory output of the diseased ventricle. Initially designed as a temporary support to allow ventricular recovery or as a bridge for patients to cardiac transplantation, these devices are now being used as a permanent form of "destination" therapy. Improvements in technological design, durability, and medical management have allowed individuals with VADs to be managed in their communities. Although these devices provide excellent hemodynamic support and enhance patient functional status, discharged individuals face many unique challenges. In this article, we discuss 1) the spectrum of VADs for outpatient therapy, including their basic physiology and hemodynamics; 2) the multidisciplinary approach required to care for a patient with such a device in the community; 3) routine general cardiac issues that are encountered; 4) associated long-term device and nondevice-related complications; and 5) the reported overall improvements in quality of life.
]]>Heart failure (HF) is a common, disabling, and costly disease. Despite major advances in medical therapy, morbidity and mortality remain high, in part because current pharmacological regimens may not fully address some unique requirements of the heart for energy. The heart requires a continuous supply of energy-providing substrates and amino acids in order to maintain its function. In HF, defects in substrate metabolism and cardiac energy and substrate utilization may contribute to contractile dysfunction. HF is often accompanied by a deficiency in key micronutrients required for unimpeded energy transfer. Correcting these deficits has been proposed as a method to limit or even reverse the progressive myocyte dysfunction and/or necrosis in HF. This review summarizes the existing HF literature with respect to supplementation trials of key micronutrients involved in cardiac metabolism: coenzyme Q10,
This study was designed to evaluate the impact of eplerenone on collagen turnover in preserved systolic function heart failure (HFPSF).
Despite growing interest in abnormal collagen metabolism as a feature of HFPSF with diastolic dysfunction, the natural history of markers of collagen turnover and the impact of selective aldosterone antagonism on this natural history remains unknown.
We evaluated 44 patients with HFPSF, randomly assigned to control (n = 20) or eplerenone 25 mg daily (n = 24) for 6 months, increased to 50 mg daily from 6 to 12 months. Serum markers of collagen turnover and inflammation were analyzed at baseline and at 6 and 12 months and included pro-collagen type-I and -III aminoterminal peptides, matrix metalloproteinase type-2, interleukin-6 and -8, and tumor necrosis factor-alpha. Doppler-echocardiographic assessment of diastolic filling indexes and tissue Doppler analyses were also obtained.
The mean age of the patients was 80 ± 7.8 years; 46% were male; 64% were receiving an angiotensin-converting enzyme inhibitor, 34% an angiotensin-II receptor blocker, and 68% were receiving beta-blocker therapy. Pro-collagen type-III and -I aminoterminal peptides, matrix metalloproteinase type-2, interleukin-6 and -8, and tumor necrosis factor-alpha increased with time in the control group. Eplerenone treatment had no significant impact on any biomarker at 6 months but attenuated the increase in pro-collagen type-III aminoterminal peptide at 12 months (p = 0.006). Eplerenone therapy was associated with modest effects on diastolic function without any impact on clinical variables or brain natriuretic peptide.
This study demonstrates progressive increases in markers of collagen turnover and inflammation in HFPSF with diastolic dysfunction. Despite high background utilization of renin-angiotensin-aldosterone modulators, eplerenone therapy prevents a progressive increase in pro-collagen type-III aminoterminal peptide and may have a role in management of this disease. (The Effect of Eplerenone and Atorvastatin on Markers of Collagen Turnover in Diastolic Heart Failure;
The purpose of this study was to assess the effect of remote patient monitoring (RPM) on the outcome of chronic heart failure (HF) patients.
RPM via regularly scheduled structured telephone contact between patients and health care providers or electronic transfer of physiological data using remote access technology via remote external, wearable, or implantable electronic devices is a growing modality to manage patients with chronic HF.
After a review of the literature published between January 2000 and October 2008 on a multidisciplinary heart failure approach by either usual care (in-person visit) or RPM, 96 full-text articles were retrieved: 20 articles reporting randomized controlled trials (RCTs) and 12 reporting cohort studies qualified for a meta-analysis.
Respectively, 6,258 patients and 2,354 patients were included in RCTs and cohort studies. Median follow-up duration was 6 months for RCTs and 12 months for cohort studies. Both RCTs and cohort studies showed that RPM was associated with a significantly lower number of deaths (RCTs: relative risk [RR]: 0.83, 95% confidence interval [CI]: 0.73 to 0.95, p = 0.006; cohort studies: RR: 0.53, 95% CI: 0.29 to 0.96, p < 0.001) and hospitalizations (RCTs: RR: 0.93, 95% CI: 0.87 to 0.99, p = 0.030; cohort studies: RR: 0.52, 95% CI: 0.28 to 0.96, p < 0.001). The decrease in events was greater in cohort studies than in RCTs.
RPM confers a significant protective clinical effect in patients with chronic HF compared with usual care.
The purpose of this study was to determine the lifetime burden and risk factors for hospitalization after heart failure (HF) diagnosis in the community.
