Florian Rader

Outcome of Watchful Waiting in Asymptomatic Severe Mitral Regurgitation

Background— The management of asymptomatic severe mitral regurgitation remains controversial. The aim of this study was to evaluate the outcome of a watchful waiting strategy in which patients are referred to surgery when symptoms occur or when asymptomatic patients develop left ventricular (LV) enlargement, LV dysfunction, pulmonary hypertension, or recurrent atrial fibrillation. Methods and Results— A total of 132 consecutive asymptomatic patients (age 55±15 years, 49 female) with severe degenerative mitral regurgitation (flail leaflet or valve prolapse) were prospectively followed up for 62±26 months. Patients underwent serial clinical and echocardiographic examinations and were referred for surgery when the criteria mentioned above were fulfilled. Overall survival was not statistically different from expected survival either in the total group or in the subgroup of patients with flail leaflet. Eight deaths were observed. Thirty-eight patients developed criteria for surgery (symptoms, 24; LV criteria, 9; pulmonary hypertension or atrial fibrillation, 5). Survival free of any indication for surgery was 92±2% at 2 years, 78±4% at 4 years, 65±5% at 6 years, and 55±6% at 8 years. Patients with flail leaflet tended to develop criteria for surgery slightly but not significantly earlier. There was no operative mortality. Postoperative outcome was good with regard to survival, symptomatic status, and postoperative LV function. Conclusions— Asymptomatic patients with severe degenerative mitral regurgitation can be safely followed up until either symptoms occur or currently recommended cutoff values for LV size, LV function, or pulmonary hypertension are reached. This management strategy is associated with good perioperative and postoperative outcome but requires careful follow-up.

Statins but not angiotensin-converting enzyme inhibitors delay progression of aortic stenosis

Background—Recently, statins and angiotensin-converting enzyme inhibitors (ACEIs) have been shown to slow aortic valve calcium accumulation. Although several studies also suggest that statins may reduce the hemodynamic progression of aortic stenosis (AS), no data are available for ACEIs or the combination of both. Methods and Results—A total of 211 consecutive patients (aged 70±10 years, 104 females) with native AS, defined by a peak velocity >2.5 m/s (valve area 0.84±0.23 cm2, mean gradient 42±19 mm Hg), with normal left ventricular function and no other significant valvular lesion who were examined between 2000 and 2002 and who had 2 echocardiograms separated by at least 6 months were included. Of these, 102 patients were treated with ACEIs, 50 patients received statins, and 32 patients received both. Hemodynamic progression of AS was assessed and related to medical treatment. Annualized increase in peak aortic jet velocity for the entire study group was 0.32±0.44 m · s−1 · y−1. Progression was significantly lower in patients treated with statins (0.10±0.41 m · s−1 · y−1) than in those who were not (0.39±0.42 m · s−1 · y−1; P<0.0001). This effect was observed both in mild-to-moderate and severe AS. ACEI use, however, did not significantly affect hemodynamic progression (P=0.29). Furthermore, ACEIs had no additional effect on AS progression when given in combination with statins (0.11±0.42 versus 0.08±0.43 m · s−1 · y−1 for combination versus statin only; P=0.81). Cholesterol levels did not correlate with hemodynamic progression either in the group receiving statins or in the group that did not. Conclusions—ACEIs do not appear to slow AS progression. However, statins significantly reduce the hemodynamic progression of both mild-to-moderate and severe AS, an effect that may not be related to cholesterol lowering.

