Etiologies and predictors of mortality in an all-comer population of patients with non-ischemic heart failure.

BACKGROUND: Despite progress in diagnosis and therapy of heart failure (HF), etiology and risk stratification remain elusive in many patients. METHODS: The My Biopsy HF Study (German clinical trials register number: DRKS22178) is a retrospective monocentric study investigating an all-comer population of patients with unexplained HF based on a thorough workup including endomyocardial biopsy (EMB). RESULTS: 655 patients (70.9% men, median age 55 [45/66] years) with non-ischemic, non-valvular HF were included in the analyses. 489 patients were diagnosed with HF with reduced ejection fraction (HFrEF), 52 patients with HF with mildly reduced ejection fraction (HFmrEF) and 114 patients with HF with preserved ejection fraction (HFpEF). After a median follow-up of 4.6 (2.5/6.6) years, 94 deaths were enumerated (HFrEF: 68; HFmrEF: 8; HFpEF: 18), equating to mortality rates of 3.3% and 11.6% for patients with HFrEF, 7.7% and 15.4% for patients with HFmrEF and 5.3% and 11.4% for patients with HFpEF after 1 and 5 years, respectively. In EMB, we detected a variety of putative etiologies of HF, including incidental cardiac amyloidosis (CA, 5.8%). In multivariate logistic regression analysis adjusting for age, sex and comorbidities only CA, age and NYHA functional class III + IV remained independently associated with all-cause mortality (CA: HRperui 3.13, 95% CI 1.5-6.51; p = 0.002). CONCLUSIONS: In an all-comer population of patients presenting with HF of unknown etiology, incidental finding of CA stands out to be independently associated with all-cause mortality. Our findings suggest that prospective trials would be helpful to test the added value of a systematic and holistic work-up of HF of unknown etiology.

Coronary intravascular lithotripsy and rotational atherectomy for severely calcified stenosis: Results from the ROTA.shock trial.

BACKGROUND: Severely calcified coronary lesions present a particular challenge for percutaneous coronary intervention. AIMS: The aim of this randomized study was to determine whether coronary intravascular lithotripsy (IVL) is non-inferior to rotational atherectomy (RA) regarding minimal stent area (MSA). METHODS: The randomized, prospective non-inferiority ROTA.shock trial enrolled 70 patients between July 2019 and November 2021. Patients were randomly (1:1) assigned to undergo either IVL or RA before percutaneous coronary intervention of severely calcified coronary lesions. Optical coherence tomography was performed at the end of the procedure for primary endpoint analysis. RESULTS: The primary endpoint MSA was lower but non-inferior after IVL (mean: 6.10 mm2 , 95% confidence interval [95% CI]: 5.32-6.87 mm2 ) versus RA (6.60 mm2 , 95% CI: 5.66-7.54 mm2 ; difference in MSA: -0.50 mm2 , 95% CI: -1.52-0.52 mm2 ; non-inferiority margin: -1.60 mm2 ). Stent expansion was similar (RA: 0.83 ± 0.10 vs. IVL: 0.82 ± 0.11; p = 0.79). There were no significant differences regarding contrast media consumption (RA: 183.1 ± 68.8 vs. IVL: 163.3 ± 55.0 mL; p = 0.47), radiation dose (RA: 7269 ± 11288 vs. IVL: 5010 ± 4140 cGy cm2 ; p = 0.68), and procedure time (RA: 79.5 ± 34.5 vs. IVL: 66.0 ± 19.4 min; p = 0.18). CONCLUSION: IVL is non-inferior regarding MSA and results in a similar stent expansion in a random comparison with RA. Procedure time, contrast volume, and dose-area product do not differ significantly.

Coronary venous therapy to improve microvascular dysfunction.

The coronary circulation is a complex system in which vascular resistances are determined by an interplay of forces in at least three compartments: the epicardial, the microvascular, and the venous district. Cardiologists, and particularly interventional cardiologists, normallly place the focus of their attention on diseases of the epicardial coronary circulation as possible causes of coronary syndromes and neglect the importance of the other two compartments of coronary circulation. The study of the coronary microcirculation, an increasingly recognized source of ischemia, has long been disregarded, but is witnessing a revival since the (re-)introduction of diagnostic tools in the better equipped catheterization laboratories. Unfortunately, to date our understanding of coronary microvascular disease remains incomplete and the numerous proposed classifications fail to reflect its complexity. Further, no specific therapy for these disorders is available. The coronary venous circulation is an even more neglected third vascular district. Its role in regulating coronary resistances is almost completely unexplored, but inital evidence suggests that the modulation of venous pressure might help improve coronary perfusion. Coronary sinus interventions are a group of invasive techniques (both surgical and catheter-based) that are designed to treat ischaemic heart disease by increasing coronary venous pressure and therefore redistributing coronary blood flow towards the endocardium. In this review paper, we revise the role of these interventions with particular focus on acute and chronic coronary microvascular disease.