Hospitalizations in patients with HF represent a major public health problem; however, the cumulative burden of hospitalizations after HF diagnosis is unknown, and no consistent risk factors for hospitalization have been identified.
We validated a random sample of all incident HF cases in Olmsted County, Minnesota, from 1987 to 2006 and evaluated all hospitalizations after HF diagnosis through 2007. International Classification of Diseases-9th Revision codes were used to determine the primary reason for hospitalization. To account for repeated events, Andersen-Gill models were used to determine the predictors of hospitalization after HF diagnosis. Patients were censored at death or last follow-up.
Among 1,077 HF patients (mean age 76.8 years, 582 [54.0%] female), 4,359 hospitalizations occurred over a mean follow-up of 4.7 years. Hospitalizations were common after HF diagnosis, with 895 (83.1%) patients hospitalized at least once, and 721 (66.9%), 577 (53.6%), and 459 (42.6%) hospitalized ≥2, ≥3, and ≥4 times, respectively. The reason for hospitalization was HF in 713 (16.5%) hospitalizations and other cardiovascular in 936 (21.6%), whereas over one-half (n = 2,679, 61.9%) were noncardiovascular. Male sex, diabetes mellitus, chronic obstructive pulmonary disease, anemia, and creatinine clearance <30 ml/min were independent predictors of hospitalization (p < 0.05 for each).
Multiple hospitalizations are common after HF diagnosis, though less than one-half are due to cardiovascular causes. Comorbid conditions are strongly associated with hospitalizations, and this information could be used to define effective interventions to prevent hospitalizations in HF patients.
This study was conducted to evaluate whether brain (B-type) natriuretic peptide (BNP) changes during sleep are associated with the frequency and severity of apneic/hypopneic episodes, intermittent arousals, and hypoxia.
Sleep apnea is strongly associated with heart failure (HF) and could conceivably worsen HF through increased sympathetic activity, hemodynamic stress, hypoxemia, and oxidative stress. If apneic activity does cause acute stress in HF, it should increase BNP.
Sixty-four HF patients with New York Heart Association functional class II and III HF and ejection fraction <40% underwent a baseline sleep study. Five patients with no sleep apnea and 12 with severe sleep apnea underwent repeat sleep studies, during which blood was collected every 20 min for the measurement of BNP. Patients with severe sleep apnea also underwent a third sleep study with frequent BNP measurements while they were administered oxygen. This provided 643 observations with which to relate apnea to BNP. The association of log BNP with each of 6 markers of apnea severity was evaluated with repeated measures regression models.
There was no relationship between BNP and the number of apneic/hypopneic episodes or the number of arousals. However, the burden of hypoxemia (the time spent with oxygen saturation <90%) significantly predicted BNP concentrations; each 10% increase in duration of hypoxemia increased BNP by 9.6% (95% confidence interval: 1.5% to 17.7%, p = 0.02).
Hypoxemia appears to be an important factor that underlies the impact of sleep abnormalities on hemodynamic stress in patients with HF. Prevention of hypoxia might be especially important for these patients.
The purpose of this study was to determine whether different profiles of cardiac troponin T (cTnT) values assessed over time would yield incremental prognostic information on clinically stable outpatients with heart failure (HF).
cTnT levels were used to estimate prognosis in HF; however, most studies evaluated hospitalized patients using single measurements.
A cohort of 172 New York Heart Association functional class III to IV outpatients was prospectively studied with serial cTnT measurements collected every 3 months over a 2-year period. The primary end point was death or cardiac transplantation, and secondary end points included HF hospitalization.
Of the 172 patients, 22 (13%) died or underwent transplantation during the first year. Therefore, 150 patients were included in the second-year analysis of 3 pre-determined groups: 1) no serial cTnT elevations (defined as <0.01 ng/ml); 2) 1 or more, but not all cTnT values elevated ≥0.01 ng/ml; and 3) all cTnT values elevated during the first year. During the second year, 30 events occurred: 53 patients had persistently normal cTnT levels (<0.01 ng/ml) with 6 primary events (11%); 57 patients had 1 or more but not all cTnT levels elevated with 11 events (19%); 40 patients demonstrated persistently elevated cTnT levels with 13 (33%) primary events (odds ratio: 3.77; 95% confidence interval: 1.28 to 11.07, p = 0.02).
Elevations in cTnT, even using a low threshold of 0.01 ng/ml, detected during routine clinical follow-up of ambulatory patients with HF, are highly associated with an increased risk of events, particularly with frequent or persistent cTnT elevations of ≥0.01 ng/ml. Therefore, the ability to monitor clinical change through serial cTnT measurements may add to risk assessment in the ambulatory HF population.
This study was designed to evaluate the safety, procedural success, and short-term effectiveness of the Melody transcatheter pulmonary valve (Medtronic, Inc., Minneapolis, Minnesota) in patients with dysfunctional right ventricular outflow tract conduits.
Conduit dysfunction has recently been treated with transcatheter pulmonary valve placement. There have been no prospective, multicenter trials evaluating this technology.