Projected Valve Area at Normal Flow Rate Improves the Assessment of Stenosis Severity in Patients With Low-Flow, Low-Gradient Aortic Stenosis The Multicenter TOPAS (Truly or Pseudo-Severe Aortic Stenosis) Study

Background— We sought to investigate the use of a new parameter, the projected effective orifice area (EOAproj) at normal transvalvular flow rate (250 mL/s), to better differentiate between truly severe (TS) and pseudo-severe (PS) aortic stenosis (AS) during dobutamine stress echocardiography (DSE). Changes in various parameters of stenosis severity have been used to differentiate between TS and PS AS during DSE. However, the magnitude of these changes lacks standardization because they are dependent on the variable magnitude of the transvalvular flow change occurring during DSE. Methods and Results— The use of EOAproj to differentiate TS from PS AS was investigated in an in vitro model and in 23 patients with low-flow AS (indexed EOA <0.6 cm2/m2, left ventricular ejection fraction ≤40%) undergoing DSE and subsequent aortic valve replacement. For an individual valve, EOA was plotted against transvalvular flow (Q) at each dobutamine stage, and valve compliance (VC) was derived as the slope of the regression line fitted to the EOA versus Q plot; EOAproj was calculated as EOAproj=EOArest+VC×(250−Qrest), where EOArest and Qrest are the EOA and Q at rest. Classification between TS and PS was based on either response to flow increase (in vitro) or visual inspection at surgery (in vivo). EOAproj was the most accurate parameter in differentiating between TS and PS both in vitro and in vivo. In vivo, 15 of 23 patients (65%) had TS and 8 of 23 (35%) had PS. The percentage of correct classification was 83% for EOAproj and 91% for indexed EOAproj compared with percentages of 61% to 74% for the other echocardiographic parameters usually used for this purpose. Conclusions— EOAproj provides a standardized evaluation of AS severity with DSE and improves the diagnostic accuracy for distinguishing TS and PS AS in patients with low-flow, low-gradient AS.

B-type natriuretic peptide in low-flow, low-gradient aortic stenosis : Relationship to hemodynamics and clinical outcome: Results from the multicenter truly or pseudo-severe aortic stenosis (TOPAS) study

Background— The prognostic value of B-type natriuretic peptide (BNP) is unknown in low-flow, low-gradient aortic stenosis (AS). We sought to evaluate the relationship between AS and rest, stress hemodynamics, and clinical outcome. Methods and Results— BNP was measured in 69 patients with low-flow AS (indexed effective orifice area <0.6 cm2/m2, mean gradient ≤40 mm Hg, left ventricular ejection fraction ≤40%). All patients underwent dobutamine stress echocardiography and were classified as truly severe or pseudosevere AS by their projected effective orifice area at normal flow rate of 250 mL/s (effective orifice area ≤1.0 cm2 or >1.0 cm2). BNP was inversely related to ejection fraction at rest (Spearman correlation coefficient rs=−0.59, P<0.0001) and at peak stress (rs=−0.51, P<0.0001), effective orifice area at rest (rs=−0.50, P<0.0001) and at peak stress (rs=−0.46, P=0.0002), and mean transvalvular flow (rs=−0.31, P=0.01). BNP was directly related to valvular resistance (rs=0.42, P=0.0006) and wall motion score index (rs=0.36, P=0.004). BNP was higher in 29 patients with truly severe AS versus 40 with pseudosevere AS (median, 743 pg/mL [Q1, 471; Q3, 1356] versus 394 pg/mL [Q1, 191 to Q3, 906], P=0.012). BNP was a strong predictor of outcome. In the total cohort, cumulative 1-year survival of patients with BNP ≥550 pg/mL was only 47±9% versus 97±3% with BNP <550 (P<0.0001). In 29 patients who underwent valve replacement, postoperative 1-year survival was also markedly lower in patients with BNP ≥550 pg/mL (53±13% versus 92±7%). Conclusions— BNP is significantly higher in truly severe than pseudosevere low-gradient AS and predicts survival of the whole cohort and in patients undergoing valve replacement.