Admission heart rate in relation to presentation and prognosis in patients with acute myocardial infarction. Treatment regimens in German chest pain units.

BACKGROUND: Higher heart rates on admission have been associated with poor outcomes in patients with an acute coronary syndrome in previous cohorts. Whether such a linear relationship still exists in contemporary high-level care is unclear. METHODS: Prospectively collected data from patients presenting with myocardial infarction (MI) in centers participating in the Chest Pain Unit (CPU) Registry between December 2008 and July 2014 were analyzed. Patients were classified according to their initial heart rate (I: < 50; II: 50-69; III: 70-89; IV: ≥ 90 bpm). A total of 6,168 patients out of 30,339 patients presenting to 38 centers were included in the study. RESULTS: Patients in group IV had more comorbidities, while patients in group I more often had a history of MI. Patients in the lowest heart rate group presented significantly earlier to the hospital (4 h 31 min vs. 7 h 37 min; p < 0.05) and had the highest rate of interventions. The overall survival after 3 months was significantly worse in group IV after adjusting for baseline variables. In the subgroup analysis, heart rate was a prognostic factor in the non-ST-segment elevation MI group but not in the ST-segment elevation MI group. The correlation between heart rate and major adverse cardiac events followed a J-shaped curve with worst outcomes in the lowest and highest heart rate groups. CONCLUSION: Patients admitted to a dedicated CPU with the diagnosis of MI and a heart rate > 90 bpm experience reduced survival at 3 months despite optimal treatment. Patients with bradycardia also seem to be at increased risk for cardiovascular events despite much earlier presentation and treatment.

Tissue oxygen partial pressure in the tibialis anterior muscle in patients with claudication before, during and after a two-stage treadmill stress test.

BACKGROUND: The role of the microcirculation in the pathophysiology and symptoms of peripheral arterial obliterative disease (PAOD) has been progressively emphasized during the past decades. Under resting conditions, already, the tissue oxygen partial pressure in the m. tibialis anterior (pO2im) is reduced to about 50% compared to healthy subjects. METHODS: In the framework of this study the pO2im of patients with PAOD stage II according to Fontaine (n=16) in the m. tibialis anterior was measured under resting conditions and during walking on a treadmill in comparison to healthy subjects (n=10). RESULTS: Under resting conditions the pO2im only marginally differed between PAOD patients and healthy subjects. But during exercise the pO2im dropped significantly more severely in PAOD patients and a return to baseline values could only be reached when the treadmill was stopped and the patients stood still. The pO2im minima correlated clearly with the clinical symptom of calf pain. CONCLUSION: The data revealed that the pO2im values were lower in PAOD patients and dropped significantly faster during walking compared to the pO2im values in healthy subjects. The pO2im decrease correlated with the calf pain occurring when the pO2im values approached or fell below 10 mmHg.

Porto-spleno-mesenteric venous thrombosis.

Porto-spleno-mesenteric (PSM) venous thrombosis is a rare clinical condition that, while being mostly unrecognized, is nonetheless often severe with a high morbidity and mortality. PSM venous thrombosis is the cause of as many as 5-10% of all abdominal ischemic events, and it presents with a highly variable and non-specific pattern of abdominal symptoms. Such complex and non-specific presentation can delay diagnosis, determining the poor clinical outcome of this condition. This review article discusses the information available on the pathogenesis, clinical presentation, diagnosis and general management of PSM venous thrombosis, with a focus on a number of some clinical issues that remain unaddressed. In particular, the current understanding of the predisposing factors and the heterogeneous clinical manifestations of this condition are described in detail. The recent advances in imaging techniques, which are leading to an improved diagnostic accuracy and facilitate an early diagnosis are also presented. Further, the indications and limits of both pharmacological and surgical treatment options are discussed.