Standardized entry criteria, implantation, and follow-up protocols were used. Nonimplanting core laboratories were used to evaluate results.
Between January 2007 and September 2007, 34 patients underwent catheterization for intended Melody valve implantation at 3 centers. Mean age was 19.4 ± 7.7 years. Initial conduit Doppler mean gradient was 28.8 ± 10.1 mm Hg, and 94% of patients had moderate or severe pulmonary regurgitation (PR). Implantation was successful in 29 of 30 attempts and not attempted in 4 patients. Procedural complications included conduit rupture requiring urgent surgery and device removal (n = 1), wide-complex tachycardia (n = 1), and distal pulmonary artery guidewire perforation (n = 1). Peak systolic conduit gradient fell acutely from 37.2 ± 16.3 mm Hg to 17.3 ± 7.3 mm Hg, and no patient had more than mild PR. There were no deaths or further device explants. At 6-month follow-up, conduit Doppler mean gradient was 22.4 ± 8.1 mm Hg, and PR fraction by magnetic resonance imaging was significantly improved (3.3 ± 3.6% vs. 27.6 ± 13.3%, p < 0.0001). Stent fracture occurred in 8 of 29 implants; 3 of these were treated with a second Melody valve for recurrent stenosis later in follow-up.
Implantation of the Melody valve for right ventricular outflow tract conduit dysfunction can be performed by experienced operators at multiple centers, appears safe, and has encouraging acute and short-term outcomes.
This study was designed to facilitate clinical use of central pulse pressure (PP). We sought to determine a value that might predict adverse outcome and thereby provide a target for assessment of intervention strategies.
We previously documented that central PP more strongly relates to carotid hypertrophy and extent of atherosclerosis and, more importantly, better predicts incident cardiovascular disease (CVD) than brachial PP.
Radial applanation tonometry was performed in the third Strong Heart Study examination to determine central blood pressure. Cox regression analyses were performed using pre-specified covariates and quartiles of central and brachial PP.
Among 2,405 participants without prevalent CVD, 344 suffered CVD events during 5.6 ± 1.7 years. Quartiles of central PP (p < 0.001) predicted outcome more strongly than quartiles of brachial PP (p = 0.052). With adjustment for covariates, only the event rate in the fourth quartile of central PP (≥50 mm Hg) was significantly higher than that in the first quartile (hazard ratio [HR]: 1.69, 95% confidence interval [CI]: 1.20 to 2.39, p = 0.003). Central PP ≥50 mm Hg was related to outcome in both men (HR: 2.06, 95% CI: 1.39 to 3.04, p < 0.001) and women (HR: 2.03, 95% CI: 1.55 to 2.65, p < 0.001); in participants with (HR: 1.84, 95% CI: 1.41 to 2.39, p < 0.001) and without diabetes (HR: 1.91, 95% CI: 1.29 to 2.83, p = 0.001); and in individuals younger (HR: 2.51, 95% CI: 1.59 to 3.95, p < 0.001) and older (HR: 1.53, 95% CI: 1.19 to 1.97, p = 0.001) than the age of 60 years.
Central PP ≥50 mm Hg predicts adverse CVD outcome and may serve as a target in intervention strategies if confirmed in other populations and in prospective studies.
This study was designed to compare the efficacy of angiogenic gene delivery by ultrasound-mediated (UM) destruction of intravenous carrier microbubbles to direct intramuscular (IM) injections.
Current trials of gene therapy for angiogenesis remain limited by suboptimal, invasive delivery techniques.
Hind-limb ischemia was produced by iliac artery ligation in 99 rats. In 32 rats, UM delivery of green fluorescent protein (GFP)/vascular endothelial growth factor-165 (VEGF165) plasmid deoxyribonucleic acid was performed. Thirty-five animals received IM injections of VEGF165/GFP plasmid. Remaining rats received no treatment. Before delivery (day 14 after ligation) and at days 17, 21, and 28 and week 8 after ligation, microvascular blood volume and microvascular blood flow to the proximal hind limbs were assessed by contrast-enhanced ultrasound (n = 8 per group). Total transfection was assessed by reverse transcriptase–polymerase chain reaction, and localization of transfection was determined by immunohistochemistry.
By day 28, both IM and UM delivery of VEGF165 produced significant increases in microvascular blood volume and microvascular blood flow. Whereas increases in microvascular blood volume were similar between treatment groups, microvascular blood flow was greater (p < 0.005) in UM-treated animals as compared with IM-treated animals, persisting to week 8. The VEGF165/GFP messenger ribonucleic acid expression was greater (p < 0.05) for IM-treated animals. A strong GFP signal was detected for both groups and was localized to focal perivascular regions and myocytes around injection sites for IM and to the vascular endothelium of arterioles/capillaries in a wider distribution for UM delivery.
Despite lower transfection levels, UM delivery of VEGF165 is as effective as IM injections. The UM delivery results in directed vascular transfection over a wider distribution, which may account for the more efficient angiogenesis.