Benefit of atrial septal defect closure in adults: impact of age

AIMS To evaluate the effect of age on the clinical benefit of atrial septal defect (ASD) closure in adults. METHODS AND RESULTS Functional status, the presence of arrhythmias, right ventricular (RV) remodelling, and pulmonary artery pressure (PAP) were studied in 236 consecutive patients undergoing transcatheter ASD closure [164 females, mean age of 49 ± 18 years, 78 younger than 40 years (Group A), 84 between 40 and 60 years (Group B) and 74 older than 60 years (Group C)]. Defect size [median 22 mm (inter-quartile range, 19, 26 mm)] and shunt ratio [Qp:Qs 2.2 (1.7, 2.9)] did not differ among age groups. Older patients had, however, more advanced symptoms and both, PAP (r = 0.65, P < 0.0001) and RV size (r = 0.28, P < 0.0001), were significantly related to age. Post-interventionally, RV size decreased from 41 ± 7, 43 ± 7, and 45 ± 6 mm to 32 ± 5, 34 ± 5, and 37 ± 5 mm for Groups A, B, and C, respectively (P < 0.0001), and PAP decreased from 31 ± 7, 37 ± 10, and 53 ± 17 mmHg to 26 ± 5, 30 ± 6, and 43 ± 14 mmHg (P < 0.0001), respectively. Absolute changes in RV size (P = 0.80) and PAP (P = 0.24) did not significantly differ among groups. Symptoms were present in 13, 49, and 83% of the patients before and in 3, 11, and 34% after intervention in Groups A, B, and C. Functional status was related to PAP. CONCLUSIONS At any age, ASD closure is followed by symptomatic improvement and regression of PAP and RV size. However, the best outcome is achieved in patients with less functional impairment and less elevated PAP. Considering the continuous increase in symptoms, RV remodelling, and PAP with age, ASD closure must be recommended irrespective of symptoms early after diagnosis even in adults of advanced age.

PDE5 inhibition alleviates functional muscle ischemia in boys with Duchenne muscular dystrophy.

Objective: To determine whether phosphodiesterase type 5 (PDE5) inhibition can alleviate exercise-induced skeletal muscle ischemia in boys with Duchenne muscular dystrophy (DMD). Methods: In 10 boys with DMD and 10 healthy age-matched male controls, we assessed exercise-induced attenuation of reflex sympathetic vasoconstriction, i.e., functional sympatholysis, a protective mechanism that matches oxygen delivery to metabolic demand. Reflex vasoconstriction was induced by simulated orthostatic stress, measured as the decrease in forearm muscle oxygenation with near-infrared spectroscopy, and performed when the forearm muscles were rested or lightly exercised with rhythmic handgrip exercise. Then, the patients underwent an open-label, dose-escalation, crossover trial with single oral doses of tadalafil or sildenafil. Results: The major new findings are 2-fold: first, sympatholysis is impaired in boys with DMD—producing functional muscle ischemia—despite contemporary background therapy with corticosteroids alone or in combination with cardioprotective medication. Second, PDE5 inhibition with standard clinical doses of either tadalafil or sildenafil alleviates this ischemia in a dose-dependent manner. Furthermore, PDE5 inhibition also normalizes the exercise-induced increase in skeletal muscle blood flow (measured by Doppler ultrasound), which is markedly blunted in boys with DMD. Conclusions: These data provide in-human proof of concept for PDE5 inhibition as a putative new therapeutic strategy for DMD. Classification of evidence: This study provides Class IV evidence that in patients with DMD, PDE5 inhibition restores functional sympatholysis.

Left Ventricular Hypertrophy in Valvular Aortic Stenosis: Mechanisms and Clinical Implications

Valvular aortic stenosis is the second most prevalent adult valve disease in the United States and causes progressive pressure overload, invariably leading to life-threatening complications. Surgical aortic valve replacement and, more recently, transcatheter aortic valve replacement effectively relieve the hemodynamic burden and improve the symptoms and survival of affected individuals. However, according to current American College of Cardiology/American Heart Association guidelines on the management of valvular heart disease, the indications for aortic valve replacement, including transcatheter aortic valve replacement, are based primarily on the development of clinical symptoms, because their presence indicates a dismal prognosis. Left ventricular hypertrophy develops in a sizeable proportion of patients before the onset of symptoms, and a growing body of literature demonstrates that regression of left ventricular hypertrophy resulting from aortic stenosis is incomplete after aortic valve replacement and associated with adverse early postoperative outcomes and worse long-term outcomes. Thus, reliance on the development of symptoms alone without consideration of structural abnormalities of the myocardium for optimal timing of aortic valve replacement potentially constitutes a missed opportunity to prevent postoperative morbidity and mortality from severe aortic stenosis, especially in the face of the quickly expanding indications of lower-risk transcatheter aortic valve replacement. The purpose of this review is to discuss the mechanisms and clinical implications of left ventricular hypertrophy in severe valvular aortic stenosis, which may eventually move to center stage as an indication for aortic valve replacement in the asymptomatic patient.