Assessment of vascular function: flow-mediated constriction complements the information of flow-mediated dilatation.

OBJECTIVE: To determine whether vascular function assessed by low-flow-mediated constriction (L-FMC), a novel non-invasive method, complements the information obtained with "traditional" flow-mediated dilatation (FMD). DESIGN AND PATIENTS: In protocol 1, 12 healthy young volunteers underwent FMD and L-FMC measurements at rest and immediately after isometric exercise of the same hand. In protocol 2, 24 patients with coronary artery disease, 24 with congestive heart failure, 24 hypertensive patients and 64 healthy volunteers were enrolled to undergo L-FMC and FMD measurements. RESULTS: In protocol 1, exercise was associated with mean (SD) increases in radial artery blood flow, diameter and L-FMC (from -5.1 (1.5)% to -7.8 (3.4)%, p<0.05), while FMD was significantly blunted (from 6.0 (2.4)% to 3.0 (3.2)%, p<0.05). In protocol 2, both FMD and L-FMC were blunted in the patient groups. Receiver operating curve analysis showed that, as compared with FMD alone, the combination of L-FMC and FMD significantly improved the sensitivity and specificity in detecting patients diagnosed with cardiovascular disease (p<0.05). CONCLUSION: In the first protocol, FMD and L-FMC were shown to be reciprocally regulated. A blunted FMD may, in certain cases, be an expression of increased resting vascular activation and not only of impaired endothelial function. In the second protocol, a statistical approach showed that implementation of L-FMC provides a better characterisation than FMD of vascular function in cardiovascular disease. Vascular (endothelial) function is a complex phenomenon which requires a multifaceted approach; it is suggested that a combination of L-FMC and FMD will provide additive and complementary information to "traditional" FMD measurements.

Area at risk and viability after myocardial ischemia and reperfusion can be determined by contrast-enhanced cardiac magnetic resonance imaging.

BACKGROUND/AIMS: Clinical differentiation between infarcted and viable myocardium in the ischemic area at risk is controversial. We investigated the potential of contrast-enhanced cardiac magnetic resonance imaging (ceCMRI) in determining the area at risk 24 h after ischemia. METHODS: Myocardial ischemia was induced by percutaneous coronary intervention of the left anterior descending coronary artery in pigs. Coronary occlusion time was 30 min in group A, which caused little myocardial infarction and 45 min in group B, which led to irreversible damage. 24 h after reperfusion ceCMRI was performed at 2 and 15 min after administration of gadolinium-diethylenetriamine pentaacetic acid. The area at risk was determined by intravenous injection of Evans blue and myocardial viability by triphenyltetrazolium-chloride staining. RESULTS: The signal-intense areas at 2 and 15 min after contrast administration matched the area at risk in groups A and B. Nonviable myocardium in group A was overestimated (14-15%) while good agreement was present in group B. CONCLUSION: The area at risk of reperfused ischemic myocardium can be determined by ceCMRI 24 h after coronary recanalization. This type of information might have relevant clinical implications in the treatment and stratification of patients with acute coronary syndrome in particular after surgical interventions.

Endothelium, ischemia and the good side of oxygen free radicals.

Pathophysiological studies have clearly demonstrated that the relationship between endothelial (dys)function and tissue ischemia is bidirectional: while it is well accepted that endothelial dysfunction has a key role in the progression and the instabilization of coronary atherosclerosis, it is also well known that the endothelium is particularly sensitive to ischemia and reperfusion injury, and that this damage is an important component in determining the size of the infarction. Therefore, protecting the endothelium from ischemia has potentially important clinical implications. In this scenario, a particularly important role is played by reactive oxygen species: these elusive mediators are involved in determining the endothelial toxic effect of risk factors, are involved in reperfusion injury, but, most importantly, also have a role in endothelial preconditioning, a protective process that is characterized by a reduced sensitivity to ischemia and reperfusion. The present paper reports considerations regarding these phenomena as discussed in a lecture at the recent Conference of the European Society of Clinical Hemorheology and Microcirculation held in Dresden, Germany.

Model-based analysis of flow-mediated dilation and intima-media thickness.