Influence of Race on Atrial Fibrillation after Cardiac Surgery

Background— Despite having fewer risk factors for atrial fibrillation (AF), white patients have a greater prevalence of AF in the community than black patients, and a genetic basis has been postulated. However, it is unknown whether occurrence of new-onset AF after cardiac surgery is different in white versus black patients, and secondarily, other non-Caucasian patients. Methods and Results— From 1995 through 2005, 20 282 white, 1323 black, and 1919 other non-Caucasian patients in sinus rhythm underwent coronary artery bypass grafting with or without valve surgery. To adjust for clinical and socioeconomic confounders, we performed propensity-adjusted analyses; 7093 white patients (35%) had postoperative AF, compared with 255 (22%) black patients and 550 (29%) other non-Caucasians (P<0.0001). Whites were older than black patients, had higher socioeconomic position, and greater left atrial size but were less likely to have hypertension or congestive heart failure. In 847 propensity-matched patient pairs, postoperative AF occurred more frequently in white than in black patients (odds ratio, 1.74; 95% confidence interval, 1.7–1.78). Other than higher occurrence of bradycardia requiring pacing and reintubation in white patients, occurrence of other postoperative complications, hospital mortality, and length of postoperative stay were similar. Age and valvular surgery were the strongest predictors of AF irrespective of race. Conclusions— White patients had a markedly higher risk of postoperative AF than black and other non-Caucasian patients. The cause for racial differences of arrhythmic risk is unknown, but a genetic predisposition is plausible. Our results have implications for risk stratification and mechanistic understanding of postoperative AF.

Cocaine-Induced Vasoconstriction in the Human Coronary Microcirculation New Evidence From Myocardial Contrast Echocardiography

Background— Cocaine is a major cause of acute coronary syndrome, especially in young adults; however, the mechanistic underpinning of cocaine-induced acute coronary syndrome remains limited. Previous studies in animals and in patients undergoing cardiac catheterization suggest that cocaine constricts coronary microvessels, yet direct evidence is lacking. Methods and Results— We used myocardial contrast echocardiography to test the hypothesis that cocaine causes vasoconstriction in the human coronary microcirculation. Measurements were performed at baseline and after a low, nonintoxicating dose of intranasal cocaine (2 mg/kg) in 10 healthy cocaine-naïve young men (median age, 32 years). Postdestruction time-intensity myocardial contrast echocardiography kinetic data were fit to the equation y=A(1−e−&bgr;t) to quantify functional capillary blood volume (A), microvascular flow velocity (&bgr;), and myocardial perfusion (A×&bgr;). Heart rate, mean arterial pressure, and left ventricular work (2-dimensional echocardiography) were measured before and 45 minutes after cocaine. Cocaine increased mean arterial pressure (by 14±2 mm Hg [mean±SE]), heart rate (by 8±3 bpm), and left ventricular work (by 50±18 mm Hg·mL−1·bpm−1). Despite the increases in these determinants of myocardial oxygen demand, myocardial perfusion decreased by 30% (103.7±9.8 to 75.9±10.8 arbitrary units [AU]/s; P<0.01) mainly as a result of decreased capillary blood volume (133.9±5.1 to 111.7±7.7 AU; P<0.05) with no significant change in microvascular flow velocity (0.8±0.1 to 0.7±0.1 AU). Conclusions— In healthy cocaine-naïve young adults, a low-dose cocaine challenge evokes a sizeable decrease in myocardial perfusion. Moreover, the predominant effect is to decrease myocardial capillary blood volume rather than microvascular flow velocity, suggesting a specific action of cocaine to constrict terminal feed arteries.Background— Cocaine is a major cause of acute coronary syndrome, especially in young adults; however, the mechanistic underpinning of cocaine-induced acute coronary syndrome remains limited. Previous studies in animals and in patients undergoing cardiac catheterization suggest that cocaine constricts coronary microvessels, yet direct evidence is lacking. Methods and Results— We used myocardial contrast echocardiography to test the hypothesis that cocaine causes vasoconstriction in the human coronary microcirculation. Measurements were performed at baseline and after a low, nonintoxicating dose of intranasal cocaine (2 mg/kg) in 10 healthy cocaine-naive young men (median age, 32 years). Postdestruction time-intensity myocardial contrast echocardiography kinetic data were fit to the equation y=A(1−e−βt) to quantify functional capillary blood volume (A), microvascular flow velocity (β), and myocardial perfusion (A×β). Heart rate, mean arterial pressure, and left ventricular work (2-dimensional echocardiography) were measured before and 45 minutes after cocaine. Cocaine increased mean arterial pressure (by 14±2 mm Hg [mean±SE]), heart rate (by 8±3 bpm), and left ventricular work (by 50±18 mm Hg·mL−1·bpm−1). Despite the increases in these determinants of myocardial oxygen demand, myocardial perfusion decreased by 30% (103.7±9.8 to 75.9±10.8 arbitrary units [AU]/s; P <0.01) mainly as a result of decreased capillary blood volume (133.9±5.1 to 111.7±7.7 AU; P <0.05) with no significant change in microvascular flow velocity (0.8±0.1 to 0.7±0.1 AU). Conclusions— In healthy cocaine-naive young adults, a low-dose cocaine challenge evokes a sizeable decrease in myocardial perfusion. Moreover, the predominant effect is to decrease myocardial capillary blood volume rather than microvascular flow velocity, suggesting a specific action of cocaine to constrict terminal feed arteries. # Clinical Perspective {#article-title-51}

Natriuretic Peptides for Risk Stratification of Patients With Valvular Aortic Stenosis

Risk stratification of patients with aortic stenosis (AS) is important especially in high-risk asymptomatic patients, patients with atypical symptoms, and those with symptoms but with a high surgical or procedural risk. Current American College of Cardiology/American Heart Association guidelines for indications to proceed with aortic valve replacement (AVR) for AS are the presence of symptoms because of AS, a left ventricular (LV) ejection fraction of <50%, and the need for concomitant valve repair or coronary artery bypass grafting.1 However, reliance on patient-reported symptoms can be misleading. Patients may knowingly or unknowingly adjust their lifestyles to avoid exacerbating symptoms or may not notify their physicians at the onset of symptoms. It may also be difficult to distinguish whether symptoms are caused by AS when patients have other comorbidities, such as lung disease or deconditioning, the latter being a major concern in elderly patients. Furthermore, the requisite serial follow-up at 6- to 12-month intervals1 to ensure that patients are clinically and echocardiographically stable may be difficult for elderly, infirm, or economically disadvantaged patients. Surgical delays because of unrecognized symptoms from AS or infrequent follow-up increase the risk of lethal complications and operative risk.2 In the past few years, 2 factors have been emerged which may change the current guideline-driven approach to AVR: (1) the advent of transcatheter AVR (TAVR) and (2) the recognition that patients with low-gradient AS also benefit from AVR.1 Although the procedural risk may be lower in TAVR versus surgical AVR (SAVR), both carry potential complications, including those associated with prosthetic valves. Therefore, optimal timing for the referral to AVR remains important and any development that enhances risk stratification of patients is important for the management of asymptomatic and symptomatic patients with severe AS.2,3 As shown in Figure 1, natriuretic peptides, …