We present an end-to-end system for the automatic measurement of flow-mediated dilation (FMD) and intima-media thickness (IMT) for the assessment of the arterial function. The video sequences are acquired from a B-mode echographic scanner. A spline model (deformable template) is fitted to the data to detect the artery boundaries and track them all along the video sequence. The a priori knowledge about the image features and its content is exploited. Preprocessing is performed to improve both the visual quality of video frames for visual inspection and the performance of the segmentation algorithm without affecting the accuracy of the measurements. The system allows real-time processing as well as a high level of interactivity with the user. This is obtained by a graphical user interface (GUI) enabling the cardiologist to supervise the whole process and to eventually reset the contour extraction at any point in time. The system was validated and the accuracy, reproducibility, and repeatability of the measurements were assessed with extensive in vivo experiments. Jointly with the user friendliness, low cost, and robustness, this makes the system suitable for both research and daily clinical use.

Evidence supporting abnormalities in nitric oxide synthase function induced by nitroglycerin in humans.

OBJECTIVES: We studied the effects of nitroglycerin (GTN) therapy on the response to endothelium-dependent and independent vasoactive agents in the forearm circulation of healthy subjects. BACKGROUND: Recent evidence suggests that therapy with GTN may induce specific changes in endothelial cell function, including increased superoxide anion production and sensitivity to vasoconstrictors. Additionally, continuous GTN therapy worsens endothelial function in the coronary circulation of patients with ischemic heart disease. METHODS: Forearm blood flow was measured with venous occlusion, mercury-in-silastic strain gauge plethysmography. RESULTS: Sixteen male volunteers (26 +/- 6 years) were randomized to no therapy (control) or GTN, 0.6 mg/h/24 h, for six days in an investigator-blind, parallel-design study. The flow responses to brachial artery infusions of acetylcholine ([Ach] 7.5, 15.0, 30.0 microg/min), N-monomethyl-L-arginine (L-NMMA) (1, 2, 4 micromol/min) and sodium nitroprusside (SNP) (0.8, 1.6, 3.2 microg/min) were recorded. The vasodilator responses to Ach were blunted in the GTN group as compared with the control group (p < 0.05). The vasoconstrictor responses to L-NMMA were also blunted in the GTN group (p < 0.001). In the GTN group, paradoxical vasodilation was observed in response to the lowest infused concentration of L-NMMA. The vasodilator responses to SNP did not differ between groups. CONCLUSIONS: The response to Ach confirms the hypothesis that continuous GTN causes endothelial dysfunction. The responses to L-NMMA suggest that GTN therapy causes abnormalities in nitric oxide synthase (NOS) function; the vasodilation observed at the lowest infused concentration of L-NMMA in the GTN group also suggests that continuous GTN therapy is associated with a NOS-mediated production of a vasoconstrictor.

Folic acid prevents nitroglycerin-induced nitric oxide synthase dysfunction and nitrate tolerance: a human in vivo study.

BACKGROUND: In healthy humans, continuous treatment with nitroglycerin (GTN) causes nitric oxide synthase dysfunction, probably through the reduced bioavailability of tetrahydrobiopterin. Recent studies proposed that folic acid is involved in the regeneration of tetrahydrobiopterin in different disease states. Therefore, we investigated whether folic acid administration would prevent this phenomenon. We also sought to determine if folic acid supplementation could prevent the development of tolerance to GTN. METHODS AND RESULTS: On the first visit, 18 healthy male volunteers (aged 19 to 32 years) were randomized to receive either oral folic acid (10 mg once a day) or placebo for 1 week in a double-blind designed study. All subjects also received continuous transdermal GTN (0.6 mg/h). On the second visit, forearm blood flow was measured with venous occlusion strain gauge plethysmography in response to incremental infusions of acetylcholine (7.5, 15, and 30 microgram/min), N-monomethyl-L-arginine (1, 2, and 4 micromol/min), and GTN (11 and 22 nmol/min). Folic acid prevented GTN-induced endothelial dysfunction, as assessed by responses to intraarterial acetylcholine and N-monomethyl-L-arginine (P<0.01). Moreover, in the subjects treated with folic acid plus transdermal GTN, responses to intraarterial GTN were significantly greater than those observed after transdermal GTN plus placebo (P<0.05). CONCLUSION: Our data demonstrate that supplemental folic acid prevents both nitric oxide synthase dysfunction induced by continuous GTN and nitrate tolerance in the arterial circulation of healthy volunteers. We hypothesize that the reduced bioavailability of tetrahydrobiopterin is involved in the pathogenesis of both phenomena. Our results confirm the view that oxidative stress contributes to nitrate tolerance.